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Cost Comparison Appraisal

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378]

Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

COST COMPARISON APPRAISAL

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378]

Contents:

The following documents are made available to stakeholders:

Access the final scope and final stakeholder list on the NICE website.

1. NICE medicines optimisation team (MOT) report

2. Patient group, professional group, and NHS organisation submission from:

• a. Prostate Cancer Research b. Prostate Cancer UK

• c. Tackle Prostate Cancer

3. Expert personal perspectives from:

• a. Professor Alison Birtle, consultant oncologist – clinical expert, nominated by NICE

• b. Ellie Blake, senior policy officer – patient expert, nominated by Prostate Cancer UK

• c. Dr Stephen Allen, patient representative – patient expert, nominated by Tackle Prostate Cancer

4. External Assessment Report prepared by PenTAG

Any information supplied to NICE which has been marked as confidential, has been redacted. All personal information has also been redacted.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Abiraterone for treating newly diagnosed high-risk hormone‑sensitive metastatic prostate cancer in adults [ID6378]

NICE medicines optimisation briefing

March 2025

Key issues

• Abiraterone is an anti-androgen licensed in newly diagnosed high-risk hormone-sensitive metastatic prostate cancer.

  • However, other anti-androgens are licensed in all people with hormone-sensitive metastatic prostate cancer.

• Enzalutamide and apalutamide are also anti-androgens. However, abiraterone has a different mechanism of action to the other medicines.

• Adverse event profiles (including for falls, fractures, cognitive impairment, and seizures) differ between treatment options. The person's risk of these adverse events, and their values and preferences, should therefore be taken into account.

• Concomitant prednisolone is needed with abiraterone but not enzalutamide or apalutamide.

Technology overview

Abiraterone is an androgen biosynthesis inhibitor licensed for treating newly diagnosed high-risk metastatic hormone-sensitive prostate cancer in adults in combination with androgen deprivation therapy (summary of product characteristics [SPC] for abiraterone [Zytiga] and multiple generic products).

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Context

Abiraterone with prednisone or prednisolone plus androgen deprivation therapy for treating newly diagnosed high-risk hormone‑sensitive metastatic prostate cancer was assessed by NICE in 2021 (TA721). Abiraterone was not recommended for use within the NHS because, whilst clinical trial results showed that abiraterone was clinically effective, it was not cost-effective. Since publication of the technology appraisal, several generic versions of abiraterone have become available. Prednisone is no longer available in the UK.

In December 2024, NHS England published an interim commissioning policy recommending abiraterone and prednisolone for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer. Newly diagnosed high-risk hormone-sensitive metastatic prostate cancer is classified as having at least 2 of the following factors:

• a Gleason score of ≥ 8

• presence of ≥ 3 bone metastases on conventional imaging (CT scan or isotope bone scan)

• the presence of visceral metastasis on conventional imaging (CT scan) (excluding lymph node disease).

NICE has also assessed enzalutamide and apalutamide (both with androgen deprivation therapy) for treating hormone-sensitive metastatic prostate cancer (TA712 and TA741, respectively). Enzalutamide is recommended as an option. Apalutamide is only recommended if docetaxel is unsuitable. Darolutamide with androgen deprivation therapy and docetaxel is also recommended as another treatment option (TA903). All of these options are recommended in all people with hormone-sensitive metastatic prostate cancer whereas abiraterone is only licensed in newly diagnosed high-risk hormone-sensitive metastatic

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prostate cancer. A technology appraisal for darolutamide with androgen deprivation therapy, but without docetaxel, is in development (ID6452).

NICE has published guidance on the diagnosis and management of prostate cancer (NG131).

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Table 1: Characteristics of abiraterone compared with other treatments used for newly diagnosed high-risk hormone-sensitive metastatic prostate cancer at a similar point in the treatment pathway (different mechanisms of action)

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Current practice

Medicines for treating metastatic prostate cancer are commissioned by NHS England. Usual treatment for hormone-sensitive metastatic prostate cancer always includes androgen deprivation therapy, which may be given alone, or with:

• docetaxel with or without prednisolone,

• enzalutamide,

• apalutamide, or

• darolutamide with docetaxel.

Abiraterone with prednisolone and androgen deprivation therapy would be another treatment option.

System intelligence from NICE associates indicates that local treatment pathways follow NICE guidance and that abiraterone would be used at the same place in the treatment pathway as enzalutamide, apalutamide (where docetaxel is unsuitable), or darolutamide with docetaxel. Abiraterone is accepted for use within NHS Scotland for treating newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (Scottish Medicines Consortium: abiraterone acetate) and is

recommended by the European Society for Medical Oncology (ESMO) as a first-line option for hormone-sensitive metastatic prostate cancer with - androgen deprivation therapy (ESMO Clinical Practice Guidelines prostate cancer).

Patient centred factors

Abiraterone, like enzalutamide and apalutamide, is another option for people with hormone-sensitive metastatic prostate cancer, especially for people who cannot have docetaxel or choose not to have docetaxel.

NHS England's docetaxel commissioning policy states that docetaxel should not be used in people with a poor overall performance status

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(World Health Organization performance 3 to 4), pre-existing peripheral neuropathy, poor bone marrow function, or a life-limiting illness. Therefore, abiraterone, enzalutamide and apalutamide, may be preferred options for people who are unable to have docetaxel.

Abiraterone can cause hypertension, hypokalaemia and fluid retention because of increased mineralocorticoid levels resulting from CYP17 inhibition. Therefore, caution is needed in people whose underlying medical conditions might be affected by these adverse events (SPC). To reduce these effects, abiraterone is given with prednisolone. Concomitant prednisolone is not needed with enzalutamide or other antiandrogens. Therefore, enzalutamide or apalutamide may be preferred options for people who are unable to or do not want to take corticosteroids, for example because of diabetes and the risk of hyperglycaemia, or because of other corticosteroid-related adverse events or the increased pill burden. Prednisolone also requires additional baseline assessments and ongoing monitoring.

Adverse event profiles (including for falls, fractures, cognitive impairment, and seizures) differ between treatment options. The person's risk of these adverse events, and their values and preferences, should therefore be taken into account. Concomitant enzalutamide or apalutamide with coumarin-like anticoagulants should be avoided; therefore abiraterone may be a preferred option for people taking coumarin-like anticoagulants.

Health inequalities

The choice and treatment options for all patients should take into account a person’s values and preferences along with their clinical conditions and suitability for different treatment options.

Prostate cancer is more common in people of Black African ethnicity, people with a family history of prostate cancer and people with a

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homologous recombination repair mutation. People of Ashkenazi Jewish ethnicity have a greater risk of having a BRCA gene mutation and so have a higher risk of developing prostate cancer (TA951).

As in previous appraisals for technologies for treating prostate cancer, recommendations should apply to trans women as well as to men.

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Cost Comparison Appraisal

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormonesensitive metastatic prostate cancer (review of TA721) [ID6378]

Patient Organisation Submission

Thank you for agreeing to give us your organisation’s views on this technology and its possible use in the NHS.

You can provide a unique perspective on conditions and their treatment that is not typically available from other sources.

To help you give your views, please use this questionnaire with our guide for patient submissions.

You do not have to answer every question – they are prompts to guide you. The text boxes will expand as you type. [Please note that declarations of interests relevant to this topic are compulsory].

Information on completing this submission

• Please do not embed documents (such as a PDF) in a submission because this may lead to the information being mislaid or make the submission unreadable

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• Your response should not be longer than 10 pages.

Patient organisation submission

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About you

Patient organisation submission

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ensuring we have flexible and sustainable funding through our Events & Community, Legacies and Individual Giving fundraising.

PCR is not a membership organisation but works with thousands of patients across its various charitable activities. In the two years since we launched the infopool, an educational website to support and empower patients, we have had close to 250,000 visitors. Since launching Prostate Progress, our patient data platform, in July 2024 we have over 4,000 consented patients signed up to the platform sharing PROMs data and consenting to link their clinical data. 4b. Has the organisation In the past 12 months, PCR has received funding from the following: received any funding from • Astellas: £1,096 received for speaker services at a healthcare professional focused event the company bringing the treatment to NICE for • AstraZeneca: £15,000 received through an educational grant for a report into the socio-economic impact of prostate cancer screening, and £36,000 received in sponsorship of our ‘Empowering evaluation or any of the Communities’ project, to assist in evidence generation and intervention co-design with the Black comparator treatment community companies in the last 12 months? [Relevant • Bayer: £83,710 received for an Institute Sponsored Collaborative Study into identifying and assessing companies are listed in regional variation in prescribing practices for hormone therapy and docetaxel, and £1,260 received for the appraisal stakeholder speaker services related to a health inequalities roundtable list.] • Ipsen: £5,000 received through an educational grant for a report into the socio-economic impact of If so, please state the prostate cancer screening name of the company, • Johnson & Johnson Innovative Medicines: £1,265 received for membership of the steering committee amount, and purpose of for a real-world evidence project. funding.

4c. Do you have any No direct or indirect links with, or funding from, the tobacco industry? 5. How did you gather For personalised information and support, the infopool offers resources tailored to individuals living with information about the prostate cancer. This platform provides insights into treatment options, side effect management, and personal experiences of patients stories from others navigating similar experiences. Patient stories collected through the infopool give valuable and carers to include in your submission?

Patient organisation submission

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insights into patient experience and preferences. We have over 1,000 stories from individuals on the site which have helped inform our submission.

Additionally, we conducted an online ‘Patient Experience Survey’ hosted on PCR’s website for a period of two weeks in January 2022. The aim of this survey was “To better understand patients’ disease journeys, information needs and impact on their quality of life.” Insights from this survey have also informed our submission.

Living with the condition

Patient organisation submission

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Current treatment of the condition in the NHS

1 https://www.england.nhs.uk/publication/abiraterone-acetate-and-prednisolone-for-high-risk-hormone-sensitive-metastatic-prostate-cancer-adults-2424/

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Advantages of the technology

Disadvantages of the technology

2 James ND, Clarke NW, Cook A et al; STAMPEDE Trials Collaborative Group. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476). Int J Cancer. 2022 Aug 1;151(3):422-434. doi: 10.1002/ijc.34018. Patient organisation submission

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Patient population

11. Are there any groups of As highlighted by NHS England’s interim clinical commissioning policy, abiraterone could benefit patients with two patients who might benefit of the following factors: more or less from the • a Gleason score of ≥ 8 technology than others? If • presence of ≥ 3 bone metastases so, please describe them and explain why. • the presence of visceral metastasis (excluding lymph node disease)

This could be particularly beneficial to those patients that opt not to receive chemotherapy. Many patients may also be unable to receive chemotherapy based on their age or comorbidities they may have, and abiraterone provides an alternative option for these patients.

Equality

12. Are there any potential No equality issues that should be taken into account when considering this condition and the technology?

Patient organisation submission

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Other issues

13. Are there any other No issues that you would like the committee to consider?

Key messages

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Your privacy

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Cost Comparison Appraisal

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormonesensitive metastatic prostate cancer (review of TA721) [ID6378]

Patient Organisation Submission

Thank you for agreeing to give us your organisation’s views on this technology and its possible use in the NHS.

You can provide a unique perspective on conditions and their treatment that is not typically available from other sources.

To help you give your views, please use this questionnaire with our guide for patient submissions.

You do not have to answer every question – they are prompts to guide you. The text boxes will expand as you type. [Please note that declarations of interests relevant to this topic are compulsory].

Information on completing this submission

• Please do not embed documents (such as a PDF) in a submission because this may lead to the information being mislaid or make the submission unreadable

• We are committed to meeting the requirements of copyright legislation. If you intend to include journal articles in your submission you must have copyright clearance for these articles. We can accept journal articles in NICE Docs.

• Your response should not be longer than 10 pages.

Patient organisation submission

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About you

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Living with the condition

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Current treatment of the condition in the NHS

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Advantages of the technology

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Disadvantages of the technology

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Patient population

11. Are there any groups of This combination would expand the treatment options for patients who are unsuitable for chemotherapy or would patients who might benefit prefer to avoid it. Some patients may already have restricted options in terms of approved NHTs available to them more or less from the due to existing comorbidities, and there are likely to be patients who are unsuitable for existing NHTs. Additionally, technology than others? If while enzalutamide and apalutamide have very similar profiles of drug-drug interactions, abiraterone has a less so, please describe them similar profile, potentially making it a good option for patients taking other medications. and explain why.

Equality

12. Are there any potential Prostate cancer is a condition that can only affect people with a prostate, and therefore men and others assigned equality issues that should male at birth. be taken into account when considering this condition Recent work has highlighted that only 39.0% of mHSPC patients in England receive treatment intensification and the technology? despite level 1 evidence and NICE recommendation. Moreover, inequalities were reported in NHT uptake in this indication across practices in England, for older men, Black men, and men in deprived areas.[6] This underuse of treatment intensification is likely to also represent an issue for this treatment.

An additional equity consideration is that this treatment would increase choice for patients with currently unmet needs, including those with comorbidities.

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Other issues

13. Are there any other Since the expiry of its patent in 2022, abiraterone is now very cheap, with NHS trusts in England paying an issues that you would like average of £77 for a 28-day supply based on 2024 data,[17] compared to thousands of pounds while under the committee to consider? patent. Analysis of STAMPEDE trial data further showed that use of abiraterone as a treatment for metastatic prostate cancer would be cost saving to the NHS, highlighting the likely financial benefit of its approval across the UK.

Key messages

14. In up to 5 bullet • The impact metastatic prostate cancer can have on a patient’s life is huge – both in terms of symptoms and points, please summarise the burden of the diagnosis itself. the key messages of your • It is therefore imperative that patients have a greater treatment choice in this indication, giving them some submission. control over how treatment will affect their lives day-to-day.

• Abiraterone with prednisolone and ADT represents an effective treatment option that would particularly benefit those unsuitable for current treatment options (including other NHTs and chemotherapy).

• This treatment combination represents an effective option (in terms of survival and progression) that is comparable to other NHTs, but with the added benefit of low-cost generic versions being available.

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References

1. Cornford, P., Robijn, E., Rogers, E., Wassersug, R. & Fleure, L. Fatigue in Prostate Cancer: A Roundtable Discussion and Thematic Literature Review. Eur. Urol. Open Sci. 63, 119–125 (2024).

2. Drudge-Coates, L. et al. Recognizing Symptom Burden in Advanced Prostate Cancer: A Global Patient and Caregiver Survey. Clin. Genitourin. Cancer 16, e411–e419 (2018).

3. Sweeney, C. J. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N. Engl. J. Med. 373, 737–746 (2015).

4. James, N. D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet Lond. Engl. 387, 1163–1177 (2016).

5. Bone problems and osteoporosis in prostate cancer. https://www.cancerresearchuk.org/about-cancer/prostate-cancer/practical-emotional-support/hormonesymptoms/sex-hormones-bone-loss-men.

6. Dodkins, J. et al. Does Research from Clinical Trials in Metastatic Hormone-sensitive Prostate Cancer Treatment Translate into Access to Treatments for Patients in the “Real World”? A Systematic Review. Eur. Urol. Oncol. 7, 14–24 (2024).

7. Raval, A. D., Chen, S., Littleton, N., Constantinovici, N. & Goebell, P. J. Underutilization of androgen deprivation therapy (ADT) intensification for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC): A systematic review of real-world database studies. J. Clin. Oncol. 42, 66–66 (2024).

8. Wang, L. et al. Comparison of Systemic Treatments for Metastatic Castration-Sensitive Prostate Cancer. JAMA Oncol. 7, 412–420 (2021).

9. NHS England, . Abiraterone acetate and prednisolone for high-risk, hormone-sensitive metastatic prostate cancer (adults) [2424]. https://www.england.nhs.uk/publication/abiraterone-acetate-and-prednisolone-for-high-risk-hormone-sensitive-metastatic-prostate-cancer-adults-2424/ (2024).

10. Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N. Engl. J. Med. 377, 352–360 (2017).

11. Fizazi, K. et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 20, 686–700 (2019).

12. Ryan, C. J. et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

13. James, N. D. et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N. Engl. J. Med. 377, 338–351 (2017).

14. Colomba, E. et al. Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: Natural history, management and outcome. Eur. J. Cancer 129, 117–122 (2020).

15. Davis, I. D. et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N. Engl. J. Med. 381, 121–131 (2019).

16. Cassinello, J. et al. Optimal treatment sequencing of abiraterone acetate plus prednisone and enzalutamide in patients with castration-resistant metastatic prostate cancer: A systematic review and meta-analysis. Cancer Treat. Rev. 93, (2021).

17. Drugs and pharmaceutical electronic market information tool (eMIT). GOV.UK https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-marketinformation-emit (2024).

Patient organisation submission

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Cost Comparison Appraisal

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormonesensitive metastatic prostate cancer (review of TA721) [ID6378]

Patient Organisation Submission

Thank you for agreeing to give us your organisation’s views on this technology and its possible use in the NHS.

You can provide a unique perspective on conditions and their treatment that is not typically available from other sources.

To help you give your views, please use this questionnaire with our guide for patient submissions.

You do not have to answer every question – they are prompts to guide you. The text boxes will expand as you type. [Please note that declarations of interests relevant to this topic are compulsory].

Information on completing this submission

• Please do not embed documents (such as a PDF) in a submission because this may lead to the information being mislaid or make the submission unreadable

• We are committed to meeting the requirements of copyright legislation. If you intend to include journal articles in your submission you must have copyright clearance for these articles. We can accept journal articles in NICE Docs.

• Your response should not be longer than 10 pages.

Patient organisation submission

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About you

Patient organisation submission

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Living with the condition

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Current treatment of the condition in the NHS

Advantages of the technology

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Disadvantages of the technology

10. What do patients or carers think are the disadvantages of the technology?

If a treatment is effective and suitable then patients will accept side effects as long as they are not severe. Dosage regime should be easy and acceptable. Drug treatment does not require regular visits to hospital and most monitoring can be achieved in the community.

Patient population

11. Are there any groups of patients who might benefit Apart Scotland, use of Abiraterone in mhsPCa is not currently approved in newly diagnosed high-risk more or less from the hormone-sensitive prostate cancer. A positive decision here would make this drug universally available technology than others? If within the UK. This would seem a logical step forward. so, please describe them and explain why.

Equality

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12. Are there any potential equality issues that should N/A be taken into account when considering this condition and the technology?

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Other issues

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Key messages

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Adapted Cost-comparison Evaluation

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Clinical expert statement

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Clinical expert statement

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Please underline all confidential information, and separately highlight information that is submitted as ‘confidential [CON]’ in turquoise, and all information submitted as ‘depersonalised data [DPD]’ in pink. If confidential information is submitted, please also send a second version of your comments with that information redacted. See Health technology evaluations: interim methods and process guide for the proportionate approach to technology appraisals (section 3.2) for more information.

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Thank you for your time.

We reserve the right to summarise and edit comments received, or not to publish them at all, if we consider the comments are too long, or publication would be unlawful or otherwise inappropriate.

Comments received are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the comments we received, and are not endorsed by NICE, its officers or advisory committees.

Clinical expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 2 of 9

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Part 1: Treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancerand current treatment options

Table 1 About you, aim of treatment, place and use of technology, sources of evidence and equality

Clinical expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 3 of 9

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Clinical expert statement

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• How does healthcare resource use differ between the additional monitoring for patient but this could be telephone follow up. Most technology and current care? patient do have home blood pressure monitoring

Clinical expert statement

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Clinical expert statement

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• If surrogate outcome measures were used, do they adequately predict long-term clinical outcomes?

• Are there any adverse effects that were not apparent in clinical trials but have come to light subsequently?

21. Are you aware of any relevant evidence that might There are 6 systematic reviews and network Meta analyses including Latitutde, not be found by a systematic review of the trial CHAARTED and stampede trials in the NMA’s The post hoc sub study by James evidence? et al may not have been previously included and the five year follow u[ data from stampede may not have been included previously 22. Are you aware of any new evidence for the See above comparator treatments since the publication of NICE technology appraisal guidance TA712 and TA741? 23. How do data on real-world experience compare Favourably, no additional toxicity concerns and efficacy similar in patients with the trial data? consistent with real life practice. 24. NICE considers whether there are any equalities As above, some patients may currently not be suitable for the approved options issues at each stage of an evaluation. Are there any and there is thus an unmet need. This may also allow biologically fit older potential equality issues that should be taken into patients to be offered more than ADT alone and to improve the numbers of account when considering this condition and this patient treated . treatment? Please explain if you think any groups of people with this condition are particularly disadvantaged.

Clinical expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 7 of 9

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• exclude any people for which this treatment is or will be licensed but who are protected by the equality legislation

• lead to recommendations that have a different impact on people protected by the equality legislation than on the wider population

• lead to recommendations that have an adverse impact on disabled people.

Please consider whether these issues are different from issues with current care and why.

More information on how NICE deals with equalities issues can be found in the NICE equality scheme. Find more general information about the Equality Act and equalities issues here.

Clinical expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 8 of 9

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Part 2: Key messages

In up to 5 sentences, please summarise the key messages of your statement:

There is a current unmet need for an additional option for patients unsuitable for the currently approved androgen receptor pathway

inhibitors for metastatic hormone sensitive prostate cancer

There is robust patient support for this

There are no differences in published toxicity for abiraterone in other licensed indications

Quality of life is improved for patients and progression delayed.

Click or tap here to enter text.

Thank you for your time.

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Clinical expert statement

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Adapted Cost-comparison Evaluation

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378]

Patient expert statement

Thank you for agreeing to give us your views on this treatment and its possible use in the NHS.

Your comments are really valued. You can provide a unique perspective on conditions and their treatment that is not typically available from other sources

Information on completing this form

In part 1 we are asking you about living with newly diagnosed high-risk hormone-sensitive metastatic prostate cancernewly

diagnosed high-risk hormone-sensitive metastatic prostate cancer. The text boxes will expand as you type.

In part 2 we are asking you to provide 5 summary sentences on the main points contained in this document.

Help with completing this form

If you have any questions or need help with completing this form please email the public involvement (PIP) team at pip@nice.org.uk (please include the ID number of your appraisal in any correspondence to the PIP team).

Please use this questionnaire with our hints and tips for patient experts. You can also refer to the Patient Organisation submission guide. You do not have to answer every question – they are prompts to guide you. There is also an opportunity to raise issues that are important to patients that you think have been missed and want to bring to the attention of the committee.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 1 of 7

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Please do not embed documents (such as a PDF) in a submission because this may lead to the information being mislaid or make the submission unreadable. Please type information directly into the form.

We are committed to meeting the requirements of copyright legislation. If you want to include journal articles in your submission you must have copyright clearance for these articles. We can accept journal articles in NICE Docs. For copyright reasons, we will have to return forms that have attachments without reading them. You can resubmit your form without attachments, but it must be sent by the deadline.

Your response should not be longer than 15 pages.

The deadline for your response is 5pm on Friday 15 August. Please log in to your NICE Docs account to upload your completed form, as a Word document (not a PDF).

Thank you for your time.

We reserve the right to summarise and edit comments, or not to publish them at all, if we consider the comments are too long, or publication would be unlawful or otherwise inappropriate.

Comments received are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the comments we received, and are not endorsed by NICE, its officers or advisory committees.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 2 of 7

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Part 1: Living with this condition or caring for a patient with newly diagnosed high-risk hormone-sensitive metastatic prostate cancer

Table 1 About you, newly diagnosed high-risk hormone-sensitive metastatic prostate cancer, current treatments and equality

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 3 of 7

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Patient expert statement

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example, how they are given or taken, side effects of treatment, and any others) please describe these 9a. If there are advantages of abiraterone over current treatments on the NHS please describe these. For example, the effect on your quality of life, your ability to continue work, education, self-care, and care for others? 9b. If you have stated more than one advantage, which one(s) do you consider to be the most important, and why? 9c. Does abiraterone help to overcome or address any of the listed disadvantages of current treatment that you have described in question 8? If so, please describe these 10. If there are disadvantages of abiraterone over current treatments on the NHS please describe these. For example, are there any risks with abiraterone? If you are concerned about any potential side effects you have heard about, please describe them and explain why 11. Are there any groups of patients who might benefit more from abiraterone or any who may benefit less? If so, please describe them and explain why Consider, for example, if patients also have other health conditions (for example difficulties with mobility, dexterity or cognitive impairments) that affect the suitability of different treatments 12. Are there any potential equality issues that should be taken into account when considering newly diagnosed high-risk hormone-sensitive metastatic

Patient expert statement

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prostate cancer and abiraterone? Please explain if you think any groups of people with this condition are particularly disadvantage Equality legislation includes people of a particular age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion or belief, sex, and sexual orientation or people with any other shared characteristics More information on how NICE deals with equalities issues can be found in the NICE equality scheme Find more general information about the Equality Act and equalities issues here. 13. Are there any other issues that you would like the committee to consider?

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Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 6 of 7

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Part 2: Key messages

In up to 5 sentences, please summarise the key messages of your statement:

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

Thank you for your time.

Your privacy

The information that you provide on this form will be used to contact you about the topic above.

☐ Please tick this box if you would like to receive information about other NICE topics.

' For more information about how we process your personal data please see NICE s privacy notice.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 7 of 7

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Adapted Cost-comparison Evaluation

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378]

Patient expert statement

Thank you for agreeing to give us your views on this treatment and its possible use in the NHS.

Your comments are really valued. You can provide a unique perspective on conditions and their treatment that is not typically available from other sources

Information on completing this form

In part 1 we are asking you about living with newly diagnosed high-risk hormone-sensitive metastatic prostate cancernewly

diagnosed high-risk hormone-sensitive metastatic prostate cancer. The text boxes will expand as you type.

In part 2 we are asking you to provide 5 summary sentences on the main points contained in this document.

Help with completing this form

If you have any questions or need help with completing this form please email the public involvement (PIP) team at pip@nice.org.uk (please include the ID number of your appraisal in any correspondence to the PIP team).

Please use this questionnaire with our hints and tips for patient experts. You can also refer to the Patient Organisation submission guide. You do not have to answer every question – they are prompts to guide you. There is also an opportunity to raise issues that are important to patients that you think have been missed and want to bring to the attention of the committee.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 1 of 7

==> picture [268 x 48] intentionally omitted <==

Please do not embed documents (such as a PDF) in a submission because this may lead to the information being mislaid or make the submission unreadable. Please type information directly into the form.

We are committed to meeting the requirements of copyright legislation. If you want to include journal articles in your submission you must have copyright clearance for these articles. We can accept journal articles in NICE Docs. For copyright reasons, we will have to return forms that have attachments without reading them. You can resubmit your form without attachments, but it must be sent by the deadline.

Your response should not be longer than 15 pages.

The deadline for your response is 5pm on Friday 15 August. Please log in to your NICE Docs account to upload your completed form, as a Word document (not a PDF).

Thank you for your time.

We reserve the right to summarise and edit comments, or not to publish them at all, if we consider the comments are too long, or publication would be unlawful or otherwise inappropriate.

Comments received are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the comments we received, and are not endorsed by NICE, its officers or advisory committees.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 2 of 7

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Part 1: Living with this condition or caring for a patient with newly diagnosed high-risk hormone-sensitive metastatic prostate cancer

Table 1 About you, newly diagnosed high-risk hormone-sensitive metastatic prostate cancer, current treatments and equality

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 3 of 7

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Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 4 of 7

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9a. If there are advantages of abiraterone over current treatments on the NHS please describe these. For example, the effect on your quality of life, your ability to continue work, education, self-care, and care for others? 9b. If you have stated more than one advantage, which one(s) do you consider to be the most important, and why? 9c. Does abiraterone help to overcome or address any of the listed disadvantages of current treatment that you have described in question 8? If so, please describe these 10. If there are disadvantages of abiraterone over current treatments on the NHS please describe these. For example, are there any risks with abiraterone? If you are concerned about any potential side effects you have heard about, please describe them and explain why 11. Are there any groups of patients who might benefit more from abiraterone or any who may benefit less? If so, please describe them and explain why Consider, for example, if patients also have other health conditions (for example difficulties with mobility, dexterity or cognitive impairments) that affect the suitability of different treatments 12. Are there any potential equality issues that should be taken into account when considering newly diagnosed high-risk hormone-sensitive metastatic prostate cancer and abiraterone? Please explain if

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 5 of 7

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Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 6 of 7

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Part 2: Key messages

In up to 5 sentences, please summarise the key messages of your statement:

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

• Click or tap here to enter text.

Thank you for your time.

Your privacy

The information that you provide on this form will be used to contact you about the topic above.

☐ Please tick this box if you would like to receive information about other NICE topics.

' For more information about how we process your personal data please see NICE s privacy notice.

Patient expert statement

Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] 7 of 7

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Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378] EAG assessment report

Author contributions

This report should be referenced as follows: Allen A, Bowater J, Stevens S et al. Abiraterone (originator and generics) for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (review of TA721) [ID6378]: a cost-comparison. Peninsula Technology Assessment Group (PenTAG), 2025.

The views expressed in this report are those of the authors and not necessarily those of the National Institute of Health and Care Excellence (NICE). Any errors are the responsibility of the authors. Copyright 2024, PenTAG, University of Exeter.

Confidential information

Confidential information contained within this report is shown in Table 1.

Table 1: Confidential information in this report

Table of Contents

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List of tables

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List of figures

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Abbreviations

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Executive Summary

Background

In TA721, abiraterone (and prednisone with androgen deprivation therapy), was appraised for treatment of newly diagnosed people with high-risk hormone-sensitive metastatic prostate cancer (mHSPC). While it was found to be effective and safe for treating adults with high-risk mHSPC, it was not recommended as it was found not to be cost-effective in comparison to ADT alone and docetaxel with ADT, even accounting for a proposed commercial arrangement. However, abiraterone has become available as a generic at a substantially reduced price. Therefore, NICE decided to review the decision made in TA721 as a cost-comparison versus the relevant comparators in the NHS treatment pathway.

Clinical and technological evidence

A cost comparison case can be made if a health technology is likely to provide similar or greater health benefits than technologies recommended in published NICE technology appraisal guidance for the same indication at a similar or lower cost. The aim of the clinical review was to assess whether abiraterone does provide similar or greater health benefits versus apalutamide with ADT and enzalutamide with ADT. A network meta-analysis (NMA) was conducted using four RCTs that linked the treatments via a common comparator, ADT alone. Only one RCT (LATITUDE) recruited the relevant population, people with high-risk mHSPC. Where possible, subgroup analysis from the other RCTs was used to better reflect this population. Three of the trials had open-label extension (OLEs) appended to the end of the randomised period whereby people in the comparator arm were permitted to use the intervention until the end of the trial. These OLEs led to deviations from the intended interventions in three trials and the proportions deviating was not consistent. In response to this, NMAs were conducted using data from each trial prior to the OLE occurring and at the latest timepoint available for each trial (after crossover had been permitted). In the ARCHES trial (enzalutamide), the OLE started so early (after a median of 14.4 months on randomised treatment) that the radiographic progression-free survival (rPFS) and overall survival (OS) data were highly immature and uncertain prior to the OLE.

The NMAs consistently found abiraterone provided similar or greater health benefits in terms of OS in the analysis prior to the OLE and after the OLE as judged using benchmarking from the ASCO guidelines[1] . Two notes of caution, the 95% credible intervals were often wide offering a wide range of potential true effects and the point estimates at the longer timepoints offered a

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very small benefit for the comparators. Secondly, in the OS NMA at the later timepoint there had been a higher proportion crossing from comparator treatment to intervention treatment in the enzalutamide trial and the apalutamide trial and this biased the results in favour of abiraterone. However, the EAG were reassured by the lack of meaningful or significant difference between treatments across both analyses and therefore concluded that assuming a similar level of health benefits was reasonable.

These analyses were primarily in people with high-risk mHSPC. The NMA for rPFS was only possible prior to the OLEs and found abiraterone to be similarly effective to apalutamide. The result versus enzalutamide (ARCHES) used highly immature data and was consequently too uncertain to draw any conclusions on the similarity or dissimilarity of effect. However, recent research in Shore et al. (2025) analysed 31 RCTs in people with mHSPC (including ARCHES, LATITUDE, STAMPEDE, and TITAN) and found rPFS was a reliable surrogate for OS.[2] Therefore, given the strong evidence of similarity of effect between enzalutamide and abiraterone in OS, it is rational to assume a similarity of effect for rPFS given the absence of strong clinical evidence in either direction.

The smaller NMA on health-related quality of life (HRQoL) found no difference between abiraterone and enzalutamide. The safety analyses used the full trial populations, high-risk mHSPC from LATITUDE and mHSPC for ARCHES, STAMPEDE, and TITAN. The NMAs found people on abiraterone had statistically significantly more Grade 3 and above adverse events, than apalutamide or enzalutamide. However, in the EAG’s clinical expert’s experience of using abiraterone in their practice, adverse events were treatable and did not commonly lead to treatment discontinuation.

In sum, the NMAs consistently found abiraterone provided similar or greater health benefits in terms of OS versus both comparators and for rPFS versus apalutamide. The NMAs did find treatment with abiraterone to result in a higher adverse events burden than enzalutamide or apalutamide.

Economic evidence

The economic analysis compared the costs of abiraterone, enzalutamide and apalutamide from the perspective of the NHS over a three-year time horizon. In the base case, abiraterone was associated with lower costs than both enzalutamide and apalutamide, driven primarily by differences in acquisition costs. The difference in incremental costs considering the treatments

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at list price was -£102,973 for abiraterone vs enzalutamide and -£103,012 for abiraterone vs apalutamide. Probabilistic sensitivity analysis indicated that abiraterone remained the least costly option in all simulations. Deterministic sensitivity and scenario analysis showed that the results were most insensitive to the majority of model parameters with the only the time horizon (equal to the mean time on treatment) showing any real sensitivity.

When considering treatments at list price the QALY gains required for abiraterone to no longer be cost-effective if abiraterone were in fact less effective than comparators were considerably larger than the range considered plausible based upon previous economic analyses.

Economic analyses including confidential discounts are presented in the cPAS appendix.

Key points for decision makers

1. Three of the four trials in the NMA recruited a wider population than the relevant high-risk mHSPC but relevant subgroup analysis was available for the key OS and rPFS outcomes.

2. Three of the four trials in the NMA included an OLE where people in the comparator arm were permitted to crossover to the intervention and led to large deviations from the intended interventions at later timepoints. Where possible, two NMAs, one before crossover was permitted and one after crossover was permitted, were conducted for each outcome.

3. The NMAs consistently found abiraterone provided similar or greater health benefits in terms of OS versus both comparators and similar health benefits in rPFS versus apalutamide. Given the research published by Shore et al. (2025)[2] and the evidence of similarity of effect between enzalutamide and abiraterone in OS, it was rational to assume a similarity of effect for rPFS given the absence of strong robust clinical evidence in either direction.

4. The NMAs found people on abiraterone had statistically significantly more Grade 3 and above adverse events, including hypertension, than apalutamide or enzalutamide. The EAG’s expert advice was that they were treatable and did not commonly lead to treatment discontinuation.

5. In the EAG’s base case, abiraterone was associated with lower costs than both enzalutamide and apalutamide, driven primarily by differences in acquisition costs. The difference in incremental costs considering the treatments at list price was -£102,973 for abiraterone vs enzalutamide and -£103,012 for abiraterone vs apalutamide.

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6. When considering treatments at list price the QALY gains required for abiraterone to no longer be cost-effective if abiraterone were less effective than comparators were considerably larger than the range considered plausible based upon previous economic analyses.

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1. INTRODUCTION AND BACKGROUND

1.1. Introduction

Abiraterone acetate (ZYTIGA®), henceforth called abiraterone, is an androgen receptor pathway inhibitor (ARPI). Other ARPIs relevant to this appraisal were apalutamide, enzalutamide, and darolutamide. However, apalutamide, enzalutamide, and darolutamide are androgen receptor antagonists , while abiraterone is an androgen synthesis inhibitor . Androgen receptor antagonists work by blocking the effects of androgens, male sex hormones, by preventing them from binding to androgen receptors, which are found in prostate cells and other tissues. On the other hand, androgen synthesis inhibitors, such as abiraterone, inhibit the production of androgens, thus depriving cancer cells of the necessary fuel for growth.

In TA721, abiraterone (with prednisone and androgen deprivation therapy, hereafter ADT), was appraised for treatment of newly diagnosed people with high-risk hormone-sensitive metastatic prostate cancer (high-risk mHSPC). It was compared to ADT alone and docetaxel with ADT and not to other ARPIs. While it was found to be effective and safe for treating adults with high-risk mHSPC, it was not recommended as it was found not to be cost-effective in comparison to ADT alone and docetaxel with ADT, even accounting for a proposed commercial arrangement.

Since TA721 other ARPIs, in combination with ADT, have received recommendations and abiraterone has become available as a generic at a substantially reduced price. Therefore, NICE decided to review the decision made in TA721. The EAG’s clinical experts did note that abiraterone with ADT was already commissioned by NHS England (NHSE) at the time of writing for this report. However, NICE explained that a formal recommendation would facilitate greater access across the NHS and inform future commissioning policy.

1.2. Underlying health problem

1.2.1. Prostate cancer

Prostate cancer was the most common and most frequently diagnosed form of cancer in men in the UK in 2020.[3] There were approximately 55,100 new prostate cancer cases annually in the UK, of which 13% presented with metastatic disease at diagnosis (data from 2017-2019).[4] A recent review found that in the UK, the number of new prostate cancer cases increased from 109 to 159 per 100,000 person-years between 2000 and 2021.[5] Between 2017-2019, there were approximately 12,000 prostate cancer deaths in the UK each year.[5]

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1.2.2. Demographic risk factors

Prostate cancer risk increases significantly with age, affecting about 1 in 6 men overall.[6] However, it disproportionately impacts people with Black (Black African, Black Caribbean, and Other Black) ethnicity, with around 1 in 4 diagnosed in their lifetime.[7] Clinical experts informed the EAG that people with Black ethnicity are twice as likely than people with White ethnicity to develop the disease probably due heritable factors. Diagnosis in people with Black ethnicity is more likely to be at a higher stage due in part to delayed diagnosis, limited access to treatment, systemic healthcare barriers, mistrust, and cultural factors. A family history of prostate cancer also significantly raises the risk.

Prostate cancer can be classified based on response to androgen deprivation therapy (ADT), which is described in the treatment pathway below. Prostate cancer can initially be responsive to hormone therapy and is referred to interchangeably as hormone-sensitive prostate cancer (HSPC) or castration-sensitive prostate cancer (CSPC). This project is in people with HSPC but it is useful to note that it may eventually become resistant to hormone therapy and is then referred to interchangeably as hormone-relapsed prostate cancer (HRPC) or castration-resistant prostate cancer (CRPC).

In some people, cancer cells break away from the prostate and travel through the bloodstream or lymphatic system to other areas like bones, lymph nodes, lungs, or liver. When the cancer has spread to other parts of the body, a person has metastatic disease, also known as stage 4 prostate cancer.

Assessing risk in metastatic prostate cancer involves evaluating the extent of cancer spread and its aggressiveness. This is typically done through imaging tests like bone scans, CT scans, and PSMA PET/CT scans, as well as assessing PSA levels and Gleason score. The information gathered helps determine the best treatment approach and prognosis. This was relevant for this appraisal because the marketing authorisation for abiraterone is for people with high-risk prostate cancer. As defined in LATITUDE, a pivotal abiraterone trial, a person is deemed to have high-risk prostate cancer if they have at least two of the three following factors:

• 1. Gleason score of 8 or higher;
• 2. the presence of three or more bone lesions;
• 3. measurable visceral metastasis.

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The Gleason score is a system used to assess the aggressiveness of prostate cancer based on how abnormal the cancer cells appear under a microscope. The Gleason score ranges from 6 to 10, with higher scores indicating more aggressive cancer.

The presence of multiple bone lesions (three or more) signifies a significant burden of bone metastasis with increased risk of complications e.g. fractures and spinal cord compression. It also indicates more aggressive and widespread disease.

Measurable visceral metastasis in prostate cancer refers to the presence of measurable cancerous growths in internal organs (viscera), such as, the liver, lungs, or adrenal glands, detected during imaging scans. These metastases are typically found in advanced stages of prostate cancer and are associated with a poorer prognosis compared to bone-only metastases.

1.3. Current service provision

The first-line and second-line therapy options are detailed in the following sections. However, it is useful to note here that people are usually treated with ADT through all the lines of therapy.

1.4. First-line therapy

The EAG took advice from our clinical experts on the current treatment pathway for people with high-risk mHSPC. At the time of writing, the first-line treatments that can be offered in the NHS are described in Table 2.

Table 2: First line treatments currently offered on the NHS

Abbreviations: ADT, Androgen Deprivation Therapy; NHSE, NHS England. Note: *From this point forward in the report the EAG will refer to abiraterone and prednisone as abiraterone.

The initial decision is whether people should be offered ADT alone. There are two groups of people who could fall into this category. Firstly, there are the extremely frail who may not be offered intensified treatment. The average age of diagnosis is relatively old, but people in their 90s with performance status 3 or greater, might fall into this category. The other group are people with extremely indolent disease. Some people with metachronous disease, i.e.

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metastatic disease diagnosed many years after primary treatment, with a very slow rising PSA and a very small burden of disease, may avoid treatment intensification if the risk of side effects and effects on quality of life are thought to outweigh benefits However, these two groups are a small proportion of people with mHSPC and people with extremely indolent disease are not categorised as high-risk.

In people who are able to have treatment intensification, a decision is taken whether to offer them triplet or doublet therapy. Triplet therapy is offered based on the burden of disease and ability to tolerate the therapy. Our clinical experts said that they would consider triplet therapy in people who have, for example, visceral metastatic disease such as liver metastasis or lung metastasis with nodes and bone metastasis. The ability to tolerate the therapy is primarily judged through age (ideally under 60 years old) and performance status (0 or 1). For example, people under the age of 60 with good performance status (0 or 1) would usually receive triplet therapy. The EAG’s experts estimated that between 10-20% of people who receive treatment intensification for mHSPC would receive triplet therapy. The EAG received corroborating information from Peter Clark, the Cancer Drugs Fund Lead, that 18.6% of people who had treatment intensification for mHSPC received triplet therapy.

People for whom single agent therapy (ADT alone) or triplet therapy are not considered appropriate, receive doublet therapy. At the time of writing there were four doublet therapies available in the NHS: enzalutamide with ADT, apalutamide with ADT, abiraterone with ADT, and docetaxel (chemotherapy) with ADT. However, the EAG’s experts explained that since the introduction of ARPIs into the treatment pathway, the use of docetaxel with ADT has been substantially reduced. Many people will choose not to have chemotherapy as it is recognised to have higher toxicity than ARPIs and has a big impact on quality of life. One expert explained that in their practice, it was very unlikely for people to be offered docetaxel with ADT without ARPI at first-line. There may a very small number who cannot have an ARPI who will be offered docetaxel with ADT at first line.

Therefore, the choice of doublet therapy first-line for people with mHSPC is between enzalutamide with ADT, apalutamide with ADT, and abiraterone with ADT. The NICE recommendation for apalutamide with ADT specifies people with mHSPC for whom docetaxel is not suitable. However, as noted above first-line usage of docetaxel with ADT has reduced since the introduction of ARPIs. Also, abiraterone’s marketing authorisation is in people with high-risk mHSPC and therefore this appraisal concentrates on this as the relevant subgroup.

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The EAG’s experts explained that in people eligible for each of the three relevant doublet therapies, the decision of what to offer would be based on the side effects and co-morbidities of the person, as each ARPI has a different side-effects profile. Abiraterone can increase the risk of cardiac events, particularly in people with pre-existing cardiovascular disease, and as such, may be avoided in this population. A further concern with abiraterone is exposure of people to low dose, but long-term, steroids with prednisolone. The primary concerns specific to apalutamide and enzalutamide are in people who are prone to seizures as it crosses the bloodbrain barrier and can reduce a person’s seizure threshold. Also, both apalutamide and enzalutamide interact with medications, such as blood thinners and blood pressure medicines. If a person is on those medicines, it may be more appropriate to give a person abiraterone.

Peter Clark, the Cancer Drugs Fund Lead, disclosed the market share for people with mHSPC who had treatment intensification in the UK at the time of writing. In people who received doublet therapy (with ADT) 42.1% received enzalutamide, 43.9% received apalutamide, and 14.0% received abiraterone.

First-line therapy with ARPIs continues until there is evidence of progression. The EAG’s experts noted that the definition of progression can vary between centres. Clinical progression is when people develop symptoms (including bone pain, urinary problems, fatigue, and weight loss), biochemical progression is when their Prostate-Specific Antigen (PSA) starts to rise, and radiological progression is when progression is visible on a scan. The experts estimated that on average first-line therapy continues for three to four years.

1.5. Second-line therapy

The second-line therapy a person can be offered is informed by the first-line therapy they received. NHSE Commissioning rules mean that people who received an ARPI at first-line cannot be re-challenged with an ARPI at second-line. People who received docetaxel chemotherapy first-line will not receive docetaxel chemotherapy at second-line, and will instead receive cabazitaxel chemotherapy if treatment with a taxane is considered the best option.

Based on these rules, the most common second-line option for people who had an ARPI with ADT at first line is docetaxel with ADT or ADT alone. People who received triplet therapy firstline are most likely to receive cabazitaxel chemotherapy with ADT or ADT alone at second-line. The EAG’s experts noted that few people receive docetaxel with ADT first line, but for those

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who did, second-line options would be an ARPI with ADT, cabazitaxel chemotherapy with ADT or ADT alone.

The EAG’s experts also noted that, at the time of writing, there were further options for treating people if their disease has progressed to metastatic hormone-relapsed prostate cancer (mHRPC). In those cases, they would consider offering PARP inhibition with olaparib for people whose tumour has a BRCA mutation. Also, radium-223 can be used in the mHRPC population who have symptomatic bone metastases and no known visceral metastases and have already had docetaxel or docetaxel is contra-indicated or unsuitable.[8] Finally, enrolment in clinical trials may be considered.

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2. DECISION PROBLEM

2.1. Background

The EAG have summarised the decision-problem detailed in the final scope as issued by NICE[9] and commented on where the methods in this analysis deviate from the scope. NICE instructed the EAG to undertake the project using a cost-comparison approach and the EAG’s deviations from the final scope primarily relate to delivering a robust cost-comparison analysis.

2.2. Cost-comparisons

A cost comparison case can be made if a health technology is likely to provide similar or greater health benefits than technologies recommended in published NICE technology appraisal guidance for the same indication at a similar or lower cost.[10] NICE cost comparison appraisals use the assertion that if the treatment under investigation is found to be cost-effective versus the comparators, it is also cost-effective versus the comparators in the comparator’s appraisals. This is relevant to this appraisal because other relevant treatments, such as ADT alone and docetaxel with ADT, have not been through the NICE technology appraisal process but were comparators in the appraisal of enzalutamide with ADT (TA712). Thus, if abiraterone with ADT is found to be cost effective versus enzalutamide with ADT, it is also cost effective versus ADT alone and docetaxel with ADT as the price and evidence base for these treatments has not had any major changes since TA712.

2.3. Decision problem

The EAG considered the population and interventions in the final scope to be appropriate. However, the EAG have deviated from the final scope in relation to the comparators. NICE listed all of the first-line treatments available in the NHS for first-line treatment of people with mHSPC. As noted in Section 2.2, the relevant comparators were treatments recommended in published NICE technology appraisal guidance for the same indication at a similar or lower cost. Three of the treatments detailed in the final scope had been recommended in published NICE technology appraisal guidance: enzalutamide with ADT; apalutamide with ADT; and darolutamide with docetaxel and ADT. However, as noted in Section 1.4, the decision of whether to offer triplet therapy (darolutamide with docetaxel and ADT) is taken before the decision of what doublet therapy to offer. Therefore, the decision of which doublet therapy to offer is between enzalutamide with ADT, apalutamide with ADT, and abiraterone with ADT, and

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as such, enzalutamide with ADT and apalutamide with ADT were the relevant comparators for this appraisal.

The EAG’s clinical experts agreed that the outcomes in the final scope were relevant to people with high-risk mHSPC. They noted that PFS is really important because it allows a person to avoid “the medicalisation” of their life. They can go on holiday with some tablets and have a hormone injection every three months. They do not have to see a doctor very often and are almost living a normal life. The EAG also included two outcomes relevant from an economic perspective in the protocol: time on treatment and time to discontinuation.

The EAG planned to conduct an economic analysis in-line with a cost comparison approach. However, as a pragmatic approach to explore the impact of assuming similar effectiveness, the EAG calculated the difference in effectiveness that would be needed to justify the difference in cost between abiraterone and the other treatments within scope and commented on the plausibility of this.

Table 3: Summary table of the decision problem

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Abbreviations: ADT, androgen deprivation therapy; ARPIs, Androgen Receptor Pathway Inhibitors; EAG, external assessment group; NICE, National Institute for Health and Care Excellence; OS, overall survival; PFS, progression-free survival.

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3. TECHNOLOGIES

A brief overview of the technologies as described by the companies can be found in Table 4. Please see the scope for further details.

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Table 4: Description of technologies included in the assessment

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Abbreviations: ADT, androgen deprivation therapy; ALT, Alanine Aminotransferase; AR, androgen receptor; ARPIs, Androgen Receptor Pathway Inhibitors; DHT, dihydrotestosterone; HR, high risk; LHRH, Luteinizing Hormone-Releasing Hormone; mHSPC, metastatic hormone sensitive prostate cancer.

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4. CLINICAL AND TECHNOLOGICAL EVIDENCE SELECTION

4.1. Approach

As previously stated, a cost comparison case can be made if a health technology is likely to provide similar or greater health benefits than technologies recommended in published NICE technology appraisal guidance for the same indication at a similar or lower cost. The EAG conducted a clinical effectiveness and safety systematic literature review (SLR) and network meta-analysis (NMA), including relevant comparators, to support an assessment of whether combination therapy with abiraterone with ADT offers a similar benefit to doublet therapy with enzalutamide with ADT and apalutamide with ADT. The SLR followed the general principles published by the Centre for Reviews and Dissemination (CRD) at the University of York.[11]

4.2. Inclusion criteria

The inclusion and exclusion criteria for the clinical effectiveness and safety SLR are shown in Table 5. These criteria were informed by the final scope issued by NICE and discussion between the EAG and the NICE team. The criteria have also been informed by the need to capture the key evidence for the purposes of the assessment objectives. The inclusion criteria are consistent with the decision problem for this assessment (Section 2.3).

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Table 5: Inclusion and exclusion criteria, clinical effectiveness

Abbreviations: ADT, androgen deprivation therapy; mg, milligram; RCT, randomised controlled trial.

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4.3. Evidence search strategies and study selection

The clinical evidence searches sought to identify reports of the effectiveness and safety of the intervention and comparators, with a view to the implementation of an NMA. Database searches were performed in Medline, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and INAHTA. Trial protocols were identified from searches in ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), Embase, and Cochrane Protocols. We took a pragmatic approach to the acquisition of evidence, with the idea of building on, rather than repeating, previous systematic reviews. With this in mind, we first searched for pre-existing SLRs and NMAs. After having identified the most recent NMA, we then performed an RCT search for trials published after the date of the NMA search.

This search approach, and its rationale, is fully described in the published protocol. No amendments to the planned search process were made. Details of the search approach, including lists of databases, search strategies and outcomes can be found in Appendix A. Screening took place in Rayyan[12] and was performed using the inclusion and exclusion criteria described in the published protocol. A PRISMA diagram of the search and screen process for SLRs and NMAs is provided in Appendix B.

The SLR/MA clinical search retrieved 530 articles. Of these, 69 were selected for full text screening. Of these, one full text was unavailable and 52 were excluded, leaving 17 includes. Reasons for exclusion can be seen in Appendix C.

The most recent NMA was Wang et al. (2024),[13] whose search identified studies up to 14 June 2024. We therefore performed the RCT update search from 1 January 2024 to the present day (27 June 2025). The RCT search approach (dates) retrieved 870 articles (including 50 registry records of ongoing studies, from Embase, ClinicalTrials.gov and the ICTRP). 858 were excluded at TIAB, leaving 12 for full text appraisal. All 12 were excluded at full text. A PRISMA diagram of the RCT search and screen process can be found in Appendix B. Reasons for exclusion can be seen in Appendix C.

4.4. Included and excluded studies

The four RCTs included in the analysis are detailed below in Table 6.

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Table 6: Key studies with clinical and technological evidence

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Abbreviations: ADT, androgen deprivation therapy; AEs, adverse events; ECOG, Eastern Cooperative Oncology Group; FU, follow-up; HR, high-risk; mHSPC, metastatic hormone-sensitive prostate cancer; OLE, open-label extension; OS, overall survival; PFS, progression-free survival; QoL, quality of life; RCT, randomised controlled trial; rPFS, radiographic progression-free survival.

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5. CLINICAL AND TECHNOLOGICAL EVIDENCE REVIEW

5.1. Quality appraisal of studies

Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2)[23] was used to assess the risk of bias in in the trials included in the NMAs. Risk of bias was evaluated for each specific result reported in a RCT, rather than assessing the entire trial at once. A summary of the judgments as they pertained to specific trials results is presented in the following sections.

5.1.1. Randomisation process

All outcomes for all four of the trials were judged to be at low risk of bias for randomisation process. They each presented valid methods of randomisation and valid methods of concealment of treatment allocation from those enrolling participants and assigning treatments. Within each trial there were no differences between treatment arms in baseline characteristics to suggest random allocation was not achieved.

However, the population of interest for this appraisal were people with high-risk mHSPC and LATITUDE was the only trial where only people with high-risk cancer were included. Therefore, the NMAs often used subgroup analysis from the trials where appropriate to better match the high-risk mHSPC population.

A number of the NMAs used subgroup analysis from the ARCHES trial. This was either the high-risk mHSPC subgroup or the subgroup of people with mHSPC who had a Gleason score ≥8 (a criteria for high-risk tumours) where data specifically in the high-risk subgroup were not available. The EAG’s experts agreed that Gleason score of 8 or higher is an indicator of highrisk cancer but mentioned that it was only one of three criteria. The trial was not stratified by either of these subgroups and, as such, randomisation was broken by these analyses. Similarly, the high-risk mHSPC subgroup was reported for the STAMPEDE trial but the trial was not stratified by the high-risk mHSPC subgroup and randomisation was broken by these analyses. STAMPEDE presented baseline characteristics of the two arms in the high-risk mHSPC subgroup and this has been reproduced in Table 56 in Appendix D. The intervention and comparator arms were similar for most baseline characteristics presented with minor differences for PSA level and T stage. However, despite the apparent similarity of measured baseline characteristics in STAMPEDE, the EAG had some concerns over the risk of bias related to the breaking of randomization in the subgroup analysis in both trials.

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TITAN presented subgroup analysis (Gleason score ≥8) but the trial was stratified by Gleason score ≥8 and, as such, did not break randomisation.

5.1.2. Deviations from the intended interventions

ARCHES, LATITUDE, and TITAN were double-blind trials and there was no indication of notable deviations from the intended interventions within the randomised period of each trial. Therefore, outcomes measured in that period were judged to be at a low risk of bias for this domain. STAMPEDE was an open-label trial and the EAG had some concerns that this could have led to deviations from the intended treatment.

ARCHES, LATITUDE, and TITAN also had open-label extensions (OLEs) after the randomised period of the trial was completed. When the OLE period began people in the comparator arm who were alive and had not progressed were eligible to cross over to the intervention treatment. Therefore, there was a substantial deviation from the randomised interventions for outcomes measured in the OLE periods of ARCHES, LATITUDE, and TITAN. These outcomes were at high risk of bias for this domain.

5.1.3. Missing outcome data

All of the four trials reported less than 10% missing data for all outcomes in both the randomised period, and where applicable, the OLE periods. The EAG judged all outcomes to be at low risk of bias for this domain.

5.1.4. Measurement of the outcome

The definitions of OS were standard across all trials included in the NMAs.

The definitions of rPFS were similar across ARCHES, LATITUDE, and TITAN and each included regular radiographic assessment of progression in participants. LATITUDE defined rPFS as radiographic progression of soft-tissue lesions was evaluated by either CT or MRI on the basis of RECIST, version 1.1. Progression on bone scanning was assessed by adaptation of Prostate Cancer Working Group 2 criteria.[24] People were given a CT or MRI every 2 months. STAMPEDE reported PFS, rather than rPFS, and the EAG included the trial in the rPFS NMA based on use of the trial in previous appraisal analysis (TA721). PFS in STAMPEDE was defined as time from randomisation to the first of: new disease or progression of: distant metastases, lymph nodes or local disease; or death from prostate cancer. People had scans or X-rays repeated at 24 weeks if they were abnormal at baseline, or when clinically appropriate.

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The EAG considered STAMPEDE data to be at high risk of bias in the rPFS NMA due to the measurement of the outcome.

The EAG also noted that the number of people reporting fatigue (all grades) was notably higher in both treatment arms in STAMPEDE than the other trials, including LATITUDE, the other abiraterone trial. All four trials graded and summarised adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)[25] and it was unclear to the EAG why higher proportions of people in STAMPEDE were found to have experienced fatigue. Given the unaccounted-for difference, even between the number of people with fatigue (all grades) in the comparator arm in STAMPEDE and the comparator arms in the other trials, the EAG had some concerns over the fatigue results of STAMPEDE.

Nothing in the trial reports suggested measurement of ascertainment of the outcome differed between treatment arms.

5.1.5. Selection of the reported result

Each of the trials reported OS and rPFS/PFS as detailed in the trial protocols in the full trial populations. However, the population of interest for this appraisal were people with high-risk mHSPC, and LATITUDE was the only trial where only the relevant population were recruited.

The three other trials recruited a broader population and subgroup analysis was used in the NMA to better match the relevant high-risk mHSPC population. When trials prespecified subgroup analyses they plan to report it is normally not judged to be a risk of bias. When trials report subgroup analyses that were not pre-specified it can be a risk of bias because they are searching for a positive effect. The more subgroups analysed, the higher the chance of encountering a statistically significant effect due to random variation rather than a true effect.

Subgroup analysis was presented in ARCHES and TITAN and these subgroup analyses were pre-specified and, as such, were not at a risk of bias. STAMPEDE did not prespecify high-risk mHSPC and, as such, may be at a risk of bias. However, the EAG considered it quite reasonable that, given the marketing authorisation for abiraterone, trials of abiraterone would report the efficacy of treatment in the relevant (high-risk mHSPC) population post hoc.

5.2. Indirect comparison methods

The methods and trials used in the indirect comparison are reported in this section.

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5.2.1. Characteristics and appraisal of trials identified and included in the indirect comparisons

5.2.1.1. Treatments received during the trials and subsequent to the trials

As detailed in Table 5 in Section 4.4, three (ARCHES, LATITUDE, and TITAN) of the four trials included in the NMA reported outcomes after an initial randomised phase and then became open label extensions (OLE) where people in the placebo arm who survived, and whose cancer had not progressed, were permitted to have the trial intervention until the trial ended. The fourth trial in the NMA was STAMPEDE where people in the placebo arm did not cross over to the trial intervention after an initial analysis. The time until crossover and the number of people who crossed over is detailed below in Table 7.

In light of the varying follow-up and the permitted crossover of treatment from the placebo arm to the intervention arm, the EAG have undertaken NMAs at two different timepoints for each outcome. The first round of NMAs used datacuts reported up to a median follow-up of 40 months. These datacuts were prior to the OLEs in ARCHES, LATITUDE, and TITAN beginning and before any treatment crossover was formally permitted.

A second round of NMAs was run using the latest datacut reported for each of the trials where in the OLEs people were permitted to crossover from placebo to the intervention. For all NMAs we used intention-to-treat (ITT) data where people were analysed in the initial treatment group to which they were randomised. However, the EAG caution that the time until crossover, when crossover was permitted, varied widely across the trials. The comparator arm in ARCHES received placebo and ADT for a median 14.4 months before cross-over was permitted which led to 31.3% of participants receiving open-label treatment with enzalutamide with ADT (median time until cross-over = 21.5 months). A larger proportion of participants in TITAN crossed over to apalutamide with ADT (39.5%) compared to ARCHES although the median time until crossover was not reported. Given the variation between the trials in terms of the time until crossover was permitted and the number crossing over to the intervention treatment, along with uncertainty related to the period participants received the comparator treatment, the EAG cautioned that the treatment crossover influenced all of the outcomes presented in the analysis of latest trial data after unblinding. A higher proportion of participants in ARCHES (enzalutamide) and TITAN (apalutamide) crossed over than did in LATITUDE (abiraterone) to the intervention and therefore they were most at risk of underestimating the effectiveness of the intervention.

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Table 7: Crossover from placebo to intervention

In addition to the treatment crossover permitted in the OLEs, each of the four trials varied in terms of the first subsequent prostate cancer treatments trial participants received after disease progression (Table 8).

A higher proportion of people in the intervention (abiraterone) arms of LATITUDE and STAMPEDE received docetaxel chemotherapy than the intervention arms in ARCHES or TITAN. This may have been due to ARCHES and TITAN including a proportion of participants who had previously been given docetaxel chemotherapy for prostate cancer. In the comparator arms (placebo with ADT / ADT alone) 65.0% of participants in TITAN received docetaxel chemotherapy, followed by 50.1% in LATITUDE, and fewer in STAMPEDE and ARCHES. It was unclear to the EAG why so many more participants in TITAN were treated with docetaxel chemotherapy second-line.

The proportion of people receiving cabazitaxel was low across all arms in all four trials. It was similar (6% to 9% of those who received subsequent therapy) in LATITUDE, STAMPEDE, and ARCHES. Only 2 (1.7%) people in the apalutamide arm in TITAN. The use of cabazitaxel in the comparator arms ranged from 30 (8.0%) participants in LATITUDE down to 6 (2.7%) in ARCHES.

A slightly higher proportion of people who received subsequent therapy in the intervention arms of TITAN (30%) and ARCHES (25.2%) received ARPI therapy (abiraterone or enzalutamide) compared to LATITUDE (23.8%) and STAMPEDE (16.8%). STAMPEDE was notably lower but this may be due to the trial primarily occurring in the UK where re-treatment with ARPIs was not common practice. The EAG noted that there is evidence that people can gain resistance to these treatments[26] and, given the similarity in the mechanism of action of ARPIs, if a person’s

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cancer stops responding to one, it probably won’t respond to another.[27] Therefore, these differences in later ARPI therapy would be unlikely to bias the results.

In sum, the EAG cannot draw any firm conclusions from these differences in subsequent

treatments but understand that it added a layer of uncertainty to the estimate of effect for OS especially at the later timepoints.

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Table 8: First subsequent antineoplastic therapy for prostate cancer (not including OLE crossovers)

Abbreviations: ADT, androgen deprivation therapy; OLE, open-label extension; PBO, placebo; NE, not estimable; NR, not reported.

1 The trial specified the number of people who reported a new treatment. This was not limited to antineoplastic therapy.

2 The subsequent antineoplastic therapies received were not limited to the therapies specified in this table

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5.2.2. Populations recruited to the trials

The relevant population for this trial were people with high-risk mHSPC. This is because the marketing authorisation for abiraterone was limited to a high-risk population, as defined in LATITUDE (1.2.2). The EAG have made it clear in the results where subgroup analysis from the other trials were used in the NMAs.

5.2.3. Network meta-analyses (NMAs) of main outcomes

NMAs were undertaken where possible given the outcome data presented for the four trials in the network. There were sufficient data to conduct NMAs for OS, rPFS, HRQoL, and adverse events. On the advice of our clinical experts we completed NMAs for adverse events Grade 3-5, fatigue (all grades), and hypertension (Grade 3-5). They reasoned that all fatigue can impact on quality of life. It was not possible to extract sufficient data from the trials to conduct NMAs for response rate, time on treatment, or time to discontinuation. The input data used in the NMA and baseline characteristics of participants in the trials are detailed in Appendix D.

NMA models were fitted to trial-level reported data for the outcomes of main interest listed in Table 4 using the Bayesian approach to inference. For time-to-event data such as OS and rPFS, this was done under the assumption of proportional hazard functions for different treatment arms (Section 5.2.4) and the NMA models were fitted to the logarithms of the hazard ratios using the inverse-variance method. For binary outcomes, such as the occurrence of at least one specific adverse event in a given time period, the NMA models were fitted to the logarithms of the odds ratios using the inverse-variance method. Two models were fitted for each outcome based on the data cuts from the trials. Analysis of latest trial data up to a 40month follow-up used the trial data at the latest data cuts of ARCHES, LATITUDE, and TITAN prior to the OLEs beginning and the STAMPEDE 40-month median follow-up. Analysis of latest trial data after unblinding used the final data cuts from each of the trials including the OLEs in ARCHES, LATITUDE, and TITAN.

Apart from the analyses just discussed, a sensitivity analysis of each NMA of main interest was performed, where possible, with data for high risk mHSPC patients replaced by data for all mHSPC patients. These latter analyses were conducted to check whether the use of data for all mHSPC patients was acceptable as a surrogate for high risk mHSPC patient data in the main analyses and also to gauge the general sensitivity of results to cancer risk classification. This was necessary because for some trials no data were presented in people with high-risk mHSPC

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and either the full trial data or approximate subgroup data (Gleason score ≥8) were used in the analyses.

For all analyses, the NMAs models were fitted separately under the assumptions of fixed and random treatment effects, where possible, otherwise only fixed effects NMA was performed.[28] Non-informative prior distributions were used for the main treatment effects and reasonable approximations to non-informative prior distributions were used for the variance of the random treatment effect where applicable. Model fit and algorithm convergence were checked using standard methods. Cochran’s Q tests for heterogeneity were conducted on trial results for individual treatment comparisons where appropriate. As none of the analyses were performed on the basis of an NMA graph that contained closed loops, standard NMA consistency checks were not applicable.

5.2.4. Investigation of the proportional hazards assumption

The proportionality of hazard functions for the different arms of each trial included in the NMA were investigated in the standard way by using plots of non-parametric estimates and 95% confidence bands of the logarithm of the hazard ratio between treatment arms over time. These plots were supplemented by chi-squared tests of the correlation of the Schoenfeld residuals over time and log cumulative hazard plots (also known as log minus log survival plots) of each treatment. The individual patient survival data that was required for these analyses was obtained by digitising Kaplan-Meier curves for the relevant outcome that appeared with the - published trial results using the R package IPDfromKM (https://CRAN.R

project.org/package=IPDfromKM). The data used was the latest data cut in each of the trials prior to any subsequent removal of blinding.

The results of this analysis showed that the plots of the estimated logarithm of the hazard ratio over time were consistent with the hazard ratio being a constant, since this hypothesis lay within the 95% confidence bands of the estimated log hazard ratio function for all trials and for both of the outcomes of progression-free survival and overall survival (see the corresponding figures in Appendix E). For all trials and for both of these outcomes, the plots of the log cumulative hazard functions were parallel enough between treatment groups over periods of time with the highest frequency of events to conclude that the assumption of proportional hazard functions holds (see the corresponding figures in Appendix E). Taken as a collection of significance tests, there was not a strong indication from the results of the chi-squared tests of the correlation of the

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Schoenfeld residuals over time for each of the analyses concerned to conclude that the proportional hazards assumption fails (see the corresponding test results in Appendix E).

In summary, the results of an investigation of the assumption of proportional hazard functions between trial arms gave no evidence beyond usual sampling variability of a failure of this assumption with regard to overall survival or progression-free survival for any of the four included trials. Therefore, this justifies analysing the time-to-event data concerned using a proportional hazards survival model.

5.2.5. Effect modifiers across the network

The EAG noted that across the relevant previous appraisals (TA712, TA721, TA741) the baseline characteristics focussed on were: Gleason score, ≥3 bone metastases at screening, distant metastasis at initial diagnosis, time since diagnosis with mHSPC, and ECOG/WHO Performance status. The EAG’s clinical experts considered these to be prognostic factors rather than effect modifiers. They understood the only known effect modifier to be age (people >75 years old benefit less) as suggested by the STOPCAP analysis.[29] STOPCAP used individual participant data for completed trials, including among others LATITUDE, STAMPEDE, and TITAN, examining effects of androgen receptor pathway inhibitors for mHSPC.

The effect modifiers and prognostic factors of the participants in each trial are presented in Table 9. Each of the trials reported median age at randomisation. The median ages of the participants in the trials was as high as 70 in ARCHES with slightly lower, either 67 or 68, in the other trials. While the difference in median age was small it resulted in 29.5% of participants in ARCHES being at least 75 years old compared to 23.4% in TITAN and 20.3% in LATITUDE. The EAG understood this small difference in median age may have led to enzalutamide having a reduced apparent effectiveness in the NMA. However, it unclear to the EAG what the magnitude of the effect of having between 7% and 10% more 75 year olds would be.

Outside of age, the reporting of these factors was inconsistent and in most cases the participants in the subgroup of interest (high-risk mHSPC) were not presented. In the instance where this was presented, i.e. the LATUITUDE participants and the relevant STAMPEDE subgroup, the LATITUDE trial had a higher proportion of people with and ECOG/WHO performance status score of one or more. This indicated participants in LATITUDE had a greater degree of functional impairment and dependence at the start of the trial. However, the EAG noted that this did not have a large effect as the efficacy results of the trials were similar.

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Overall, the EAG was largely unable to find and compare the effect modifiers and prognostic factors across the relevant participants (high-risk mHSPC) in each trial and, as such, there was uncertainty as to whether the trials were well balanced for these factors. As previously stated, the EAG’s experts considered only age to be a treatment effect modifier and that potentially led to an underestimation of the enzalutamide treatment efficacy. However, the difference between the trials was small and the EAG did not consider this was likely to have had a large effect on the results of the NMA. There were differences in prognostic factors between the trials but these were not found to be treatment effect modifiers in the STOPCAP analysis[29] and, as such, would not be expected to lead to confounding of the indirect estimates.

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Table 9: Summary information for select effect modifiers and prognostic factors

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HSPC, hormone-sensitive prostate cancer; IQR, interquartile Range; mHSPC, metastatic hormonesensitive prostate cancer; NR, not reported; PSA, Prostate-Specific Antigen where results were available by arm the figures are shown separated by a bar (|). a People with at least two of these factors have high-risk cancer b Time from GnRH agonist/antagonist to first dose, (months) c WHO performance status, 0 or 1 d Median time from initial diagnosis to randomization

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5.2.6. Time on treatment in the trials

It was not possible to run an NMA using the time-on-treatment reported in the trials but the results of what the EAG could find are reported in Table 10 as they are used in the economic analysis. Prior to OLEs time on treatment was substantially lower in the ARCHES trial (12.8 months) than the other trials. When taking into account the OLEs, time on treatment was shorter in the trials of abiraterone (25.8 months and 33.2 months) as compared to enzalutamide (40.2 months) and apalutamide (39.3 months). However, these data are not directly comparable as the data from LATITUDE (25.8 months) was taken from a high-risk mHSPC population whereas the other trial estimates were in people with (high-risk and not high-risk) mHSPC.

The EAG noted that the NMA found people on abiraterone were more likely to have Grade 3+ adverse events (AEs) than people on enzalutamide or apalutamide and posited to the clinical experts that higher serious AEs may have led to shorter time on treatment. However, the EAG’s clinical experts considered that in their practices abiraterone had similar tolerability to enzalutamide and apalutamide. In sum, the EAG understood the shorter time on treatment to have occurred in LATITUDE because it was a high-risk population but it was unclear why the mHSPC subgroup in STAMPEDE had shorter time-on-treatment than the ARCHES (enzalutamide) or TITAN (apalutamide) OLEs.

Table 10: Time on treatment

Abbreviations: ADT, androgen deprivation therapy; HSPC, hormone-sensitive prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; OLE, open-label extension.

5.2.7. Adverse events in the trials

The EAG extracted Grade 3+ adverse events (AEs) experienced by at least 5% of people in one arm of a trial for use in the economic analysis. The longest timepoint reported in the trials are

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presented in Table 11. Hypertension was experienced by at least 5% of people in each of the intervention arm. It was experienced by a substantially higher proportion of people in the abiraterone arm (20.9%) and higher proportion comparator arm (9.8%) in LATITUDE. The EAG understood the high-risk population contributed to this difference. Other AEs that were higher in the abiraterone arms were hypokalaemia and increased alanine aminotransferase (ALT). The EAG’s experts stated that increased episodes of hypokalaemia compared to enzalutamide or apalutamide would be expected owing to abiraterone’s mechanism of action. However, it is rarely unmanageable and is in part due to the lower prednisolone dose given in the hormone sensitive setting. It is normally relatively simple to manage by increasing the prednisolone dose. ALT rises were also expected to be more common in people treated with abiraterone than with enzalutamide or apalutamide, but are often not symptomatic. There were also some noticeable differences between the AEs reported in the two abiraterone trials (LATITUDE and

STAMPEDE). For example, hot flushes and erectile dysfunction. The EAG understood this to be reporting related. The EAG’s experts were not concerned about this discrepancy. In sum, abiraterone did appear to result in a higher adverse events burden than enzalutamide or apalutamide but the EAG’s expert advice was that they were treatable and did not commonly lead to treatment discontinuation.

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Table 11: Grade 3 and above adverse events experienced by at least 5% of people in a treatment arm

Abbreviations: Abi+ADT, abiraterone with ADT; ADT, androgen deprivation therapy; ALT, Alanine aminotransferase; apa+ADT, apalutamide with ADT; Enza+ADT, enzalutamide with ADT; OLE, open-label extension; PBO+ADT, placebo with ADT.

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5.3. Results from the indirect comparisons

The full treatment network plot is presented in Figure 1. Where data were available the full network was used in the NMAs. However, due to a lack of trial data for some outcomes, it was necessary to use a smaller network with fewer trials. The EAG have referred to American Society of Clinical Oncology (ASCO) Cancer Research Committee guidance on defining clinically meaningful outcomes in their interpretation of the results.[1]

All the results summarised in the main report are based on assuming that treatments effects were fixed rather than random. It should be noted that it is impossible to estimate the variance of a random treatment effect (tau-squared) when fitting an NMA model if there are no closed loops in the treatment network graph and not more than one trial on each of the edges of the graph. In some analyses that were performed, this was the case, and for other analyses, there was one trial on two of the three edges of the graph and two trials on the remaining edge, which resulted in highly imprecise estimates of tau-squared due to there being only one degree of freedom available for its estimation.

The fact that tau-squared could not be precisely estimated, of course, does not mean that it is a variable that should not be taken into account when interpreting the results of the fixed effect NMAs that are about to be presented. Nevertheless, the models associated with these NMAs fitted the data adequately in most cases with no statistically significant departures from the assumption of no heterogeneity between trials in most cases.

The results of sensitivity analyses that supplement the results of the main network metaanalyses that follow are presented in Appendix F, along with additional information concerning these main analyses.

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Figure 1: Full network plot

==> picture [371 x 224] intentionally omitted <==

Abbreviations: ADT, ADT alone; EnzADT, enzalutamide with ADT; ApaADT, apalutamide with ADT; AbiADT, abiraterone with ADT.

Notes: ARCHES (EnzADT versus ADT), LATITUDE (AbiADT versus ADT), STAMPEDE (AbiADT versus ADT), TITAN (ApaADT versus ADT)

5.3.1. rPFS

5.3.1.1. Analysis of latest trial data up to a 40 month follow-up

The trials and patient sub-groups included in the analysis are presented below in Table 12. The NMA used the full network and, as previously mentioned in Section 5.2.1.1, the data were taken prior to treatment crossover in the OLEs. Three of the trials provided data in people with highrisk mHSPC with the fourth in people with mHSPC who had a tumour with a Gleason score of eight or more (a high-risk criterion). As noted in Table 6, the outcome for the STAMPEDE trial was PFS based on a clinical definition of this type of survival rather than rPFS, but the results of the two abiraterone trials were consistent.

The median follow-up in the trials varied quite widely and the EAG want to draw attention to the short median follow-up in ARCHES. It was 14.4 months, more than eight months shorter than TITAN, 16 months shorter than LATITUDE, and 25.1 months shorter than STAMPEDE. Kang et al. (2025) assessed the maturity of survival data used in economic models within NICE Single Technology Appraisals (STAs) published between 1st January 2011 to 31st December 2023 (n=301) and categorized survival data according to whether they were: ‘highly immature’ (<20%

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of events), ‘immature’ (20% - 50%) or ‘mature’ (>50%).[31] A conclusion of the paper was that the use of immature survival data is one of the main uncertainties and challenges in providing reliable cost-effectiveness evidence in cancer drug appraisals by the National Institute for Health and Care Excellence (NICE).

Most of the trial data were immature (less than fifty percent of people experiencing the event) but the data from ARCHES were highly immature with fewer than 20% having experienced the outcome in the enzalutamide with ADT arm. Given the immaturity of the ARCHES rPFS data, the EAG did not consider results of the NMA relating to enzalutamide with ADT to be robust to extrapolation over substantially longer time periods.

Table 12: Studies and populations included in the rPFS analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of an NMA analysis of rPFS are detailed in Table 13. The NMA demonstrated all three ARPIs with ADT had a statistically significant benefit over ADT alone. The comparisons of ARPIs found abiraterone with ADT to be similarly effective to apalutamide with ADT (HR: 0.97; 95% CrI: 0.73, 1.29). In contrast, the NMA found enzalutamide with ADT to have a numerical benefit over both abiraterone with ADT (HR: 0.73; 95% CrI: 0.51,1.03) and apalutamide with ADT (HR: 0.71; 95% CrI: 0.47, 1.06). The point estimates indicated a strong benefit for enzalutamide despite the credible intervals crossing the line of no effect. However, as noted above, given the high immaturity of the data taken from ARCHES, the EAG did not consider the results relating to enzalutamide with ADT to be robust and considers the results to be substantially more uncertain than indicated by the credible intervals when extrapolating to substantially longer time periods. In sum, given the parity of the NMA results for the abiraterone

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with ADT versus apalutamide with ADT comparison, the EAG concluded that both treatments had a similarity of effect for rPFS. In contrast, the results of the NMA did not find abiraterone versus enzalutamide to show a parity of effect, but given the immaturity of the data from the enzalutamide with ADT trial, the EAG considered the results of the NMA too uncertain to draw any conclusions on the similarity or dissimilarity of effect.

These results are broadly similar to the results for rPFS reported in recently published NMAs of the same treatment comparisons in similar patient subgroups that were identified by the systematic literature search described in Section 4. These previously published results can be found in Appendix G. Sensitivity analysis conducted in the mHSPC population found similar results to the primary analysis (Table 62).

Table 13: Estimates of HR for rPFS with 95% credible intervals

Statistical method: Fixed effect network meta-analysis under the assumption of proportional hazard functions. Cochran’s Q statistic for heterogeneity: 0.02 (p=0.90). Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide. Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.1.2. Analysis of latest trial data after unblinding

There were insufficient data to complete an NMA for rPFS at the longer timepoints. rPFS was not reported in the LATITUDE OLE, TITAN OLE or at 96 months in STAMPEDE.

5.3.2. OS

The EAG have referred to American Society of Clinical Oncology (ASCO) Cancer Research Committee guidance on defining clinically meaningful outcomes in their interpretation of the results.[1] The Cancer Research Committee selected OS as the primary clinical end point of interest and identified a hazard ratio of 0.8 or less corresponding to an improvement in median OS within a range of 2.5 to 6 months, as the minimum incremental improvement over standard

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therapy that would define a clinically meaningful outcome. The EAG have used a hazard ratio of 0.8 or less to delineate a minimum incremental improvement when interpreting OS in this report.

5.3.2.1. Analysis of latest trial data up to a 40-month follow-up

The trials and patient sub-groups included in the analysis are presented in Table 14. The NMA was based on the full network graph and the analysis used the latest trial data up to a 40-month follow-up. Two of the trials provided data for people with high-risk mHSPC, one for people with mHSPC who had a tumour with a Gleason score of eight or more (a high-risk criterion) and one for all people with mHSPC.

The median follow-up in the trials varied quite widely and the EAG again want to draw attention to the short median follow-up in ARCHES which was only 14.4 months. All of the trial data were immature (less than fifty percent of people experiencing the event) but the data from ARCHES were highly immature with fewer than 10% experiencing the outcome in the enzalutamide with ADT arm. Given the immaturity of the ARCHES rPFS data, the EAG did not consider results of the NMA relating to enzalutamide with ADT to be robust to extrapolation to follow-up periods of principal interest, i.e. two years or more.

Table 14: Studies and populations included in the OS analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of OS are detailed in Table 15. The NMA demonstrated that only abiraterone with ADT had a statistically significant benefit over ADT alone. In interpreting the point estimates using the ASCO guidelines[1] (5.3.2), abiraterone with ADT was found to be similarly effective to apalutamide with ADT (HR: 0.85; 95% CrI: 0.60, 1.22) and to have a clinically meaningful benefit over enzalutamide with ADT (HR: 0.77; 95% CrI: 0.49, 1.21). The EAG cautions that the 95% credible intervals crossed well over the line of no effect in both cases. However, as noted above, given the high immaturity of the data taken from ARCHES, the EAG did not consider the results relating to enzalutamide with ADT to be robust to

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extrapolation to periods of time that were longer than the median follow-up time of 14.4 months in the ARCHES trial.

In sum, interpretation of the point estimates using the ASCO guidelines[1] finds abiraterone with ADT to be similarly effect compared to apalutamide with ADT and to have a clinically meaningful benefit over enzalutamide with ADT. However, both point estimates crossed the line of no effect and the enzalutamide OS data from ARCHES was highly immature. Sensitivity analysis

conducted in the mHSPC population found similar results to the primary analysis (Table 67).

Table 15: Estimates of HR for OS with 95% credible intervals:

Statistical method: Fixed effect network meta-analysis under the assumption of proportional hazard functions. Cochran’s Q statistic for heterogeneity: 1.56 (p=0.21). Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.2.2. Analysis of latest trial data after unblinding

The trials and subgroups included in the analysis are presented in Table 16. The NMA was based on the full network graph and the analysis used the latest trial data after the trials became open-label. Two of the trials provided data for people with high-risk mHSPC, one for people with mHSPC who had a tumour with a Gleason score of eight or more (a high-risk criterion) and one for people with mHSPC. The median follow-up in all the trials was greater than 3.5 years and so there were fewer concerns about data maturity for this analysis. By this point, three trials permitted crossover from the comparator treatment to the intervention (Table 7):

• LATITUDE (abiraterone): 12.0%

• STAMPEDE (abiraterone): 0% (not permitted)

• ARCHES (enzalutamide): 31.3%

• TITAN (apalutamide): 39.5%

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The increased crossover in the enzalutamide and apalutamide biased the results in favour of abiraterone. However, it was not clear to the EAG how great an influence this had on the results of the NMA. The EAG noted that while there was no crossover in STAMPEDE and the results being from the wider mHSPC population, the OS trial results were very similar to LATITUDE: (STAMPEDE: HR: 0.62; 95% CrI: 0.53, 0.73; LATITUDE: HR: 0.66; 95% CrI: 0.56, 0.78).

Table 16: Studies and populations included in the OS analysis using latest trial data

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of OS using the latest trial data are detailed in Table 17. The NMA demonstrated all three ARPIs with ADT had a statistically significant benefit over ADT alone. While the point estimates indicated a very small benefit for the comparators, when using the interpretation of clinical efficacy in the ASCO guidelines[1] (Section 5.3.2), abiraterone with ADT was similarly effective to apalutamide with ADT (HR: 1.12; 95% CrI: 0.86, 1.46) and to enzalutamide with ADT (HR: 1.05; 95% CrI: 0.79, 1.38).

In sum, given the parity of the NMA results when comparing abiraterone with ADT, apalutamide with ADT and enzalutamide with ADT, the EAG concluded that these three ARPIs had a similarity of effect for OS. The EAG cautions that the 95% credible intervals crossed well over the line of no effect in all cases and, as noted above, a higher proportion of people in the apalutamide and enzalutamide comparator arms crossed over to the intervention in the OLE biasing the results in favour of abiraterone.

These results, and the results of the NMA outlined in Section 5.3.2.1 for analysis prior to crossover, are broadly similar to the results for OS reported in recently published NMAs of the same treatment comparisons in similar patient subgroups that were identified by the systematic literature search described in Section 4. These previously published results can be found in Appendix G. Sensitivity analysis conducted in the mHSPC population found similar results to the primary analysis (Table 70).

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Table 17: Estimates of HR for OS with 95% credible intervals:

Statistical method: Fixed effect network meta-analysis under the assumption of proportional hazard functions. Cochran’s Q statistic for heterogeneity: 0.28 (p=0.59). Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.3. HRQoL

5.3.3.1. Analysis of latest trial data up to a 40-month follow-up

The only health-related quality of life data that were published for the trials of interest and that could form the basis of a useful comparison between treatments were hazard ratios for the time to deterioration of quality of life (QoL) where the deterioration of QoL was defined as a decrease of ≥10 points in the total Functional Assessment of Cancer Therapy–Prostate (FACT-P) score from baseline. These data were only available for the LATITUDE and ARCHES trials. More specifically, the latest trial data up to a 40-month follow-up was used in this analysis.

Details about the trials and patient sub-groups concerned are presented below in Table 18. One of the trials provided data for people with high risk mHSPC and the other for all people with mHSPC. Again, the median follow-up for ARCHES was 14.4 months and for this reason, the EAG did not consider results of the NMA relating to enzalutamide with ADT to be robust to extrapolation to follow-up periods of principal interest, i.e. two years or more.

Table 18: Studies and populations included in the HRQoL analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; NR, not reported.

The results of the NMA analysis of time to deterioration are detailed in Table 19. The NMA demonstrated that neither abiraterone with ADT nor enzalutamide with ADT had a statistically

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significant benefit over ADT alone. The comparisons of ARPIs found abiraterone with ADT to have a similar effect on QoL to enzalutamide with ADT (HR: 0.89; 95% CrI: 0.71, 1.11).

In summary, given the parity of the NMA results when comparing abiraterone with ADT and enzalutamide with ADT, the EAG concluded that these two ARPIs would appear to have some similarity of effect on time to deterioration of QoL, but given the immaturity of the data from the enzalutamide with ADT trial, the EAG considered the results of the NMA too uncertain to draw any definite conclusions on the similarity or dissimilarity of effect for follow-up periods of principal interest, i.e. two years or more.

Table 17: Estimates of HR for time to deterioration of HRQoL with 95% credible intervals

Statistical method: Fixed effect network meta-analysis under the assumption of proportional hazard functions. Deterioration of QoL was defined as a decrease of ≥10 points in the total Functional Assessment of Cancer Therapy–Prostate score from baseline. Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.3.2. Analysis of latest trial data after unblinding

There were insufficient data to complete an NMA for HRQoL at the longer timepoints. It was not reported by any of the trials.

5.3.4. Grade 3 or 4 adverse events

5.3.4.1. Analysis of latest trial data up to a 40-month follow-up

The trials and subgroups included in the analysis are presented in Table 19. The NMA was based on the full network graph and the analysis used the latest trial data up to a 40-month follow-up. Data was provided for people with high-risk mHSPC in LATITUDE and the wider mHSPC population in the other three trials.

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Table 19: Studies and populations included in the Grade 3 or 4 adverse events analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of Grade 3 or 4 adverse events are detailed in Table 20. The NMA demonstrated that the use of abiraterone with ADT led to a statistically significant increase in Grade 3 or 4 adverse events compared to the use of ADT alone (OR: 1.81; 95% Crl: 1.57, 2.09), apalutamide with ADT (OR: 1.71; 95% Crl: 1.29, 2.27), and enzalutamide with ADT (OR: 1.95; 95% Crl: 1.44, 2.63). The results of the NMA led the EAG to conclude that the use of abiraterone with ADT causes more Grade 3 or 4 events than the use of either ADT alone, enzalutamide with ADT or apalutamide with ADT. Sensitivity analysis conducted in the mHSPC population found similar results to the primary analysis (Table 78).

Table 20: Estimates of OR for a Grade 3 or 4 adverse event with 95% credible intervals

Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 0.03 (p=0.8711) Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.4.2. Analysis of latest trial data after unblinding

The trials and subgroups included in the analysis are presented in Table 21. The NMA was based on the full network graph and the analysis used the latest trial data after the trials became open label. Data was provided for people with high-risk mHSPC in LATITUDE and all people with mHSPC in the three other trials.

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Table 21: Studies and populations included in the Grade 3 or 4 adverse events analysis using latest trial data

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of Grade 3 or 4 adverse events are detailed in Table 22. The NMA demonstrated that the use of any one of the three ARPIs with ADT led to a substantially greater number of grade 3 or 4 adverse events than the use of ADT alone and the differences concerned were statistically significant. The comparisons of ARPIs found abiraterone with ADT to cause a substantially greater number of Grade 3 or 4 adverse events than the use of

apalutamide with ADT and the difference concerned was statistically significant (OR: 1.48; 95% CrI: 1.10, 2.20). While no statistically significant difference was found in the number of Grade 3 or 4 adverse events between the use of abiraterone with ADT and the use of enzalutamide with ADT (OR: 1.22; 95% CrI: 0.90, 1.65) and between the use of enzalutamide with ADT and the use of apalutamide with ADT (OR: 1.22; 95% CrI: 0.86, 1.72), it was probable that abiraterone with ADT caused more Grade 3 or 4 adverse events than enzalutamide with ADT and that enzalutamide with ADT caused more Grade 3 or 4 adverse events than apalutamide with ADT.

In summary, the results of the NMA led the EAG to conclude that the use of abiraterone with ADT causes substantially more Grade 3 or 4 adverse events than the use of ADT alone and apalutamide with ADT and that it is probable that it causes more Grade 3 or 4 adverse events than the use of enzalutamide with ADT. Sensitivity analysis conducted in the mHSPC population found similar results to the primary analysis (Table 80).

Table 22: Estimates of OR for a Grade 3 or 4 adverse event with 95% credible intervals

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Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 0.25 (p=0.62) Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide.

Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.5. Fatigue

5.3.5.1. Analysis of latest trial data up to a 40-month follow-up

The trials and subgroups included in the analysis are presented in Table 23. The NMA was based on the full network graph and the analysis used the latest trial data up to a 40-month follow-up. Data was provided for people with high-risk mHSPC in LATITUDE and all people with mHSPC in the three other trials.

Table 23: Studies and populations included in the fatigue (all grades) analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns.

The results of the NMA analysis of any reported fatigue are detailed in Table 24. These results show that, compared to the use of ADT alone, the use of abiraterone with ADT led to a

statistically significant increase in fatigue. In comparison to the other ARPIs, abiraterone led to similar fatigue with the point estimates slightly favouring enzalutamide and apalutamide. However, the conference intervals were wide and the true relative effect was uncertain. Finally, it should be remarked that the results clearly demonstrate that the measurement of reported fatigue in the STAMPEDE trial was very different from the other three trials and that the degree of heterogeneity between the ORs for LATITUDE and STAMPEDE, i.e. the two trials that tested the use of abiraterone, was statistically significant (p=0.002).

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In sum, the results of the NMA led the EAG to conclude that the lack of data and the doubtful quality of available data means that it is difficult to draw any definite conclusions about whether the use of abiraterone with ADT leads to a similar or dissimilar frequency of reported fatigue to the use of ADT alone, enzalutamide with ADT and apalutamide with ADT.

Sensitivity analysis conducted in the mHSPC population (excluding LATITUDE) found quite different results compared to the primary analysis (Table 85). This was due to the measurement of reported fatigue in the STAMPEDE trial was very different from the other three trials and the analysis without LATITUDE meant the abiraterone data came purely from STAMPEDE. The heterogenous results between the main analysis and sensitivity analysis support the EAG’s reasoning that it is difficult to draw any definite conclusions from these data.

Table 24: Estimates of OR for fatigue (all grades) with 95% credible intervals

Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 9.27 (p=0.002) Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide Note: The comparison is the row-forming treatment against the column-forming treatment.

5.3.5.2. Analysis of latest trial data after unblinding

The trials and patient sub-groups included in the analysis are presented in Table 25. The NMA was based on the full network graph and the analysis used the latest trial data after the trials became open label. Data was provided for people with high-risk mHSPC in LATITUDE and all people with mHSPC in the three other trials.

Table 25: Studies and populations included in the fatigue (all grades) analysis using latest trial data

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Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of any reported fatigue are detailed in Table 26. The NMA demonstrated that the use of either abiraterone with ADT or enzalutamide with ADT leads to a statistically significant increase in the incidence of reported fatigue compared to the use of ADT alone. However, while the use of apalutamide with ADT led to a numerical increase in the incidence of reported fatigue compared to the use of ADT alone. In the comparison of ARPIs use of abiraterone with ADT led to a numerical reduction in fatigue versus enzalutamide with ADT. Fatigue was similar between abiraterone and apalutamide, the point estimated favoured apalutamide but the credible intervals were wide. Finally, it should again be remarked that the results clearly demonstrated that the measurement of reported fatigue in the STAMPEDE trial was very different from the other three trials and that the degree of heterogeneity between the ORs for LATITUDE and STAMPEDE, i.e. the two trials that tested the use of abiraterone, was again statistically significant (p=0.001).

In summary, although the results of the NMA appear to indicate that the use of abiraterone may lead to a lower incidence of reported fatigue compared to the use of enzalutamide, the EAG concluded that the lack of data and the doubtful quality of available data means that it is difficult to draw any definite conclusions about whether the use of abiraterone with ADT leads to a similar or dissimilar incidence of reported fatigue to either the use of enzalutamide with ADT or the use of apalutamide with ADT.

Sensitivity analysis conducted in the mHSPC population (excluding LATITUDE) found some differences in the results compared to the primary analysis (Table 87). This was due to the measurement of reported fatigue in the STAMPEDE trial was very different from the other three trials and the analysis without LATITUDE meant the abiraterone data came purely from STAMPEDE. The heterogenous results between the main analysis and sensitivity analysis support the EAG’s reasoning that it is difficult to draw any definite conclusions from these data.

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Table 26: Estimates of OR for fatigue (all grades) with 95% credible intervals

Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 10.70 (p=0.001)

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide

Note: The comparison is the row-forming treatment against the column-forming treatment.

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5.3.6. Grade ≥ 3 Hypertension

5.3.6.1. Analysis of latest trial data up to a 40-month follow-up

The trials and subgroups included in the analysis are presented in Table 27. The NMA was based on the full network graph and the analysis used the latest trial data up to a 40-month follow-up. Data was provided for people with high-risk mHSPC in LATITUDE and all people with mHSPC in the three other trials.

Table 27: Studies and populations included in the Grade ≥ 3 Hypertension analysis up to 40 months

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of Grade ≥ 3 hypertension events are detailed in Table 28. The NMA demonstrated that the use of abiraterone with ADT leads to a substantial increase in the number of Grade ≥ 3 hypertension events compared to the use of ADT alone and the difference concerned was statistically significant (OR: 2.60; 95% CrI: 1.94, 3.49).

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The comparisons of ARPIs found abiraterone with ADT to cause a substantially greater number of Grade ≥ 3 hypertension events than the use of apalutamide with ADT and the difference concerned was statistically significant (OR: 2.84; 95% CrI: 1.70, 4.79). On the other hand, the difference in the number of Grade ≥ 3 hypertension events between using abiraterone with ADT and enzalutamide with ADT was not statistically significant and the corresponding 95% credible interval was too wide to draw any definite conclusions about the relative effect of the two ARPIs concerned on the incidence of these events (OR: 1.30; 95% CrI: 0.55, 2.97).

In summary, the results of the NMA led the EAG to conclude that the use of abiraterone with ADT causes a substantially greater number of Grade ≥ 3 hypertension events than the use of apalutamide with ADT but the lack of data meant that it was not possible to draw any definite conclusions about whether there is similarity or dissimilarity in the incidence of Grade ≥ 3

hypertension events between using abiraterone with ADT and using enzalutamide with ADT. Sensitivity analysis conducted in the mHSPC population found similar results to the primary analysis (Table 93).

Table 28: Estimates of OR for grade ≥ 3 hypertension with 95% credible intervals

Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 1.32 (p=0.25) Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide

Note: The comparison is the row-forming treatment against the column-forming treatment.

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5.3.6.2. Analysis of latest trial data after unblinding

The trials and subgroups included in the analysis are presented in Table 29. For the trials included in this analysis, the latest trial data after the trials became open label was used. Since no new data on Grade ≥ 3 hypertension was published after the TITAN trial become open label and the data that was available for this adverse event corresponded to a median follow-up time of 22.7 months which was substantially lower than the median follow-up times for the data that was available for the other three trials after they became open label, this NMA did not include any data on Grade ≥ 3 hypertension from the TITAN trial.

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For the included trials, data was provided for people with high-risk mHSPC in LATITUDE and all people with mHSPC in the remaining two trials.

Table 29: Studies and populations included in the Grade ≥ 3 Hypertension analysis using latest trial data

Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide; GS, Gleason Score; mths, months; SC, some concerns

The results of the NMA analysis of Grade ≥ 3 hypertension events are detailed in Table 30. The NMA demonstrated that the use of either abiraterone with ADT or enzalutamide with ADT leads to a substantial increase in the number of Grade ≥ 3 hypertension events compared to the use of ADT alone and the differences concerned are statistically significant. The comparison of the use of abiraterone with ADT and the use of enzalutamide with ADT showed no difference in the impact of these treatments on the number of Grade ≥ 3 hypertension events, but the 95% credible interval concerned was too wide to draw any definite conclusions about this treatment comparison (OR: 1.00; 95% CrI: 0.47, 2.02).

In summary, the results of the NMA led the EAG to conclude that the lack of data meant that it was not possible to draw any definite conclusions about whether there is similarity or dissimilarity in the frequency of Grade ≥ 3 hypertension events between using abiraterone with ADT and using enzalutamide with ADT. Sensitivity analysis conducted in the mHSPC population found similar results but with substantially wider credible intervals in comparison to the primary analysis (Table 95).

Table 30: Estimates of OR for Grade ≥ 3 hypertension with 95% credible intervals

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Statistical method: Fixed effect network meta-analysis. Cochran’s Q statistic for heterogeneity: 2.36 (p=0.12) Abbreviations: ADT, Androgen deprivation therapy; Apa, Apalutamide; Abi, Abiraterone and prednisolone; Enz, Enzalutamide

Note: The comparison is the row-forming treatment against the column-forming treatment.

5.4. Conclusions on clinical equivalence

The objective of the clinical SLR conducted for this appraisal was to assess whether abiraterone with ADT is likely to provide similar or greater health benefits than technologies recommended in published NICE technology appraisal guidance for the same indication. The relevant population for this appraisal were people with high-risk mHSPC and the relevant comparators for were enzalutamide with ADT and apalutamide with ADT (Section 2.3).

An NMA was conducted using four RCTs linking each of the interventions via the common comparator ADT alone. The trials were each well conducted but variations in the trials led to concerns related to the risk of bias in the NMA. LATITUDE recruited the population of interest, people with high-risk mHSPC, but the other RCTs recruited more widely; STAMPEDE (HSPC), ARCHES (mHSPC), TITAN (mHSPC). Where possible subgroup analysis presented in the trials were used in the NMAs but in a number of cases this was not possible. In addition, LATITUDE, ARCHES, and TITAN were trials with open-label extensions (OLEs) and this led to large deviations from the intended interventions at the longer timepoints in the trials. The ARCHES trial was notable because its OLE began after a median 14.4 treatment leading to highly immature time to event data in the period before unmasking and treatment crossover. Also, a higher proportion of people in the comparator arms in ARCHES (enzalutamide; 31.3%) and TITAN (apalutamide; 39.5%) crossed over compared to LATITUDE (abiraterone; 12.0%) or STAMPEDE (abiraterone; 0%). Given the OLE structures of three of the RCTs it was appropriate to conduct NMAs prior to any treatment crossovers where data were often immature and at the latest timepoints after treatment crossover where data were more mature but at a high risk of bias.

It was only possible to conduct an NMA for rPFS at the randomised period, prior to any permitted treatment crossover. The NMA used high-risk mHSPC data from three trials, people with mHSPC and a Gleason score eight or more in the fourth. The NMA found abiraterone and apalutamide to be similarly effective but the outcome data for enzalutamide, from ARCHES, was too immature and consequently too uncertain to draw any conclusions on the similarity or dissimilarity of effect. However, recent research in Shore et al. (2025) analysed 31 RCTs in people with mHSPC (including ARCHES, LATITUDE, STAMPEDE, and TITAN) and found rPFS

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was a reliable surrogate for OS.[2] Therefore, given the strong evidence of similarity of effect between enzalutamide and abiraterone in OS, it is rational to assume a similarity of effect for rPFS given the absence of strong clinical evidence in either direction. The rPFS results in this report’s NMA was broadly similar to the results for rPFS reported in recently published NMAs of the same treatment comparisons in similar mHSPC subgroups (Appendix G).

NMAs were conducted for OS at the randomised period and at the final timepoint after people had been permitted to crossover from comparator to the intervention in the three OLEs. Both NMAs used high-risk mHSPC from two trials, people with mHSPC and a Gleason score eight, in one, and people with mHSPC in the fourth. The NMAs consistently found abiraterone to be noninferior to the comparators. The OS results were broadly similar to the results for OS reported in recently published NMAs of the same treatment comparisons in similar patient subgroups (Appendix G.).

The smaller HRQoL NMA, time to a decrease of 10 points in FACT-P score from baseline. This NMA used people with high-risk mHPSC from LATITUDE and people with mHSPC from ARCHES, and found no difference between the treatments.

NMAs were also undertaken for safety outcomes and these analyses used people with high-risk mHSPC from LATITUDE and people with mHSPC from the other trials. The NMAs found people on abiraterone had more Grade 3+ AEs than those treated with enzalutamide or apalutamide and more hypertension (Grade 3+) than those treated with apalutamide. It was not possible for the EAG to draw any conclusions related to fatigue (all grades).

In sum, differences between the trials led to NMAs caveated with noted uncertainties linked to immature data and large deviations from the intended interventions at the later timepoints. However, the analysis consistently found abiraterone provided similar or greater health benefits in terms of OS and, immature ARCHES data aside, rPFS. The NMAs did find treatment with abiraterone to result in a higher adverse events burden than enzalutamide or apalutamide. However, in the EAG’s clinical expert’s experience of using abiraterone in their practice, adverse events were treatable and did not commonly lead to treatment discontinuation.

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6. ECONOMIC EVIDENCE SEARCHES AND SELECTION

6.1. Evidence search strategy and study selection

Three targeted reviews were undertaken to identify relevant evidence to inform the appraisal of abiraterone and broader considerations given this is the first pilot of appraisal of a generic treatment where the originator product was not recommended. This three-pronged search rationale is fully described in the published protocol. No amendments to the planned search process were made.

Across all three searches, only English language publications were included, and only those studies in which the healthcare system setting was comparable to the NHS in England.

6.2. Search strategy for previous NICE submissions

Prior NICE appraisals of androgen receptor pathway inhibitors (ARPIs) were identified by iterative searches of the NICE website, using scoped intervention and comparator terms. All relevant articles from the “History” tab of the identified prior appraisals (including the committee papers, final appraisal documents, appraisal consultation documents, and expert submissions) were downloaded and evaluated by the project team.

6.3. Search strategy for previous economic evaluations

Details of the search approach for previous economic evaluations of abiraterone conducted since the NICE appraisal (published 18th August 2021), including lists of databases, search strategies and outcomes, can be found in Appendix A. Screening took place in Rayyan[12] and was performed using the inclusion and exclusion criteria described in the published protocol. A PRISMA diagram of the search and screen process for previous economic evaluations is provided in Figure, Appendix B.

6.4. Search strategy for literature related to assessment of biosimilars and generics

Details of the search approach for recent publications evaluating the cost-effectiveness of the introduction of biosimilars or generics into a clinical pathway, and the methods used for these types of evaluation, can be found in Appendix A. This search – in addition to database screening – also included the trawling of key HTA bodies’ websites to identify any relevant methods documentation. Screening took place in Rayyan[12] and was performed using the

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inclusion and exclusion criteria described in the published protocol. A PRISMA diagram of the search and screen process for previous economic evaluations is provided in Figure 8, Appendix B.

6.5. Included and excluded studies

None of the previous models identified addressed the NICE decision problem for this appraisal directly.

6.5.1. Review of previous NICE submissions

Four relevant previous NICE submissions were identified. The Excel files for the economic models were provided to the EAG by the NICE team.

• TA903: Darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer. Published 21 June 2023

• TA741: Apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer. Published 28 October 2021

• TA721: Abiraterone for treating newly diagnosed high risk metastatic hormone naïve prostate cancer. Published 18 August 2021, not recommended

• TA712: Enzalutamide for treating hormone-sensitive metastatic prostate cancer. Published 7 July 2021

None of the appraisals compared any of the treatments within scope for this appraisal. TA903 included enzalutamide as a comparator, apalutamide was removed from the final scope as a comparator as it was only recommended in patients not suitable for docetaxel.

6.5.2. Review of previous economic evaluations

There were 21 economic evaluations that met the inclusion criteria, plus the four previous TAs making a total of 25 publications included for the review. Of those, five were UK based (four previous TAs and Clarke et al, 2022[32] ; Table 31). Clarke et al was a 2022 cost utility analysis to evaluate the cost effectiveness of abiraterone in men initiating long-term ADT treatment for prostate cancer based on the STAMPEDE trial.

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Table 31: Number of evaluations by setting

Of the 25 evaluations included, 16 were cost-utility analyses, three were cost-effectiveness analyses, and the other six were a combination of systematic reviews, registry studies, resource utilisation studies and rapid evidence reviews. The majority of evaluations used the healthcare system payers perspective (21 out of 25).

From the UK setting, most of the cost and QALY information from the previous TAs was redacted. Clarke et al. (2022)[32] did report costs and QALYs for abiraterone and ADT monotherapy. The QALYs for abiraterone were 3.79 and the costs were £116,658 based on a daily cost of £94.69 using 2018 BNF prices.

Table 32 provides the evaluations that reported QALY outcomes as part of the evaluation results. 11 of the 25 evaluations reported QALYs for one or more of the interventions and comparators.

*********************************************************************************************************** ************************************************ .

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********.Sung 2021 and Wang 2022 were considered the most appropriate evaluations to inform the analysis of QALY outcomes. Both studies used lifetime models and included all of the clinical trials associated with the treatments included in the de novo NMA presented in this report (STAMPEDE, LATITUDE, TITAN). Both studies were conducted from a US perspective, appeared to be of reasonable quality, calibrated OS estimates to available observed data and were not sponsored by any of the involved manufacturers. The incremental QALYs for enzalutamide vs ADT in Sung 2021 was 2.85 (83%) and 0.54 (16%) in Wang 2022. ************ ********************************** ************************************************************************************************************ ************************************************************************************************************ *************************************************************The incremental QALYs for apalutamide vs ADT in Sung 2021 was 2.07 (61%) and 1.63 (48%) in Wang 2022. **************************** *********************************************************************************************************** *********************************************************************************************************** **************************************************** ************************************************************************************************************ ************************************************************************************************************ ********************************************************The incremental QALYs for abiraterone vs ADT in Sung 2021 was 1.98 (58%) and 1.38 (41%) in Wang 2022. **************************** *********************************************************************************************************** *********************************************************************************************************** .

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Table 32: QALY outcomes by treatment

Abbreviations: Abi, abiraterone; ADT, androgen deprivation therapy; Apa, apalutamide; Enza, enzalutamide; Doc, docetaxel; Dar, darolutamide; NR, not reported; QALYs, quality adjust life years; TA, technology appraisal

Note: cPAS marking indicates data taken from company models from previous appraisals

aNavqi 202434 is an abstract and does not define high and low volume disease. CHAARTED and GETUF-AFU 15 define high volume as the presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis Kyriakopoulos et al, 2018.[43]

Litvin 2025[38] and Naqvi 2024[34] stratified patients by their risk profile, either high or low risk in the mHSPC state and reported costs and QALYs by risk stratification.

The relevant costs for monitoring and adverse events that were extracted from the previous TAs and Clarke 2022[32] are presented in section 7.1.2.2 and section 7.1.2.3 respectively as cost parameters used to inform the cost-comparison model.

Table 33 provides a summary of evaluations which compared abiraterone with either apalutamide or enzalutamide. None of these were conducted from a UK perspective.

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Table 34 shows the range of incremental QALY gains in evaluations which compared abiraterone to apalutamide was -0.33 to 1.56. Studies were highly inconsistent as to which treatment was expected to demonstrate greater benefit. Table 35 shows the range of incremental QALY gains in evaluations which compared abiraterone to enzalutamide was 0.84 to -0.74. All studies except Barbier 2022[33] (a study by the Swiss Medical Board which uses nonstandard methods to estimate comparative effectiveness) and Wang 2022 predicted enzalutamide to be the more effective treatment.

Sung 2021 and Wang 2022 were considered the most appropriate evaluations to inform the QALY gain range required for apalutamide and enzalutamide in order for abiraterone to be no longer cost effective. The upper and lower bounds of the QALY gains required for apalutamide are 0.09 and 0.25. The QALY gains required for enzalutamide are 0 and 0.87.

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Table 33: Evaluations that analysed abiraterone, apalutamide and enzalutamide

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• Abbreviations: Abi, abiraterone; ADT, androgyn deprivation therapy; Apa, apalutamide; CRPC, castrate resistant prostate cancer; Doc, docetaxel; Daro, darolutamide; Enz, enzalutamide; mCRPC, metastatic castrate resistant prostate cancer; mCSPC, metastatic castrate sensitive prostate cancer; mHSPC, metastatic hormone sensitive prostate cancer; OS, overall survival; PFS, progression free survival

Latest trial data cuts have been noted using bold text in the table.

Notes: ENZAMET was not included in the EAG NMA as it could not be connected to the network without major assumptions the comparator was ADT + standard non-steroidal antiandrogen (bicalutamide, nilutamide or flutamide) and docetaxel was given as required during the trial. PEACE-1 was not included in the EAG NMA as it could not be connected to the network without major assumptions. Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m [2] once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone.

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Table 34: Incremental costs, QALYs and ICER for abiraterone vs apalutamide

Abbreviations: EUR, euro currency; ICER, incremental cost effectiveness ratio; INR, Indian rupee currency; QALYs, quality adjusted life years; USD, united states dollar currency

Table 35: Incremental costs, QALYs and ICER for abiraterone vs enzalutamide

Abbreviations: EUR, euro currency; ICER, incremental cost effectiveness ratio; INR, Indian rupee currency; QALYs, quality adjusted life years; USD, united states dollar currency

6.5.3. Review of literature related to assessment of biosimilars and generics

Available literature on the appraisal of generics or biosimilars for new indications in which the originator product was not recommended were sparse. This is likely in part due to a lack of commercial incentives for this type of analysis.[51]

The NICE manual 2022 specifies that NICE will do surveillance of guidance because of loss of marketing exclusivity when:

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the original guidance (including for technologies that are used in combination with other technologies) resulted in the technology being recommended (as an option) in specific circumstances (optimised use), recommended only in research context or not recommended

the biosimilars or generics of the technology are licensed for the same indication

the original economic model can be used for the purpose of the update and consent has been received from the originator company for the model to be used for this purpose.

The EAG is not aware of any instances of this.

The prior assessment conducted by the AWMSG for generic abiraterone was the most relevant study identified.[52] Only a budget impact assessment was conducted. Median treatment durations were compared naively from individual trials and the AWMSG concluded that on the basis of similarity (medians 33 – 40 months) all patients would have approximately 3 years of treatment. Clinical experts indicated 5-10% of patients receiving androgen-receptor targeted treatment would be eligible for abiraterone and based upon data from the Velindre Cancer Centre (which covers ~50% of the population in Wales) that in the absence of abiraterone 40% of patients would receive apalutamide and 60% would receive enzalutamide.

In Canada specific guidance was produced for the assessment of biosimilars in the context of biologics.[53] Canadian policy initial required a full CADTH assessment for biosimilar,[53,54] however, in later years this requirement was removed and instead companies moved straight to price negotiation. The process for this was unclear from the documentation.

In Scotland a full submission was originally required for indication(s)/populations where the reference product is not recommended by SMC/HIS.[55] Since March 2024 this has no longer been the case; not recommended advice for the originator now no longer applies once generic or biosimilar medicines become available and instead decisions are made on inclusion in local / regional formularies separately.

ICER guidelines provide similar guidance to NICE appraisals on accounting for cost variation for generics and biosimilars: their reference case is to use the median cost across all versions with sensitivity analysis using the lowest and highest price.[56] NICE guidelines specify use of the midpoint, lowest and highest prices with sensitivity and scenario analysis using the midpoint.[57]

As noted in Hughes 2019,[54] considerations for biosimilars differ somewhat to generics as generics can be shown to be identical to the reference drug whereas for biosimilars the

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manufacturer has to demonstrate that it is unlikely that differences in quality attributes would have an adverse effect on safety or efficacy. There are a small number of studies (such as NOR-SWITCH in Crohn’s disease which looked biosimilar vs originator infliximab[58] and the REOLA real-world study for follitropin alfa in fertility treatment[59] ) which suggest reduced effectiveness for patients using the biosimilar product. This may in part be attributable to the “nocebo” effect which occurs when there is a loss of effectiveness or presence of adverse events due to a patient’s negative expectations of the treatment.[60] However, Hughes’s exploration of the cost-effectiveness implications of the small reduction in effectiveness from the NOR-SWITCH study did, however, find this was unlikely to impact on cost-effectiveness conclusions (mean incremental costs -$46,194 vs mean incremental QALYs -0.13) which would be expected to be the case for the majority of biosimilars.

The models identified which looked at the introduction of a new biosimilar into a treatment pathway where the originator product was not recommended[61-63] or which investigated extension of the patient population[64] did not describe any preferred method to account for any potential differences in effectiveness between biosimilar and originator product.

One previous submission looking at biosimilar products in comparison to the originator did account for these types of differences, however, this was not technically within the scope of this review.[65]

The prior assessment conducted by the AWMSG for generic abiraterone was the most relevant study identified.[52]

A key issue with appraisal of biosimilars / generics outside of the current situation, as highlighted in Clarke et al. (2024)[66] and Cornes et al. (2022),[64] is the likelihood of increased coverage with these products compared to reference products. The likelihood of this and the impact of relevant comparators should be assessed on a disease-specific basis. In our case, based upon clinical expert input received, it is unlikely that a significant proportion of patients would not already be receiving treatment in addition to ADT.

Another key issue identified in Clarke et al. (2024)[66] is continuity of supply. Communication from Peter Johnson at NHS England indicated that they did not expect any supply issues for generic abiraterone as the volume of use is expected to be sufficient to make it economically viable.

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7. ECONOMIC EVALUATION

7.1. Economic evaluation

7.1.1. Evaluation structure

The primary economic evaluation was performed under a cost comparison framework which assumes similar or greater benefits for similar or lower costs (see Section 5.4). As the assumption of similar effectiveness was deemed to have some uncertainty we produced an assessment of the difference in quality-adjusted life-years (QALYs) that would be required to justify the increased cost of comparator treatments based upon £20,000 and £30,000 per QALY willingness to pay thresholds. This was then critiqued using available literature to determine the plausibility of difference in QALY gains.

The economic evaluation was conducted from the perspective of the NHS and PSS in England and Wales using a time horizon equal to the expected time on treatment of three years. This in line with the median time on treatment ranges from ARCHES-OLE (40.2 months), LATITUDEOLE (25.8 months), STAMPEDE mHSPC (33.2 months) and TITAN-OLE (39.3 months) (Table 10). A scenario analysis of a two year time horizon was conducted as this is in line with the median time on treatment in the high-risk population in LATITUDE.

In line with the underlying assumption of similar effectiveness a similar duration of treatment was assumed for all interventions.

The model had a 28-day cycle length (in line with the pack sizes for included treatments). Discounting was not included in line with NICE guidance for cost comparison submissions. When we explored the QALYs required to justify increased costs we included discounting, at a rate of 3.5%, for both costs and QALYs, in line with the NICE reference case.

Costs included were acquisition costs, treatment-specific monitoring costs and adverse event costs. Resource use linked to prostate cancer rather than to treatment-specific monitoring was not included because if the treatments are similarly effective this would be expected to be similar. Similarly, the cost of subsequent treatment was not included as it also would be expected to be similar.

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7.1.2. Resource use and cost parameters

7.1.2.1. Acquisition costs

Treatment costs (Table 36) were collected from the eMIT national database 2024[67] where available, where unavailable costs were collected from the BNF medicinal forms for the treatment.[68,69] Costs are presented at list price for all treatments. Costs including confidential price discounts are included in the cPAS appendix. ADT costs were not included in the analysis as they are expected to be equal across treatments. Dosage information was collected from the SmPC for each treatment. Data on relative dose intensity was available apalutamide from TITAN (mean 95.76%); ******************************************************************************** ******************************************************************************** . Given this an RDI of

100% was assumed for all treatments in the EAG base case and scenario analysis conducted assuming an RDI of 95% for all treatments to test the impact.

Table 36: Acquisition costs

*prednisone is no longer available in the UK

Abbreviations: BNF, British national formulary; eMIT, electronic market information tool; mg, milligrams; RDI, relative dose intensity; smPC, summary of product characteristics

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7.1.2.2. Monitoring and administration costs

The only difference in monitoring expected across treatments was the need for additional blood tests and associated oncology visits for abiraterone in the first 3 months of treatment. It was assumed that all 3 treatments require full blood counts and an oncology visit every 4 weeks after the first 3 months with people on abiraterone requiring these every 2 weeks for the first 3 months of treatment (Table 37). This was broadly in line with TA721, clinical expert input to the EAG and monitoring information from the abiraterone SmPC.[70] PSA and testosterone testing, liver and kidney function tests and CT scans were all assumed to be conducted at the same frequency for all 3 treatments and were therefore not included in the model base case.

Administration costs are not included in the analysis as abiraterone, enzalutamide, apalutamide and prednisolone are all taken as oral tablets.

To explore the impact of less frequent long-term monitoring, a scenario analysis was conducted in which the monitoring frequency for enzalutamide and apalutamide was reduced from every 4 weeks to every 6 weeks. This is consistent with the reduced frequency of monitoring assumed in the enzalutamide and apalutamide appraisals and the frequency assumed for enzalutamide in the mCRPC setting in TA721.

Table 37: Monitoring costs

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Abbreviations: EAG, External Assessment Group; NHS, National Health Service; PSSRU, Personal Social Services Research Unit; SmPC, summary of product characteristics; TA, technology appraisal

7.1.2.3. Adverse event costs

The annual rate of adverse events (Table 39) for abiraterone were calculated as a weighted average of the rates seen in STAMPEDE and LATITUDE-OLE clinical trial data relative to ADT monotherapy, converted to an annual rate. The annual rates for enzalutamide were converted to annual rates from the ARCHES-OLE clinical trial data relative to ADT monotherapy. For apalutamide, the rates for hypertension, hypokalaemia and ALT increase from TITAN relative to ADT monotherapy were calculated as annual rates. For skin rash the TITAN OLE rate was used and calculated as an annual rate. TITAN-OLE only reported skin rash as an adverse event and TITAN only reported hypertension, hypokalaemia, and ALT increase. The negative cost for enzalutamide is reflective of the reduction in the rate of musculoskeletal events in ARCHES between enzalutamide and ADT.

Musculoskeletal events were reported in ARCHES and STAMPEDE for enzalutamide and abiraterone respectively. In line with expert opinion and NICE TA951[76] (Olaparib with abiraterone for untreated hormone-relapsed metastatic prostate cancer), musculoskeletal

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