Single Technology Appraisal

Darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971]

Committee Papers

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971]

Contents:

The following documents are made available to stakeholders:

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

Pre-technical engagement documents

1. Company submission from Bayer: a. Full submission b. Summary of Information for Patients (SIP)

2. Clarification questions and company responses

3. Patient group, professional group, and NHS organisation submissions from: a. Prostate Cancer UK b. Tackle Prostate Cancer

4. External Assessment Report prepared by Southampton Health Technology Assessment Centre

5. External Assessment Report – factual accuracy check

Post-technical engagement documents

6. Technical engagement response from company

7. Technical engagement responses and statements from stakeholders:

• a. Prostate Cancer Research b. Prostate Cancer UK c. Tackle Prostate Cancer

8. External Assessment Group critique of company response to technical engagement prepared by Southampton Health Technology Assessment Centre

• 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

Single technology appraisal

Darolutamide with androgen deprivation therapy and docetaxel for treating hormonesensitive metastatic prostate cancer [ID3971]

Document B

Company evidence submission

September 2022

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Contents

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Tables

Table 1: The decision problem ................................................................................. 11 Table 2: Technology being evaluated ...................................................................... 14 Table 3: Clinical effectiveness evidence ................................................................... 25 Table 4: Summary of trial methodology for ARASENS............................................. 28 Table 5: Baseline characteristics of patients in ARASENS (FAS) ............................ 33 Table 6: Summary of statistical analysis for ARASENS ........................................... 36 Table 7: Summary of primary and secondary endpoint results in ARASENS (FAS) 41 Table 8: Overall survival (FAS) ................................................................................ 43 Table 9: Time to CROD summary (FAS) .................................................................. 45 Table 10: Implicated enzymes and interacting drugs for DDIs using Lexicomp and Micromedex compendia ........................................................................................... 55 Table 11: Overview of studies included in the systematic literature review .............. 59 Table 12: Detailed trial design of studies identified by clinical SLR and included in the base case NMA ........................................................................................................ 64 Table 13: Summary of studies identified by clinical SLR and included in the NMA .. 66 Table 14: Summary of similarities and differences of definitions used for base case PFS network ............................................................................................................. 69 Table 15: Summary of similarities and differences of definitions used for alternative PFS network ............................................................................................................. 70 Table 16: Data used in NMAs .................................................................................. 73 Table 17: NMAs conducted ...................................................................................... 77 Table 18: Relative effect of darolutamide+docetaxel+ADT compared to all treatment – OS 78 Table 19: Relative effect of darolutamide+docetaxel+ADT compared to all treatment – PFS base network ................................................................................................. 79 Table 20: Relative effect of darolutamide+docetaxel+ADT compared to all treatment – PFS alternative network ........................................................................................ 80 Table 21: Overview of TEAEs (SAS) ........................................................................ 83 Table 22: Incidences and exposure-adjusted incidence rates of the most common TEAEs by MedDRA PT occurring in ≥ 10% of patients in either treatment group (SAS) 87 Table 23: Incidence of worst Grade 3 or 4 TEAEs by MedDRA PT occurring in ≥ 1.5% of patients in either treatment group (SAS) ..................................................... 90 Table 24: Study drug and docetaxel-related TEAEs by MedDRA and worst CTCAE grade occurring in ≥ 5% of patients (SAS) ............................................................... 92 Table 25: Incidences and exposure-adjusted incidence rates of TEAEs of special interest associated with ADT or anti-androgens (SAS) ............................................ 95 Table 26: Summary list of published cost-effectiveness studies ............................ 104 Table 27: Previous NICE TAs ................................................................................ 107 Table 28: Features of the economic analysis ......................................................... 112 Table 29: Breakdown of ADT treatments used in the model .................................. 117 Table 30: AIC and BIC statistical fit statistics for docetaxel OS .............................. 120 Table 31: Comparison of docetaxel OS extrapolations and published data ........... 121 Table 32: OS estimates over time for all modelled treatments ............................... 122 Table 33: AIC and BIC statistical fit statistics for docetaxel TTCROD .................... 125 Table 34: Comparison of docetaxel TTCROD extrapolations and published data . 126 Table 35: TTCROD estimates over time for all modelled treatments ..................... 126 Table 36: AIC and BIC statistical fit statistics for darolutamide ToT ....................... 129 Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 4 of 201 RESTRICTED

Table 37: Comparison of darolutamide ToT extrapolations with ARASENS ToT and modelled darolutamide TTCROD data ................................................................... 129 Table 38: ToT estimates over time for all modelled treatments .............................. 130 Table 39: Health-related quality of life results for TAs identified by the SLR .......... 134 Table 40: mHSPC adverse event rates used in economic model .......................... 136 Table 41: mHRPC adverse event rates used in economic model .......................... 137 Table 42: mHSPC symptomatic skeletal event rates used in a scenario analysis versus docetaxel .................................................................................................... 138 Table 43: Adverse event disutilities ........................................................................ 139 Table 44: Symptomatic skeletal event disutilities ................................................... 139 Table 45: Health state utilities used in the model base case .................................. 140 Table 46: Drug acquisition costs ............................................................................ 141 Table 47: Treatment dosing schedules .................................................................. 142 Table 48: Treatment stopping rules ........................................................................ 144 Table 49: Drug administration costs ....................................................................... 145 Table 50: Resource use costs used in the model ................................................... 146 Table 51: Visits and testing frequencies included as HRU for patients receiving darolutamide+docetaxel+ADT or docetaxel+ADT in mHSPC ................................ 147 Table 52: Visits and testing frequencies included as HRU for patients receiving darolutamide+ADT (i.e. after the last cycle of docetaxel) in mHSPC ..................... 148 Table 53: Visits and testing frequencies included as HRU for patients receiving enzalutamide+ADT, and ADT alone in mHSPC in the model ................................. 148 Table 54: Visits and testing frequencies included as HRU for patients receiving docetaxel+ADT in mHRPC in the model while on treatment .................................. 149 Table 55: Visits and testing frequencies included as HRU for patients receiving enzalutamide+ADT, and ADT alone in mHRPC in the model ................................ 150 Table 56: Visits and testing frequencies included as HRU for patients receiving abiraterone+ADT in mHRPC in the model ............................................................. 150 Table 57: Visits and testing frequencies included as HRU for patients receiving cabazitaxel+ADT or radium-223+ADT in mHRPC in the model while on treatment 151 Table 58: Subsequent treatment distribution per received mHSPC treatment ....... 152 Table 59: Subsequent treatment durations and PFS used for the subsequent treatment calculations ............................................................................................ 152 Table 60: One-off lump-sum subsequent treatment and administration costs per mHSPC treatment, applied upon progression ........................................................ 153 Table 62: Subsequent treatment distribution from ARASENS ................................ 153 Table 63: TEAE-related unit costs .......................................................................... 156 Table 64: SSE-related unit costs ............................................................................ 157 Table 65: Summary features of QALY shortfall analysis ........................................ 158 Table 66: Summary of QALY shortfall analysis ...................................................... 158 Table 67: Summary of variables applied in the economic model ........................... 160 Table 68: Key model assumptions ......................................................................... 164 Table 69: Base case results ................................................................................... 166 Table 70: Probabilistic sensitivity analysis results: pairwise comparison................ 168 Table 71: Comparison of deterministic and probabilistic ICERs ............................. 168 Table 72: Top 10 most influential parameters for darolutamide+docetaxel+ADT versus docetaxel+ADT ........................................................................................... 173 Table 73: Top 10 most influential parameters for darolutamide+docetaxel+ADT versus enzalutamide+ADT ..................................................................................... 173

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Table 74: Top 10 most influential parameters for darolutamide+docetaxel+ADT versus ADT alone ................................................................................................... 174 Table 75: Scenarios explored in the cost-effectiveness model ............................... 176 Table 76: Deterministic scenario results versus docetaxel, ranked by difference in iNMB 177 Table 77: Probabilistic scenario results versus docetaxel, ranked by difference in iNMB 178 Table 78: Deterministic scenario results versus enzalutamide, ranked by difference in iNMB ................................................................................................................... 179 Table 79: Probabilistic scenario results versus enzalutamide, ranked by difference in iNMB 179 Table 80: Deterministic scenario results versus ADT, ranked by difference in iNMB 180 Table 81: Probabilistic scenario results versus ADT, ranked by difference in iNMB 181 Table 82: Comparison of median OS from the model to available docetaxel trial data 185 Table 83: Discounted LYG results of the current model compared to the results reported in TA741 .................................................................................................. 186

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Figures

Figure 1: Darolutamide mode of action .................................................................... 17 Figure 2: Stages of prostate cancer ......................................................................... 19 Figure 3: Clinical pathway of care for prostate cancer and proposed darolutamide plus docetaxel and ADT positioning ......................................................................... 23 Figure 4: Study scheme for ARASENS .................................................................... 27 Figure 5: Kaplan–Meier curves of overall survival (FAS) .......................................... 42 Figure 6: Kaplan–Meier curves of time to CRPC (FAS) ........................................... 44 Figure 7: Kaplan–Meier curves of time to CROD (FAS) ........................................... 46 Figure 8: Kaplan–Meier curves of time to pain progression (FAS) ........................... 47 Figure 9: Kaplan–Meier curves of SSE-FS (FAS) .................................................... 48 Figure 10: Kaplan–Meier curves for time to first SSE (FAS) .................................... 49 Figure 11: Kaplan–Meier curves of time to initiation of subsequent systemic antineoplastic therapy (FAS) .................................................................................... 50 Figure 12: Kaplan–Meier curves of time to worsening of disease-related physical symptoms (FAS) ...................................................................................................... 51 Figure 13: Kaplan–Meier curves of time to PSA progression according to PCWG3 (FAS) 53 Figure 14: pDDIs identified in nmCRPC patients ..................................................... 57 Figure 15: NMA network diagram ............................................................................. 75 Figure 16: Model structure ..................................................................................... 109 Figure 17: Docetaxel OS extrapolations using independent standard parametric models .................................................................................................................... 120 Figure 18: Docetaxel TTCROD extrapolations using independent standard parametric models .................................................................................................. 124 Figure 19: Darolutamide ToT extrapolations using independent standard parametric models .................................................................................................................... 128 Figure 20: ARASENS darolutamide + docetaxel + ADT post-progression survival stratified by post-progression treatment ................................................................. 155 Figure 21: ARASENS docetaxel + ADT post-progression survival stratified by postprogression treatment ............................................................................................ 155 Figure 22: Cost-effectiveness plane – darolutamide+docetaxel+ADT vs docetaxel+ADT ....................................................................................................... 169 Figure 23: Cost-effectiveness plane – darolutamide+docetaxel+ADT vs enzalutamide+ADT ................................................................................................. 169 Figure 24: Cost-effectiveness plane – darolutamide+docetaxel+ADT vs ADT alone 170 Figure 25: Cost-effectiveness acceptability curve .................................................. 171 Figure 26: Tornado plot of most influential parameters for darolutamide+docetaxel+ADT vs docetaxel+ADT .................................................. 174 Figure 27: Tornado plot of most influential parameters for darolutamide+docetaxel+ADT vs enzalutamide+ADT ............................................ 175 Figure 28: Tornado plot of most influential parameters for darolutamide+docetaxel+ADT vs ADT alone ......................................................... 175

Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 7 of 201 RESTRICTED

Abbreviations

Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 8 of 201 RESTRICTED

Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 9 of 201 RESTRICTED

B.1 Decision problem, description of the technology and clinical care pathway

B.1.1 Decision problem

This submission covers the technology’s full marketing authorization for this indication: ‘for the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel’. Further details are provided in the decision problem summary presented in Table 1.

Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971]

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Table 1: The decision problem

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RESTRICTED

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B.1.2 Description of the technology being appraised

A summary description of darolutamide is presented in Table 2.

The draft summary of product characteristics (SmPC) for the licence extension to the mHSPC patient population is presented in Appendix C. The UK Public Assessment Report (UKPAR) can be provided on receipt.

Darolutamide in combination with docetaxel and ADT offers the first multimodal, triplet combination therapy option for patients with mHSPC. Darolutamide is a structurally distinct non-steroidal androgen receptor (AR) inhibitor for the treatment of patients with prostate cancer. It binds with high affinity and selectivity to AR when compared to known second-generation anti-androgens.[1] Both darolutamide and its active metabolite inhibit testosterone-induced translocation of AR to the nucleus, decreasing the activation of genes required for the growth and survival of prostate cancer cells.[1, 2] Combining darolutamide with ADT and docetaxel gives a multimodal approach to the treatment of mHSPC: docetaxel targets the androgen-insensitive component of the tumour, thus addressing tumour heterogeneity; the AR axis is targeted centrally with ADT; and by adding darolutamide, a highly effective AR antagonist, targeting of the AR axis is optimized.

The mechanism of action of darolutamide is depicted in Figure 1.

Table 2: Technology being evaluated

Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 14 of 201 RESTRICTED

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Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 16 of 201 RESTRICTED

Figure 1: Darolutamide mode of action

==> picture [269 x 304] intentionally omitted <==

Key: AR, androgen receptor; ARE, androgen-response element; DHT, dihydrotestosterone; HSP, heat shock protein; P, phosphate; PSA, prostate-specific antigen. Source: Fizazi et al. 2018.[2]

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B.1.3 Health condition and position of the technology in the treatment pathway

B.1.3.1 Disease overview

Prostate cancer continues to be the most common cancer diagnosed in males in the UK; it accounted for 1 in 4 (26.3%) male cancer diagnoses in 2017.[6] Risk factors for prostate cancer include age (prostate cancer is most common in men aged 75-79 years), ethnicity (Black African males), a family history of prostate cancer and prostate-specific antigen (PSA) level.[7, 8]

The stages of prostate cancer are shown in Figure 2. In metastatic disease, prostate cancer progresses from the localized site and spreads to more distant parts of the body. The most common site for prostate cancer to spread to is the bones, followed by lymph nodes and viscera (e.g. lung and liver). Patients with metastatic hormonesensitive prostate cancer (mHSPC) have either not previously received hormone therapy (hormone-naïve), are continuing to respond to hormone therapy, have de novo or synchronous disease, or have metastases after local treatment such as radiotherapy and/or surgery (metachronous).[9, 10] Most patients with mHSPC will develop metastatic hormone-relapsed prostate cancer (mHRPC), defined as disease progression, despite treatment to achieve castrate testosterone levels.[9, 11] This disease state is associated with deterioration in HRQL and poor survival varying from 9 to 30 months.[12] Hormone-relapsed prostate cancer (HRPC) is often used interchangeably with castration-resistant prostate cancer (CRPC).

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Figure 2: Stages of prostate cancer

==> picture [459 x 148] intentionally omitted <==

Key: mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer. Source: Ng et al. 2020.[9]

Between 2018 and 2020, 13% of prostate cancer patients were diagnosed with metastatic disease in England.[13, 14] In a study of 1,643 patients in the UK with localized prostate cancer, 3.8% (n = 62) developed metastases within 10 years of follow-up.[15] In England, there are estimated to be 7,400 patients diagnosed with mHSPC each year (see budget impact analysis for details of calculation).

Factors associated with poor prognosis in mHSPC patients include a Gleason score ≥ 8, the presence of measurable visceral metastases and ≥ 3 bone metastases.[16] The Gleason score is a common prostate cancer grading system based on the microscopic appearance of cancer cell; the score ranges between 6–10, with higher scores indicating more aggressive disease.

B.1.3.2 Clinical outcomes

The overall median five-year survival rate is 87% for patients with prostate cancer, but when diagnosed at a metastatic stage the five-year survival rate drops to 49%[17] The reduced survival is predominantly due to the progression of mHSPC to mCRPC, highlighting the importance of treatments that prevent progression to mCRPC.[18]

Historically ADT alone was the standard of care (SoC) for mHSPC to achieve castrate levels of testosterone using surgery (e.g. orchiectomy) or medical therapies (e.g. luteinizing hormone releasing hormone [LHRH] agonists/antagonists). However, within approximately 12 months of developing mHSPC, most patients progress

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towards mCRPC on ADT alone.[19-21] The prognosis of mHSPC patients treated with ADT alone has been shown to be dependent on whether the disease is de novo or recurrent; median overall survival (OS) is worse for de-novo versus recurrent mHSPC patients, with de-novo high volume disease patients having the worst OS (5year OS-free: 37%; median OS: 43.2 months) compared to recurrent high volume disease (5-year OS-free: 42%; median OS: 55.2 months).[22]

Adding docetaxel chemotherapy to ADT showed improved outcomes in mHSPC patients, with median OS increasing by approximately 5–14 months compared to ADT alone.[19, 21, 23] However, the majority of patients still progress to mCRPC on docetaxel and ADT; in the CHAARTED long-term study (median follow-up: 53.7 months), 64.7% (n = 257/397) of patients developed mCRPC, with a median time to mCRPC of 19.4 months.[24] A real-world study showed worse progression outcomes, where 82% of patients receiving docetaxel and ADT developed mCRPC over the study duration (median follow-up: 42 months), with a median time to mCRPC of 15.6 months.[25] Of note, this study population was slightly older, had higher PSA at baseline, higher Gleason scores and higher metastatic burden compared to patients in CHAARTED.

Androgen receptor-targeted agents such enzalutamide can also be used in combination with ADT to treat mHSPC. In the ARCHES study, enzalutamide and ADT extended the median radiographic progression-free survival (PFS) by approximately 11 months and reduced the risk of death by 34% compared to placebo and ADT (median OS not reached in either group after a median follow-up of 44.6 months).[26] However, there is no head-to-head data comparing enzalutamide and ADT to docetaxel and ADT.

B.1.3.3 Burden of disease

In patients with metastatic disease, health-related quality of life (HRQL) scores were found to be clinically and statistically significantly lower than in those with localized disease.[27] Both fatigue and pain were found to be the most important factors associated with poor HRQL.[27] The most commonly reported symptoms in metastatic prostate cancer patients include fatigue, urinary symptoms, sexual dysfunction symptoms and bone pain[28] , all of which negatively impact the patients’ HRQL.

Patients reported the most challenging aspect of dealing with advanced prostate Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 20 of 201 RESTRICTED

cancer was the decreasing ability to maintain their lifestyle, while caregivers recognized pain management and the emotional impact on the patient’s family as the most prominent challenges faced by the patient.[28]

Delaying progression to mCRPC is critical as this disease state is associated with deterioration in HRQL and poorer prognosis.[12] HRQL and well-being are impacted in both mHSPC and mCRPC patients, however, mCRPC patients reported the lowest HRQL scores and highest pain scores.[29] In both disease areas, there is a considerable time burden on caregivers with the majority of care provided by spouses/partners. mCRPC patients with bone metastases are at high risk of skeletalrelated events (SREs), including pathological fracture and spinal cord compression, which significantly decrease HRQL.[30]

The consequential psychological burden of inevitable progression to mCRPC is high. Fear of cancer recurrence and PSA anxiety are prominent symptoms for prostate cancer patients; they are associated with poorer quality of life and mental health symptoms such as depression and generalized anxiety.[31] Although the burden of disease for patients with mHSPC is high, it is significantly worse for patients with mCRPC, highlighting the need for treatments that prevent progression to mCRPC without further impacting their HRQL.

B.1.3.4 Clinical pathway of care

The clinical pathway of care for prostate cancer is depicted in Figure 3.

In NHS England, treatment options for mHSPC include ADT alone (LHRH agonists/antagonists [including leuprorelin, goserelin, triptorelin, buserelin and degarelix] or orchidectomy), docetaxel plus ADT (with or without prednisolone), enzalutamide plus ADT and apalutamide plus ADT if docetaxel is not suitable.[32-34] Apalutamide plus ADT is not a relevant comparator for this appraisal, as patients unable to receive docetaxel would be unable to receive darolutamide in combination with docetaxel and ADT. Although the use of docetaxel plus ADT in the hormonenaïve and hormone-sensitive setting was considered an off-label use when the NICE guideline was developed,[32, 33, 35] the SmPC for docetaxel was expanded in November 2019 to include docetaxel plus ADT (with or without prednisone or prednisolone) for the treatment of patients with mHSPC.[36] Clinicians confirmed the

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clinical pathway (Figure 3) and the use of docetaxel plus ADT in current NHS England practice.[37]

If patients progressed to mCRPC while on treatment with a novel androgen receptor targeted agent (ARTA; i.e. darolutamide, apalutamide, enzalutamide or abiraterone) it would be expected that the metastatic cancer would be resistant to treatment with another ARTA due to their similar mechanisms of action.[34] Therefore, novel hormonal agents can only be used once in the treatment pathway for prostate cancer.[38, 39]

Other clinical guidelines for the management of metastatic prostate cancer are available from the European Society for Medical Oncology (ESMO) and the European Association of Urology (EAU).[40, 41] In general, these guidelines are consistent with the NICE guidelines for metastatic prostate cancer. However, they also recommend abiraterone with prednisone plus ADT for hormone-naïve and firstline treatment of metastatic disease. In August 2021, abiraterone with prednisone or prednisolone plus ADT was not recommended by NICE for treating newly diagnosed high-risk mHSPC.[42]

Darolutamide in combination with docetaxel and ADT offers the first licensed triplet combination therapy option for patients with mHSPC in NHS, as depicted in Figure 3. As discussed in Section B.1.2, targeting both androgen receptor-dependent and independent mechanisms at initiation of therapy provides an opportunity to prolong survival and delay disease progression without further deterioration in HRQL beyond docetaxel plus ADT. There is a strong recommendation to offer early systemic treatment to metastatic prostate cancer patients in the EAU guidlines[41] , which supports adding darolutamide plus docetaxel and ADT early in the treatment pathway.

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Figure 3: Clinical pathway of care for prostate cancer and proposed

darolutamide plus docetaxel and ADT positioning

==> picture [484 x 230] intentionally omitted <==

Key: ADT, androgen deprivation therapy.

Notes:[a] Recommended only if docetaxel is not suitable;[b] only if a novel anti-hormonal agent (i.e. darolutamide, enzalutamide, apalutamide or abiraterone) has not been used before;[c] only if patients have already had docetaxel, or if docetaxel is contraindicated or is not suitable. Green refers to the proposed positioning of darolutamide plus docetaxel and ADT.

Source: Adapted from NICE prostate cancer: diagnosis and management (NG131)[32] ; NHS England commissioning policy statement for docetaxel[33] ; BNF treatment summary for prostate cancer.[34]

B.1.3.5 Unmet need

Novel treatment approaches are needed to improve disease control, improve survival and delay progression to mCRPC, which is associated with debilitating symptoms, deterioration in HRQL and poorer prognosis. Approximately 10% to 20% of prostate cancer patients develop CRPC within 5 years and have a poor median survival expectancy of 9 to 30 months.[12] Treatment with docetaxel plus ADT

improved survival of mHSPC patients, however, the majority of patients still progress to mCRPC within approximately 20 months.[24, 25]

Newer alternative treatments include AR inhibitors such as enzalutamide. However, enzalutamide has more potential drug-drug interactions (pDDIs) than darolutamide[37, ] 43 (Section B.2.6.4.1), which may result in sub-optimal treatment of comorbidities while being treated with enzalutamide for mHSPC. This may impact the proportion of patients that are able to successfully receive enzalutamide. Additionally, there is a lack of robust evidence of how enzalutamide performs against docetaxel plus ADT

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as there is no head-to-head data directly comparing them. Enzalutamide is not licensed in a triplet combination that would address an early treatment intensification strategy.

A novel treatment approach for mHSPC is required to address this unmet need and delay progression to mHSPC. Treatment approaches that decrease PSA through early treatment intensification and subsequently reduce PSA-related anxiety are also needed. ARASENS demonstrated that the addition of darolutamide to docetaxel and ADT significantly increases OS, significantly increases the time to progression to mCRPC and almost halves the proportion of patients who progressed to mCRPC within 44 months of follow-up (Section B.2.6).[44] This was a large and robust study that compared the treatment against placebo in combination with docetaxel and ADT which is a standard of care comparator more active than other comparators typically used in other mHPSC trials. These superior efficacy results, combined with the acceptable safety (Section B.2.10) and favourable pDDI (Section B.2.6.4.1) profiles, support a positive benefit-risk profile of this first licensed triple combination therapy for patients with mHSPC, and reinforce its use early on in this aggressive metastatic pathway.

B.1.4 Equality considerations

Prostate cancer is more common in Black African men than white men.[7] The introduction of darolutamide plus docetaxel and ADT provides an alternative and more effective treatment option which will support all men with mHSPC.

B.2 Clinical effectiveness

B.2.1 Identification and selection of relevant studies

A systematic literature review (SLR) was conducted to identify all existing evidence assessing the efficacy, safety and tolerability of approved and upcoming treatments of mHSPC. See Appendix D for full details of the process and methods used to identify and select the clinical evidence relevant to the technology being evaluated.

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B.2.2 List of relevant clinical effectiveness evidence

Table 3 summarizes the clinical effectiveness evidence supporting darolutamide in addition to standard docetaxel and ADT for the treatment of patients with mHSPC.

Table 3: Clinical effectiveness evidence

The study reported by Appukkuttan et al. 2021[43] which investigated the pDDIs of

darolutamide, apalutamide and enzalutamide was not used to populate the economic

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model but the results are included in Section B.2.6.4.1. The results of this study support the reduced pDDIs of darolutamide in comparison to apalutamide and enzalutamide. This study was not included in the economic model because the relationship between pDDIs, patient HRQL and costs to the NHS is uncertain and there is no precedence of modelling pDDIs in past prostate cancer appraisals.

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B.2.3 Summary of methodology of the relevant clinical effectiveness evidence

Table 4 provides a summary of the trial methodology for ARASENS.

ARASENS is a Phase III international randomized double-blind placebo-controlled trial that evaluates the efficacy and safety of darolutamide in combination with docetaxel and ADT (hereafter termed darolutamide+docetaxel ) in comparison with placebo in combination with docetaxel and ADT (hereafter termed

placebo+docetaxel ) in patients with mHSPC.[44, 45] The study was conducted in 286 centres in 23 countries, including North America, Asia-Pacific, Europe, Australia, Brazil, Israel and Mexico. In total, 29 patients were randomized across eight trial centres in the UK.

Patients were randomized in a 1:1 ratio to receive one of the study drugs (darolutamide or placebo): darolutamide 600 mg (2 tablets of 300 mg) taken twice daily with food (equal to a total daily dose of 1,200 mg), or placebo that matched darolutamide tablets in appearance taken twice daily with food.[44, 45] Randomization was performed in a double-blind fashion and a randomization number was assigned through the Interactive Voice/Web Response System (IxRS) based on information supplied by the investigator at the time of randomization. All patients were required to receive treatment with ADT of the investigator’s choice as standard therapy before randomization. Six cycles of docetaxel were planned to be administered after randomization, with the first cycle to be administered within six weeks after the start of the study drug. Patients continued to receive darolutamide or placebo (treatment period) and were evaluated every 12 weeks until symptomatic disease progression, a change in antineoplastic therapy, unacceptable toxic effects, patient or physician decision, death or nonadherence. After treatment discontinuation, patients entered the active follow-up period where assessments were performed approximately every 12 weeks for up to one year. Patients then entered the long-term (survival) follow-up period until the end of the study (Figure 4).

Patients were stratified at randomization by extent of disease (non-regional lymph nodes metastases only equivalent to TNM M1a; bone metastases with or without lymph node metastases equivalent to TNM M1b; and visceral metastases with or

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without lymph node metastases or with or without bone metastases equivalent to TNM M1c) and alkaline phosphatase (ALP) level (ALP < upper limit of normal [ULN] and ALP ≥ ULN).[46] The dose of study drug could be interrupted or reduced to manage clinically significant toxicities. If a dose of the study drug was delayed/missed, the dose could be taken up to 6 hours later. Any discrepancies between actual and expected amount of returned study medication was discussed with the patient at the time of the visit and any explanation documented.

The primary endpoint of the ARASENS trial was OS, defined as the time from the date of randomization until death from any cause.[44] Secondary endpoints included time to CRPC, time to pain progression, symptomatic skeletal event-free survival (SSE-FS), time to first symptomatic skeletal event (SSE), time to initiation of subsequent systemic antineoplastic therapy, time to worsening or disease-related physical symptoms and time to initiation of opioid use for ≥ 7 consecutive days. Exploratory endpoints included time to PSA progression and HRQL measured by the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Prostate Symptom Index (NCCN-FACT-FPSI-17) and Brief Pain Inventory – Short Form (BPI-SF) questionnaires. See Table 4 for details and definitions of study endpoints.

Figure 4: Study scheme for ARASENS

==> picture [494 x 179] intentionally omitted <==

Key: ADT, androgen deprivation therapy; LHRH, luteinizing hormone releasing hormone; SAE, serious adverse event; SSE, symptomatic skeletal event. Notes:[a] The following assessments were performed approximately every 12 weeks for up to one year: HRQL, pain assessment, analgesic consumption, survival status, subsequent antineoplastic treatments for prostate cancer, SSEs and study drug–related SAEs;[b] the following assessments were

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performed approximately every 12 weeks: antineoplastic treatments for prostate cancer, study drug– related SAEs and survival status. Source: ARASENS clinical study protocol.[46]

Table 4: Summary of trial methodology for ARASENS

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B.2.3.1 Summary of clinical validation

A clinical advisory board was conducted with nine clinical oncologists from hospitals across the UK managed by the NHS Foundation Trust. The agenda for the session was structured around discussion sessions and presentations of clinical data that were targeted to address questions regarding the health technology assessment (HTA) of darolutamide in combination with docetaxel and ADT in mHSPC. The advisors were posed a number of questions related to UK clinical practice and the generalizability of ARASENS data and asked to formulate a consensus response. The advisors were aware that their names and anonymised responses would be utilized as part of this submission.

B.2.3.2 Baseline characteristics

Table 5 provides a summary of baseline characteristics, including demographics and clinical characteristics.

The characteristics of the patients at baseline were generally well-balanced between the treatment groups.[45] The median age was 67 years in both treatment groups. The majority of patients in both treatment groups (darolutamide+docetaxel versus placebo+docetaxel) presented with bone metastases with or without lymph node metastases (79.4% versus 79.5%), had Stage IV metastatic disease at initial diagnosis (85.7% versus 86.5%) and a Gleason score of ≥ 8 (77.6% versus 78.9%).

Table 5: Baseline characteristics of patients in ARASENS (FAS)

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B.2.4 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence

Table 6 provides a summary of the statistical analysis for ARASENS.

The ARASENS study was designed to investigate whether the combination of darolutamide with docetaxel and ADT improves the OS in patients with mHSPC.[44] Approximately 1,300 patients were planned to be randomized to achieve 90% power and to detect a 25% decrease in risk of death with darolutamide compared with placebo with a one-sided test with a Type I error of 0.025. The primary analysis was performed when the targeted number of OS events, approximately 509 deaths, was reached. This submission presents data from the primary analysis of OS with a data cut-off date of 25 October 2021. This constitutes the final analysis of efficacy. The full analysis set (FAS) was used for the primary efficacy analysis, which includes all patients who were randomized.

The secondary efficacy endpoints were tested with a hierarchical gatekeeping procedure; if the prior endpoint in the hierarchy was significant, then the next

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endpoint in the order was tested for significance.[44] The hierarchical order was as follows: time to CRPC; time to pain progression; symptomatic skeletal event-free survival (SSE-FS); time to first symptomatic skeletal event (SSE); time to initiation of subsequent systemic antineoplastic therapy; time to worsening of disease-related physical symptoms; time to initiation of opioid use for ≥ 7 consecutive days. An algorithm included in the statistical analysis plan (SAP) was to be used to impute partial or missing event dates.

Table 6: Summary of statistical analysis for ARASENS

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Time to initiation of subsequent antineoplastic therapy: patients with no subsequent antineoplastic therapy before or at data cut-off date were censored to the date of last known alive date, date of death or randomization date (censored at Day 1 if there was no follow-up available), whichever was later.

Time to worsening of disease-related physical symptoms: patients with no baseline or post-baseline event assessment were censored to the date of randomization (censored at Day 1 if there no follow-up was available). Patients with no worsening of disease-related physical symptoms before or at the data cut-off date were censored to the date of last assessment or randomization date (censored to Day 1 if no follow-up was available), whichever was later.

Time to initiation of opioid use for ≥ 7 consecutive days: patients with no opioid use for ≥ 7 consecutive days before or at data cut-off date were censored to the date of last visit at which analgesic consumption question was collected or randomization date (censored at Day 1 if no follow-up was available), whichever was later. Patients who used opioids for ≥ 7 consecutive days at or before randomization date were censored to the date of randomization (Day 1).

Time to PSA progression: patients with no baseline or post-baseline event assessment were censored to the date of randomization (censored at Day 1 if no follow-up was available). Patients with PSA progression even immediately after two or more consecutive missing assessments were censored to the date of the last PSA assessment before the consecutive missed ones. Patients without PSA progression before or of data cut-off were censored at the last PSA assessment before discontinuation or randomization date (censored at Day 1 if no follow-up was available), whichever was later.

Key: BPS-SF, Brief Pain Inventory – Short Form; CI, confidence interval; CRPC, castration-resistant prostate cancer; eCRF; electronic case report form; ePRO, electronic patient-reported outcome; FAS, full analysis set; GCP, good clinical practice; HR, hazard ratio; HRPC, hormone-relapsed prostate cancer; IxRS, Interactive Voice/Web Response System; OS, overall survival; PSA, prostate-specific antigen; SAS, safety analysis set; SSE, symptomatic skeletal event; SSE-FS, symptomatic skeletal event-free survival. Source: ARASENS CSR[44] and ARASENS SAP.[47]

B.2.4.1 Patient disposition data

A total of 1,686 patients were enrolled in the study between November 2016 (first patient first visit) and June 2018 (last patient first visit), of which 1,306 were randomly assigned in a 1:1 ratio to the study drug.[45] One patient was excluded from the analysis due to a GCP violation, leaving 651 patients in the

darolutamide+docetaxel group and 654 patients in the placebo+docetaxel group.

Of the randomized patients, 100.0% in the darolutamide+docetaxel group and 99.5% in the placebo+docetaxel group received at least one dose of the study drug.[45] In total, three patients were randomized but were never administered study drug; all of

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these patients were in the placebo+docetaxel group. Two of these patients were withdrawn from the treatment period at the investigator’s discretion without receiving study drug, entered follow-up, and received docetaxel as subsequent antineoplastic therapy during follow-up. One patient did not receive study drug and did not receive docetaxel; this patient was withdrawn from treatment per patient decision.

At the time of the database cut-off (25 October 2021), 45.9% of patients in the darolutamide+docetaxel group and 19.1% in the placebo+docetaxel group were ongoing with study treatment.[45] A smaller percentage of patients had discontinued study treatment in the darolutamide+docetaxel group (54.1%) than in the placebo+docetaxel group (80.4%). The most commonly reported primary reason for permanent treatment discontinuation was progressive disease (clinical progression), which was reported in a lower percentage of patients in the darolutamide+docetaxel group than in the placebo+docetaxel group (19.5% versus 41.6%, respectively), followed by radiological progression (12.9% versus 20.2%, respectively).

Overall, ''''''''''% of patients in the darolutamide+docetaxel group and ''''''''''% of patients in the placebo+docetaxel group had entered active follow-up, with '''''''% and ''''''''% ongoing.[44] The most common primary reason for discontinuation of active follow-up was death, which occurred in ''''''''''% of the patients in the

darolutamide+docetaxel group and ''''''''''% of the patients in the placebo+docetaxel group. For the survival follow-up, ''''''''''% of patients in the darolutamide+docetaxel group and ''''''''''% of patients in the placebo+docetaxel group had entered survival follow-up, with '''''''''''% and '''''''''''%, respectively, still ongoing. The most common primary reason for discontinuation of survival follow-up was death, which occurred in ''''''''''% of patients in the darolutamide+docetaxel group and '''''''''''% of patients in the placebo+docetaxel group.

The Consolidated Standards of Reporting Trials (CONSORT) flow diagrams and summary of patient disposition for the ARASENS study are presented in Appendix D.

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B.2.5 Critical appraisal of the relevant clinical effectiveness evidence

A quality assessment of the ARASENS study was conducted using the NICE checklist; the full details of this checklist are in Appendix D.

The study was approved by the institutional review board and independent ethics committee and was conducted according to good clinical practice. Overall, the study is considered to be a methodologically robust and high-quality study with a comprehensive approach to patient allocation, control of confounding factors, and an overall low risk of bias.

Patients were randomized to receive darolutamide or matching placebo in a doubleblind fashion, such that neither the investigator, the sponsor nor the patient knew which agent was being administered. All efficacy and safety parameters, and the methods to measure them, are standard variables and methods used in clinical studies and/or clinical practice. They are widely used and generally recognized as reliable, accurate and relevant.

B.2.6 Clinical effectiveness results of the relevant trials

A summary of the efficacy results from ARASENS is presented in Table 7. Darolutamide in combination with docetaxel and ADT significantly prolonged OS compared with placebo in combination with docetaxel and ADT. Darolutamide was also associated with consistent benefits with respect to secondary endpoints, including time to CRPC. Further details are presented in Section B.2.6.1 and Section B.2.6.2.

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Table 7: Summary of primary and secondary endpoint results in ARASENS

(FAS)

B.2.6.1 Primary efficacy outcome

B.2.6.1.1 Overall survival

At the time of the database cut-off date (25 October 2021), a total of 533 OS events had occurred, with 229 deaths in the darolutamide+docetaxel group (35.2% of patients) and 304 deaths in the placebo+docetaxel group (46.5% of patients).[45] The relative risk of death was reduced by 32.5% in the darolutamide+docetaxel group compared with the placebo+docetaxel group (HR: 0.68; 95% CI: 0.57, 0.80; p < 0.001). Median OS was not reached (95% CI: NE [not estimable], NE) in the darolutamide+docetaxel group and was 48.9 months (95% CI: 44.4, NE) in the

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placebo+docetaxel group (Figure 5 and Table 8). The median follow-up time from randomization to the last contact or death was 43.7 months in the darolutamide+docetaxel group and 42.4 months in the placebo+docetaxel group.

After approximately 6 months, the survival rate was greater in the darolutamide+docetaxel group than in the placebo+docetaxel group, and continued to be greater throughout the duration of the study.[44] At 48 months, the survival rate was 62.7% in the darolutamide+docetaxel group and 50.4% in the placebo+docetaxel group (Table 8) which is considered a meaningful benefit.[45]

Figure 5: Kaplan–Meier curves of overall survival (FAS)

==> picture [452 x 297] intentionally omitted <==

Key: CI, confidence interval; FAS, full analysis set. Source: Smith et al. 2022.[45]

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Table 8: Overall survival (FAS)

OS was longer for patients in the darolutamide+docetaxel group despite a higher percentage of patients receiving subsequent life prolonging antineoplastic therapy after discontinuation of study treatment in the placebo+docetaxel group.[45] In the darolutamide+docetaxel group, 56.8% of the 315 patients who entered active or survival follow-up started life-prolonging systemic antineoplastic therapy compared with 75.6% of the 495 patients in the placebo+docetaxel group (Appendix M).

Results of the pre-specific sensitivity analyses and post-hoc sensitivity analysis (using extent of disease stratification data according to central imaging review and by number of docetaxel cycles received) '''''''''''' '''''''''''''''''''''''' '''''''''' '''''''''' '''''''''''''''''''''''' ''''' ''''''' '''''''''''''''' ''''''''''''''''''''' ''''' ''''''''.[44] A summary of the sensitivity analyses is provided in Appendix M.

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B.2.6.2 Secondary efficacy outcome

B.2.6.2.1 Time to CRPC

Overall, 225 patients (35%) in the darolutamide+docetaxel group and 391 patients (60%) in the placebo+docetaxel group progressed to CRPC (Appendix M).[45]

A statistically significant prolonged time to CRPC was observed for patients in the darolutamide+docetaxel group compared with the placebo+docetaxel group, with an HR of 0.36 (95% CI: 0.30, 0.42; p < 0.001).[45] The median time to CRPC was not reached (95% CI: NE, NE) in the darolutamide+docetaxel group and was 19.1 months (95% CI: 16.5, 21.8) in the placebo+docetaxel group (Figure 6).

Results of the sensitivity analyses were ''''''''''''''''''''''''' '''''''''' ''''''''' '''''''''''''''''''''''' '''' '''''''

''''''''''''''''' ''''''''''''''''''' ''''' ''''''''' '''' '''''''''''''''', with an HR of ''''''''''''' (95% CI: ''''''''''''', ''''''''''''; p < ''''''''''''''; Appendix M).[44]

Figure 6: Kaplan–Meier curves of time to CRPC (FAS)

==> picture [452 x 295] intentionally omitted <==

Key: CI, confidence interval; CRPC, castration-resistant prostate cancer; FAS, full analysis set. Source: Smith et al. 2022.[45]

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B.2.6.2.1.1 Time to CRPC or death exploratory outcome

Time to CRPC did not capture death as events, therefore, time to CRPC or death (CROD) was derived from ARASENS CRPC data and used in the partitioned survival model of the economic analysis (Section B.3.3.2). It is defined as the time from randomization to a CRPC event (radiological or PSA progression) or death if a patient has no CRPC event.

A statistically significant prolonged time to CROD was observed for patients in the darolutamide+docetaxel group compared with the placebo+docetaxel group, with an HR of '''''''''' (95% CI: ''''''''''', ''''''''''''). The median time to CROD was ''''''''''' months (95% CI: '''''''''', ''''''') in the darolutamide+docetaxel group and '''''''''''' months (95% CI: ''''''''''', '''''''''') in the placebo+docetaxel group (Table 9 and Figure 7).

Table 9: Time to CROD summary (FAS)

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Figure 7: Kaplan–Meier curves of time to CROD (FAS)

==> picture [455 x 299] intentionally omitted <==

Key: CROD, castration-resistant prostate cancer or death; FAS, full analysis set.

B.2.6.2.2 Time to pain progression

There were 34% of patients in the darolutamide+docetaxel group and 38% in the placebo+docetaxel group with pain progression (Appendix M).[45]

A statistically significant delay in time to pain progression was observed for patients in the darolutamide+docetaxel group, with an HR of 0.79 (95% CI: 0.66, 0.95; p = 0.01).[45] The median time to pain progression was not reached (95% CI: 30.5, NE) in the darolutamide+docetaxel group and was 27.5 months (95% CI: 22.0, 36.1) in the placebo+docetaxel group (Figure 8).

Results of the sensitivity analyses were ''''''''''''''''''''''''' ''''''''' '''''''''' ''''''''''''''''''''''''' ''''' ''''''''

''''''''''''''''' '''''''''''''''''''' ''''' '''''''''' '''' '''''''''' ''''''''''''''''''''''''''''.[44] A summary of the sensitivity analyses

is provided in Appendix M.

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Figure 8: Kaplan–Meier curves of time to pain progression (FAS)

==> picture [452 x 298] intentionally omitted <==

Key: CI, confidence interval; FAS, full analysis set. Source: Smith et al. 2022.[45]

B.2.6.2.3 Symptomatic skeletal event-free survival

There were 40% of patients in the darolutamide+docetaxel group and 50% in the placebo+docetaxel group with an SSE-FS event, with the majority of events being ''''''''''''''' (Appendix M).[44, 45]

SSE-FS was significantly longer in the darolutamide+docetaxel group, with an HR of 0.61 (95% CI: 0.52, 0.72; p < 0.001).[44, 45] The median SSE-FS was 51.2 months (95% CI: '''''''''', '''''''') in the darolutamide+docetaxel group and 39.7 months (95% CI: '''''''''', '''''''''''') in the placebo+docetaxel group (Figure 9).

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Figure 9: Kaplan–Meier curves of SSE-FS (FAS)

==> picture [452 x 348] intentionally omitted <==

Key: FAS, full analysis set; SSE-FS, symptomatic skeletal event-free survival. Notes: At-risk patient counts were calculated as at start of timepoint. Source: Figure 9-6. ARASENS CSR.[44]

B.2.6.2.4 Time to first symptomatic skeletal event

Overall, SSEs were reported in 15% of patients in the darolutamide+docetaxel group compared with 17% in the placebo+docetaxel group (Appendix M).[44, 45] The majority of the first SSEs were external beam radiation therapy (EBRT) to relieve skeletal symptoms, reported for ''''''''''% of patients with an SSE in the darolutamide+docetaxel group and '''''''''''% of patients with an SSE in the placebo+docetaxel group.

Statistically significant delays in time to first SSE were observed for patients in the darolutamide+docetaxel group, with an HR of 0.71 (95% CI: 0.54, 0.94; p = 0.02).[44, ] 45 The median time to first SSE was not reached (95% CI: ''''''', ''''''') in either

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treatment arm. The results were consistent with the results of SSE-FS, where in addition to SSE, death was considered as an event.

Figure 10: Kaplan–Meier curves for time to first SSE (FAS)

==> picture [452 x 316] intentionally omitted <==

Key: FAS, full analysis set; SSE, symptomatic skeletal event. Notes: At-risk patient counts were calculated as at start of timepoint. Source: Figure 9-7. ARASENS CSR.[44]

B.2.6.2.5 Time to initiation of subsequent systemic antineoplastic therapy

There were 34% of patients in the darolutamide+docetaxel group who started a new systemic antineoplastic therapy, compared with 60% in the placebo+docetaxel group (Appendix M).[45]

Statistically significant delays in the time to initiation of subsequent systemic antineoplastic therapy were observed for patients in the darolutamide+docetaxel group compared with the placebo+docetaxel group (HR: 0.39, 95% CI: 0.33, 0.46; p < 0.001).[44, 45] The median time to initiation of subsequent systemic antineoplastic

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therapy was not reached (95% CI: ''''''', '''''''') in the darolutamide+docetaxel group and was 25.3 months (95% CI: ''''''''''', '''''''''') in the placebo+docetaxel group (Figure 11).

Subsequent systemic antineoplastic therapies were for prostate cancer, however, ''''''''''''' patients in the darolutamide+docetaxel arm and ''''''''' patients in the placebo+docetaxel arm received a first antineoplastic therapy for an additional primary malignancy.[44]

Figure 11: Kaplan–Meier curves of time to initiation of subsequent systemic antineoplastic therapy (FAS)

==> picture [452 x 244] intentionally omitted <==

Key: FAS, full analysis set. Notes: At-risk patient counts were calculated as at start of timepoint. Source: Figure 9-8. ARASENS CSR.[44]

B.2.6.2.6 Time to worsening of disease-related physical symptoms

The time to worsening of disease-related physical symptoms was based on the results from the FPSI–DRS–P subscale in the NCCN-FACT-FPSI-17 questionnaire. Worsening of disease-related physical symptoms was observed for 54% of patients in the darolutamide+docetaxel group and 47% of patients in the placebo+docetaxel group (Appendix M).[45]

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There was no significant difference in time to worsening of disease-related physical symptoms between the treatment arms (HR: 1.04; 95% CI: 0.89, 1.22; p = 0.59).[44, 45] The median time to worsening of disease-related physical symptoms was 19.3 months (95% CI: '''''''''', '''''''''') in the darolutamide+docetaxel group and 19.4 months (95% CI: '''''''''''', ''''''''''') in the placebo+docetaxel group (Figure 12). The results indicate that HRQL was maintained in patients in the darolutamide+docetaxel group compared with the placebo+docetaxel group during the study.

The results of the sensitivity analysis ''''''''''' ''''''''''''''''''''' ''''''''' '''''''' '''''''''' '''''''''''''''''''' ''''''''' '''''''

'''''''' ''''' ''''''''''''' '''''''''''' ''''''' '''''''''''''''' '''''''''''''' ''' ''' ''''''''''''''').[44] Median times to worsening of disease-related physical symptoms were ''''''''''' months (95% CI: '''''''''''', ''''''''''') in the darolutamide+docetaxel group and '''''''''' months (95% CI: ''''''''''', '''''''''') in the placebo+docetaxel group (Appendix M).

Figure 12: Kaplan–Meier curves of time to worsening of disease-related physical symptoms (FAS)

==> picture [452 x 300] intentionally omitted <==

Key: FAS, full analysis set. Notes: At-risk patient counts were calculated as at start of timepoint. Source: Figure 9-9. ARASENS CSR.[44]

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B.2.6.2.7 Time to initiation of opioid use for ≥ 7 consecutive days

The secondary endpoints of the study were pre-specified in a hierarchical testing scheme to be tested for significance if the results of all previous endpoints were significant.[44] As the preceding endpoint “Time to worsening of disease-related physical symptoms” did not reach the pre-specified significance level for this analysis, “Time to initiation of opioid use for ≥ 7 consecutive days” was not tested for significance (nominal p-values are provided for information only). However, a benefit in favour of the darolutamide+docetaxel group was observed (HR: '''''''''''''''' 95% CI: ''''''''''''''', ''''''''''''''; p = '''''''''''''''''; Appendix M).

B.2.6.3 Exploratory outcomes

B.2.6.3.1 Time to PSA progression

Baseline PSA values were comparable between the treatment arms (median ''''''''''''' ng/mL in the darolutamide+docetaxel group and ''''''''''''''' ng/mL in the placebo+docetaxel group.[44] A smaller percentage of patients in the darolutamide+docetaxel group ('''''''''' patients, '''''''''''%) than in the placebo+docetaxel group (''''''''' patients, ''''''''''%) had PSA progression (Appendix M).

Treatment with darolutamide in combination with docetaxel resulted in a longer time to PSA progression than placebo in combination with docetaxel, with an HR of '''''''''''''' (95% CI: ''''''''''''', ''''''''''''''; p < ''''''''''''''''''.[44] The median time to PSA progression was not reached (95% CI: ''''''', ''''''') in the darolutamide+docetaxel group and was ''''''''''' months (95% CI: ''''''''''', '''''''''') in the placebo+docetaxel group (Figure 13). The results supported the analysis of time to CRPC, as PSA progression was a component event of progression to CRPC.

Results of the sensitivity analyses '''''''''''' ''''''''''''''''''''' ''''''''' '''''''''' ''''''''''''''''''''''''''' ''''' ''''''''

'''''''''''''''''''' '''''''''''''''''' .[44] A summary of the sensitivity analyses is provided in Appendix M.

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Figure 13: Kaplan–Meier curves of time to PSA progression according to PCWG3 (FAS)

==> picture [452 x 301] intentionally omitted <==

Key: FAS, full analysis set; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostatespecific antigen. Notes: At-risk patient counts were calculated as at start of timepoint. Source: Figure 9-11. ARASENS CSR.[44]

B.2.6.3.2 PSA response

Patients in the darolutamide+docetaxel group ('''''''''''%) demonstrated a significantly higher relative PSA response rate of ''' ''''''% reduction from baseline at 12 months after randomization than patients in the placebo+docetaxel group (''''''''''''%), with a rate difference of ''''''''''''''% (95% CI: '''''''''''''; ''''''''''''; p '''' ''''''''''''''''). Overall, both absolute PSA response rates (PSA level < 0.2 ng/mL) and relative PSA response rates (≥ 90%, ≥ 50% and ≥ 30% reduction in PSA from baseline) were significantly higher in the darolutamide+docetaxel group than in the placebo+docetaxel group at all evaluated time points.

A summary of the PSA response data is provided in Appendix M.

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B.2.6.3.3 Health-related quality of life

B.2.6.3.3.1 NCCN-FACT-FPSI-17

Completion rates of NCCN-FACT-FPSI-17 questionnaires were similar between the treatment groups throughout treatment and follow-up.[44] Other than at Visit 1 (''''''''''%), over '''''''% of patients completed all the questions at each visit during the study treatment, and at most visits this value was > ''''''%. During active follow-up, completion rates dropped to > ''''''%.

At baseline (i.e. Screening or Visit 1/Day 1), disease-related physical symptoms, disease-related emotional symptoms, treatment side effects, function and well-being and total scores were similar between the treatment groups.[44] Changes in mean values from baseline for the disease-related physical symptoms, disease-related emotional symptoms, treatment side effects and total scores were similar in both treatment groups, and there were no clinically meaningful nor statistically significant differences between the treatment groups (Appendix M).

B.2.6.3.3.2 BPI-SF

Completion rates of the BPI-SF questionnaires were comparable between the treatment groups throughout treatment and follow-up.[44] Other than at Visit 1 ('''''''''''%), over ''''''% of patients completed all the questions at each visit during the study treatment, and at most visits this value was > ''''''%. During active follow-up, the completion rates dropped to > ''''''%.

At baseline (i.e. Screening or Visit 1/Day 1), the BPI-SF pain interference and pain severity scores were similar between the treatment groups.[44] Changes in mean values from baseline for the pain severity and pain interference scores were observed in both treatment groups, and there were no clinically meaningful differences between the treatment groups (Appendix M). The pain interference score and pain severity score results favoured the darolutamide+docetaxel group (lower scores represent less pain) but were not statistically significant nor clinically meaningful.

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B.2.6.4 Additional supporting evidence for darolutamide

B.2.6.4.1 Drug-drug interactions

A retrospective observational cohort study used data from an administrative claims database to compare the risks of pDDIs of darolutamide, enzalutamide and apalutamide among patients with non-metastatic castration-resistant prostate cancer (nmCRPC).[43] Although in a different indication to this appraisal, the theoretical analysis performed in the study is informative for the mHSPC population as both populations are elderly with multiple comorbidities[9, 43] , and pDDIs are an important consideration for clinicians.[37]

In total, there was one pDDI for darolutamide in both the Lexicomp and Micromedex compendia (Table 10).[43] For enzalutamide and apalutamide, there were 22 pDDIs each observed in both compendia. There were less frequent severe pDDIs for darolutamide compared with enzalutamide and apalutamide.

In the nmCRPC population (n = 718), a pDDI was identified among 34.5% of patients receiving enzalutamide, 17.1% on apalutamide and 7.0% on darolutamide according to Lexicomp (Figure 14).[43] With respect to Micromedex, a pDDI was identified among 9.3% of nmCRPC patients receiving enzalutamide, 8.5% on apalutamide, and 7.0% on darolutamide.

These results are further supported by additional studies that demonstrate darolutamide has limited DDIs when administered alongside medications commonly used to treat comorbidities in an elderly patient population, such as calcium channel blockers and anticoagulants.[48-50]

Table 10: Implicated enzymes and interacting drugs for DDIs using Lexicomp and Micromedex compendia

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Figure 14: pDDIs identified in nmCRPC patients

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Key: nmCRPC, non-metastatic castration-resistant prostate cancer; pDDIs, potential drug-drug interactions. Source: Appukkuttan et al. 2021.[43]

B.2.7 Subgroup analysis

Pre-specified subgroup analyses were conducted for the primary efficacy endpoint OS, based on the FAS population.[44] Descriptive statistics and HR estimates with 95% CI were given for the subgroups, provided that at least 10 total events were observed within the subgroup across both treatment groups. All subgroup analyses were performed using an unstratified Cox model.

A consistent OS benefit for darolutamide in combination with docetaxel was observed across all pre-specified subgroups including baseline extent of disease, ALP, age, race, geographical region, PSA, ECOG PS, Gleason score, and metastasis at initial diagnosis.[44] For some subgroups there were a low number of events (e.g. extent of disease: non-regional lymph node metastases; race: Black or African American; race: other or not reported; and metastasis at initial diagnosis: no), for which the results must be interpreted with caution.

A summary of results for the analysed subgroups is provided in Appendix E.

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B.2.8 Meta-analysis

The main evidence for the use of darolutamide in combination with docetaxel and ADT in the treatment of mHSPC is from ARASENS. No other studies investigating the safety and efficacy of this triplet combination therapy were identified. Therefore, no meta-analysis is required.

B.2.9 Indirect and mixed treatment comparisons

Appendix D include full details of the methodology for the indirect comparison or mixed treatment comparison.

The relative efficacy of darolutamide in combination with docetaxel and ADT was compared with enzalutamide+ADT, docetaxel+ADT and ADT alone for patients with mHSPC using network-meta analysis (NMA) methods.

B.2.9.1 Study selection

A systematic literature review (SLR) was conducted and searches for the SLR were designed to capture relevant studies from a multi-country perspective and to meet the requirements of global HTA agencies (detailed in Appendix D), so comparators that are not relevant for this submission (e.g. radiotherapy and apalutamide) were included. Only studies that included treatments informing the comparisons relevant for this submission are discussed in further detail.

Treatments, trial design and patient characteristics of the identified trials were assessed to determine the suitability of conducting an indirect treatment comparison (ITC) and for informing the appropriate methodology for these analyses. Indirect methods are generally considered acceptable if applied with consideration to the basic assumptions of homogeneity, similarity and consistency as reported in Song et al. 2009.[51] The appropriateness of an NMA was considered in terms of these criteria for each endpoint.

The SLR identified 27 studies as potentially relevant for darolutamide + docetaxel + ADT NMAs, presented in Table 11. The STAMPEDE trial was a multi-arm platform randomized controlled trial (RCT), and each stage of the platform design was

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considered as a separate study in this NMA in line with the enzalutamide technology appraisal (TA).[38]

Table 11: Overview of studies included in the systematic literature review

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B.2.9.1.2 Treatments

To assess trial comparability of the 27 studies identified, the differences and similarities between treatments of interest, treatment dosing, frequency, delivery, and treatment cycle were investigated (tables summarizing treatments are included in Table 7 Appendix D). The relevant comparators for darolutamide+docetaxel+ADT are enzalutamide+ADT, docetaxel+ADT and ADT alone. Abiraterone+ADT is not considered a relevant comparator, but, as it has been a treatment studied in STAMPEDE against both docetaxel+ADT and ADT alone (two of the comparators in this appraisal), studies that investigated abiraterone were considered if they provided indirect evidence to enrich the network through the formation of loops.

35 treatments were identified across 27 trials in the evidence base. 14 trials did not include relevant comparators of interest and were excluded (Boccon-Gibod 1997, Chang 1996, Chodak 1995, EORTC-30892, EORTC-TRIAL 30843, Kaisary 1995, Kirby 1999, PEACE-1, STAMPEDE-5, STAMPEDE-6, STAMPEDE-7, SWOG S1216, Thorpe 1996 and TITAN). All ADT treatments were grouped into one node, and four trials comparing ADT versus ADT were excluded as they did not provide comparisons of interest (Brunn 1996, the HERO study, Iverson 1996 and Vogelzang 1995 between them include buserelin, goserelin, LHRH analogues and orchiectomies, which are all forms of ADT).

STAMPEDE-1 included metastatic and non-metastatic patients whereas STAMPEDE-3 included only the metastatic patients from STAMPEDE-1, so STAMPEDE-1 was excluded.

ENZAMET compared enzalutamide+ADT±docetaxel or standard nonsteroidal antiandrogen (SNA)+ADT±docetaxel, and the administration of docetaxel was applied as a stratification factor. About 45% of patients received

enzalutamide+ADT+docetaxel (not a comparator of interest) or SNA+ADT+docetaxel, and the remaining patients received enzalutamide+ADT (comparator of interest) or SNA+ADT. Baseline characteristics were not available for each treatment group (treated with docetaxel versus not treated with non-docetaxel), but it is assumed that patients who receive docetaxel have a worse prognosis than those who do not, as docetaxel is a form of chemotherapy (Kaplan–Meier curves presented in Davis 2019 suggested that patients who were not treated with

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docetaxel appeared to have better survival than those treated with docetaxel[61] ). Due to lack of availability of baseline characteristics for the docetaxel/non-docetaxel treatment groups in ENZAMET, it was not possible to assess the presence of heterogeneity as any characteristics of the overall trial population would probably be skewed. Therefore, ENZAMET has been excluded from the base case NMA but included in a scenario analysis. Similarly to ENZAMET, Vaishampayan 2021 compared enzalutamide + ADT with SNA + ADT; this study was excluded from the base case due to the high risk of bias, low power, early stop in patient accrual, and short follow-up, but was included in scenario analysis around the NMA network.

A further four studies included SNA+ADT (compared to ADT) which is not a treatment of interest but were relevant to the scenario analysis including ENZAMET and Vaishampayan 2021 as they provide an indirect link between these trials and ADT. These studies are Ferrari 1996, Kulkarni 2003, SWOG study S8894, and Zalcberg 1996. Out of these four studies, Ferrari 1996 and Kulkarni 2003 were excluded as outcome data were not reported.

Detailed reasons for exclusion of each study included in the SLR are detailed in Table 8 Appendix D.

Eight trials (ARASENS, ARCHES, CHAARTED, GETUG-AFU 15, LATITUDE, STAMPEDE-2, STAMPEDE-3 and STAMPEDE-4) were included in the base case NMA as they included relevant treatments. All trials were evaluated and found to be similar in terms of dose, frequency, delivery and treatment cycles of docetaxel, except GETUG-AFU 15 where patients could receive up to nine cycles (as detailed in Appendix D). GETUG-AFU 15 was included in the base case NMA, but a sensitivity analysis was performed excluding GETUG-AFU 15.

B.2.9.1.3 Trial heterogeneity assessment

After excluding studies based upon the investigated treatments, there were eight trials remaining for the base case NMA (including three studies from the STAMPEDE trial) whose trial design was considered for comparability. A summary of trial design is presented in Table 12; the STAMPEDE trial has been included as a single trial in this table due to the multi-arm, multi-stage platform design. Studies were either double-blind or open label. All studies were multi-centre RCTs. Five studies (83.3%)

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were Phase III and one study was Phase II/III. Half of the studies had placebo-/best supportive care (BSC)-controlled comparators (50%), 33.3% had active and placebo/BSC-controlled comparators and one had an active controlled comparator.

Trial population was defined slightly differently across the studies. Our focus was on patients with mHSPC. Studies used the interchangeable terms ‘metastatic hormonesensitive prostate cancer’ (ARASENS, ARCHES, CHAARTED) and ‘metastatic castration-sensitive prostate cancer’ (LATITUDE). The trial population in STAMPEDE was defined as ‘hormone-naïve prostate cancer’, and patients who had metastatic, non-metastatic and high-risk hormone-naïve prostate cancer were included in this trial. However, only results from the metastatic subgroup have been included in the NMA. The trial population in GETUG-AFU 15 was described as ‘noncastrate metastatic prostate cancer’. Both metastatic hormone-naïve prostate cancer and non-castrate metastatic prostate cancer are classified as mHSPC. The HRs from the overall trial population were used in the NMA from all trials in the evidence base, except STAMPEDE where results from the metastatic subgroup only was used.

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Table 12: Detailed trial design of studies identified by clinical SLR and included in the base case NMA

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The trial inclusion/exclusion criteria and baseline characteristics of the patient populations were compared for the eight trials considered for inclusion in the NMAs (STAMPEDE 2, 3 and 4 are each considered to be their own study). Inclusion/exclusion criteria and baseline characteristics by study are presented in detail in Appendix D, Section D.1.6.4.

No studies were excluded due to the inclusion/exclusion criteria or due to the baseline characteristics.

Exploratory analysis was performed with the ARASENS trial patient-level data to identify potential treatment effect modifiers. There was no evidence of treatment effect modification from the exploratory analysis of the ARASENS trial data (Appendix D, Figures 7 and 8). This was confirmed by HTA and clinical expert input.[37, 80]

Most studies were similar to ARASENS in terms of inclusion and exclusion criteria. Eastern Cooperative Oncology Group (ECOG) inclusion/exclusion criteria varied slightly; ARASENS and ARCHES included 0–1, and LATITUDE, GETUG-AFU 15 and CHAARTED included 0-2. However, baseline characteristics showed that no study was a clear outlier for ECOG. Age ranges across the studies were similar and the method of confirmed disease was similar between the studies. Some of the studies had different inclusion criteria to ARASENS, with some allowing the patient to have received prior chemotherapy before beginning trials. This is a source of heterogeneity in the evidence base that occurs in a minority of the selected studies. Patients in all studies used in the base case NMA received prior treatment. A variety of prior treatments were given, such as docetaxel, ADT, prostatectomy, surgery, hormone therapy and antiandrogen treatments. Duration of prior treatment was not well reported in the evidence. Since prior docetaxel was administered to only 17.8% of patients in ARCHES and the results of the overall population and the ‘no prior docetaxel treated’ subgroup are similar, the HR from the overall population has been used in the analysis.

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Table 13: Summary of studies identified by clinical SLR and included in the

NMA

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B.2.9.1.4 Outcomes

Two outcomes were considered for the NMAs: OS and PFS. Kaulkarni 2003 and Ferrari 1996 did not report relevant outcome data for NMAs, so they were excluded from the evidence base. Outcomes from the ITT study populations were used throughout these analyses (results from STAMPEDE from the metastatic only subgroup were used).

B.2.9.1.4.1 Overall survival

OS was defined similarly across all trials.

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B.2.9.1.4.2 Progression

The PFS outcome definitions were not fully aligned across the trials, so we have conducted two progression NMAs:

• A base PFS network based on time to CROD from ARASENS (CROD is an endpoint that captures both progression and death) and using the best matching progression outcomes across the other trials. The following data were used for each trial:

  • Time to CROD was used for ARASENS

  • Radiological PFS (rPFS) was used for ARCHES, LATITUDE, and GETUGAFU 15

  • Clinical PFS (cPFS) was used for CHAARTED

  • Failure-free survival (FFS) was used for STAMPEDE-2, STAMPEDE-3 and STAMPEDE-4

• To test the robustness of the base PFS network, we also ran an alternative PFS network based on time to CRPC from ARASENS. This network used the most closely aligned best matching progression outcomes across the other trials where time to CRPC was not reported. Time to CRPC was not reported in LATITUDE, GETUG-AFU 15, STAMPEDE-2, STAMPEDE-3 and STAMPEDE-4, so the following data were used instead:

  • Time to CRPC for ARASENS, ARCHES, and CHAARTED

  • Time to subsequent prostate cancer therapy for LATITUDE

  • Biochemical PFS for GETUG-AFU 15

  • FFS for STAMPEDE-2, STAMPEDE-3 and STAMPEDE-4

Differences and similarities between definitions are summarized in Table 14 and Table 15, based on the information available in the publications that were identified in the SLR.

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Table 14: Summary of similarities and differences of definitions used for base case PFS network

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Table 15: Summary of similarities and differences of definitions used for alternative PFS network

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Proportional hazards assumption

Proportionality of hazards was assessed for time-to-event outcomes that were included in the NMA for all outcomes with an available Kaplan–Meier curve. If Kaplan–Meier curves were available, these were digitized using the method of Guyot et al. (2012) to generate pseudo patient-level data.[81] The proportionality of hazards assumption check was performed using a log-cumulative hazards plot, a Schoenfeld residuals plot and Schoenfeld's global test (p < 0.05 suggests a possible violation of proportional hazards [PH]). These findings are described in Appendix D, Section D.1.6.6. Where possible, the PH assumption was assessed in detail across all trials and endpoints. For OS, the PH assumption was borderline implausible for one study of interest (CHAARTED) and a sensitivity analysis removing this study was performed. For both PFS networks, the PH assumption was considered plausible for all trials reporting Kaplan–Meier curves and no sensitivity analyses were deemed necessary.

Data used in the NMA

Table 16 summarizes the available data for the endpoints of interest for the NMAs and whether proxy data were used for specific endpoints. All data were identified from the SLR.

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Table 16: Data used in NMAs

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B.2.9.1.5 Studies included and excluded from NMA

The eight studies identified for inclusion in the base case NMA and those included in sensitivity analyses are presented in Figure 15.

Figure 15: NMA network diagram

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Key: ADT, androgen deprivation therapy; NMA, network meta-analysis ; SNA, nonsteroidal antiandrogen

B.2.9.2 Methods

B.2.9.2.1 Network meta-analysis

The NMA was carried out using a Bayesian approach, as this captures the uncertainty in model parameters while preserving correlation between treatment effects. All NMA methods are consistent with the NICE Decision Support Unit (DSU) Technical Support Documents (TSD) 2–4.[82-85] Relative treatment effects were estimated using Markov chain Monte Carlo (MCMC) methods. One fixed-effects (FE) model and one random-effects (RE) model were fitted with a prior distribution for the RE which was non-informative and in line with those specified in NICE DSU TSD 2, as this allowed the posterior distribution to be primarily driven by the data. For each of the RE models, a non-informative uniform (0, 5) distribution was used as the prior distribution for the between-study standard deviation. This prior distribution assumes that any values between 0 and 5 are equally probable. The Unif(0, 5) was used as it indicates a vague prior on the between-trial standard deviation. This was in agreement with HTA expert input and in line with TA712.[38, 80]

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Based on the advice from HTA experts, the preferred model was selected based on clinical plausibility of the estimated relative treatment effects and by assessing the residual deviance statistic and the deviance information criterion (DIC).[86] Inconsistency was assessed with a ‘node-splitting’ technique, which used the method of van Valkenhoef et al. (2016).[87]

For each NMA, treatments were ranked based on their surface under the cumulative ranking curve (SUCRA) values. SUCRA is a numerical presentation of the overall ranking and presents a single number associated with each treatment. SUCRA values range from 0 to 100%. The larger the SUCRA, the higher the treatment in the hierarchy according to the outcome. Rankings are presented alongside the NMA results.

B.2.9.2.2 Time-to-event endpoints

For time-to-event endpoints, the analysis used the reported hazard ratio (HR) and an associated variance estimate such as the standard error or 95% confidence interval (CI) to derive the input data for the analysis.

The time-to-event endpoints included in these analyses were:

• OS

• PFS:

  • The base PFS network was based on time to CROD from ARASENS and used the best matching progression outcomes from across the other trials

  • The alternative PFS network was based on time to CRPC from ARASENS and used the best matching progression outcomes from across the other trials

B.2.9.2.3 NMAs conducted

The NMAs conducted are summarized in Table 17. A base case NMA and different sensitivity analyses were performed to explore the limitations described in the conclusions and uncertainties in the indirect and mixed treatment comparisons section (Section 2.9.4).

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Table 17: NMAs conducted

B.2.9.3 Results

The HR (for time-to-event outcomes) are reported with 95% credible intervals (CrI). Results focus on the comparisons of darolutamide+docetaxel+ADT to enzalutamide+ADT, docetaxel+ADT and ADT alone due to the relevance to the decision problem. Results for abiraterone acetate+ADT have been included in tables for completeness. NMA sensitivity analyses results and fit statistics are reported in detail in Appendix D, Section D.1.6.9.

B.2.9.3.1 Overall survival

Results of the NMAs for OS are presented in Table 18. This includes HRs and 95% CIs for the relative effect of darolutamide+docetaxel+ADT compared to each treatment. The FE model was selected as the base case model based on model fit; it had the lowest DIC when compared with the RE model. Model fit is summarized in Appendix D.

Darolutamide+docetaxel+ADT had a '''''''''''''''''''''''' ''''''''''''''''''''''''' ''''''''''''' '''''''''''''''' ''''' ''''''''''''''

''''''''''' ''''''''''''''''''''''''''''''''' '''''''''' ''''''''''' ''''''''''''' and was '''''''''''''''''''''''''''' ''''''''''''''' ''''''''''

''''''''''''''''''''''''''''''''''''''''''''''' . The SUCRA rankings of this analysis suggest that

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darolutamide+docetaxel+ADT is ''''''''''' ''''''''''' ''''' '''''' '''''''' ''''''''' ''''''''''''''''''''''' ''''' '''''''' '''''''''''''''''''

''''''''''' '''''' '''''''' . The inconsistency assessment for OS, which is presented in Appendix D, showed no evidence of statistically significant inconsistency. A number of sensitivity analyses were carried out as described in Table 17, the direction of effect remained consistent in all analyses conducted. (Appendix D Section D.1.6.9).

Table 18: Relative effect of darolutamide+docetaxel+ADT compared to all

treatment – OS

B.2.9.3.2 PFS base network

Results for PFS base network NMAs are presented in Table 19 for each treatment in relation to darolutamide+docetaxel+ADT. The random-effect Unif(0,5) model was selected as the base case, as it had the lowest DIC when compared with the FE model (model fit is summarized in Appendix D, Section D.1.6.9). Selecting the RE model for this outcome acknowledges the heterogeneity caused by using proxy outcomes in the analysis.

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For the PFS base network, darolutamide+docetaxel+ADT had a '''''''''''''''''''''''

'''''''''''''''''''''''''''''' '''''''''''''' '''''''''''''''' ''''' '''''''''''''''''''''''''''''' '''''''''' ''''''''''' ''''''''''''' '''''''''' ''''''''''''''''''''''''''''''''''''''' It

was also ''''''''''''''''''''''''' '''''''''''''' ''''''''''' ''''''''''''''''''''''''''''''''''''''''''''''' The SUCRA values suggest

that darolutamide+docetaxel+ADT is '''''''''''' ''''''''''''' ''''' '''''' '''''''' '''''''''' '''''''''''''''''''''' ''''' ''''''''

'''''''''''' ''''''''''' '''''''''''''''''' ''''''''''''''''''''''' ''''''''''''. The inconsistency assessment for the PFS base network, which is presented in Appendix D, showed no evidence of statistically significant inconsistency.

Table 19: Relative effect of darolutamide+docetaxel+ADT compared to all

treatment – PFS base network

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----- Start of picture text -----
Treatment NMA models Rank
SUCRA (%)
Base case RE,
FE
Unif(0,5) RE model
HR (95% CrI)
HR (95% CrI)
Darolutamide + docetaxel + '''''''' '''''''''''''''
ADT
'''''''''' ''''''''''' ''''' '''''''''''' ''''''''''' ''''''''''''' ''''' ''''''''' '''''''''''''''
Enzalutamide + ADT '''''''''''
'''''''''''' ''''''''''' ''''' ''''''''''''' '''''''''' ''''''''''''' '''' ''''''''' ''''''''''''''
Abiraterone acetate + ADT* ''''''''''''
''''''''' '''''''''''' ''''' '''''''''''' ''''''''''' '''''''''''' ''''' ''''''' ''''''''''''''
Docetaxel + ADT '''''''''''
'''''''''''' ''''''''''''' ''''' '''''''''''' '''''''''''' '''''''''''' ''''' ''''''''' ''''''''''''
ADT '''''''''''''
Key: ADT, androgen deprivation therapy; Crl, credible interval; FE, fixed effect; HR, hazard ratio;
OS, overall survival; NMA, network meta-analysis; OS, overall survival; RE, random effect; SUCRA;
surface under the cumulative ranking.
Note: *Abiraterone acetate + ADT is not a treatment of interest but was included in the network to
provide additional indirect evidence for the relative treatment effects.
----- End of picture text -----

B.2.9.3.3 PFS alternative network

Results for the alternative PFS network are presented in Table 20 for each treatment in relation to darolutamide+docetaxel+ADT. The random-effect Unif(0,5) model was selected as the base case as this model had the lowest DIC when compared with the FE model (model fit is summarized in Appendix D). Selecting the RE model for this outcome acknowledges the heterogeneity caused by using proxy outcomes in the analysis.

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For the alternative PFS network, darolutamide+docetaxel+ADT had '''' ''''''''''''''''''''''''

''''''''''''''''''''''''''' ''''''''''''' ''''''''''''''' ''''' ''''''''''''''''''''''''''' ''''''''''' '''''''''''''''''''''''''''''''''''' ''''''''' ''''''''''' ''''''''''''' It was

''''''''''''''' '''''''''' '''''''''''''''''''''''''''''''''''''''''''''''' also '''''''''''''''''''''''''''''' . The SUCRA values suggest that

darolutamide+docetaxel+ADT is the ''''''''''' '''''''''''' ''''' '''''' '''''''' '''''''''' ''''''''''''''''''''' '''' ''''''''' '''''''''''

''''''''''''''''''''''''''' ''''''''''''''''''' '''''''''''''''''''' '''''''''''. The inconsistency assessment for the

alternative PFS network, which is presented in Appendix D, showed no evidence of statistically significant inconsistency.

Table 20: Relative effect of darolutamide+docetaxel+ADT compared to all

treatment – PFS alternative network

B.2.9.4 Conclusions and uncertainties in the indirect and mixed

treatment comparisons

The NMAs indicates that darolutamide+docetaxel+ADT has ''' ''''''''''''' ''''''''''''''' ''''' '''''''''''''

'''''''''' '''''''''''''''''''''''''''' '''''''''''''' ''''''''''' '''''''' '''''''''' '''''''''''' ''''''''' '''''''''''' ''''''''''''''''''''''' ''''''''''''''''''''''''

'''''''''''''''''''''' ''''''''' ''''''''''''' ''''''''''''''''''''''' '''''' '''''''''''''''''''''' '''''''''''''''''''''' ''''''''''''''''''''''''''''''''''''''''''''

''''''''''''''''''''''''''''''''''''''''' ''''''''' '''''''''' ''''''''''''. These results should be considered alongside the

limitations of this NMA analysis.

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Two NMAs on progression outcomes were conducted. The base PFS network used time to CROD (also used in the cost-effectiveness model) from ARASENS and the best matching progression outcomes from across the other trials. This prioritized outcomes that included death as an event (where possible) in order to be consistent with the modelling. To test the robustness of the base PFS network, an alternative PFS network using time to CRPC from ARASENS was conducted using best matching progression outcomes from across the other trials. The PFS base and PFS alternative network NMAs provided relatively comparable results. Similarities and differences between best matching progression outcomes are further summarized in Section B.2.9.1.1.2 and Appendix D.

Two trials in the NMA evidence base, ARCHES and LATITUDE, allowed for crossover of patients. Cross-over typically occurs when patients whose disease progresses under the comparator treatment are crossed over into the experimental arm. The methods for crossover adjustments are associated with numerous uncertainties, ARCHES and LATITUDE both used the rank preserving structure failure time modelling (RPSFTM). Using the unadjusted approach aligns with the Committee recommendations from NICE TA741[88] , which stated that an analysis that did not adjust survival estimates for crossover could be reasonable, as patients receiving placebo plus ADT in clinical practice would probably be offered enzalutamide plus ADT as their first subsequent treatment.

An investigation of the studies’ baseline characteristics can be found in Appendix D. In general, studies were considered reasonably comparable. There was no evidence of treatment effect modification from the exploratory analysis of the ARASENS trial data. The amount of missing data varied across the studies, which made it difficult to assess the heterogeneity for all studies robustly. It was also not appropriate to exclude studies due to outliers in these baseline characteristics as none of them were identified as treatment effect modifiers (see Appendix D). Furthermore, all studies reported various prior treatments, but duration of prior treatment received was poorly reported across the evidence base and could not be fully assessed. However, no studies were excluded on this basis.

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15 from the network. However, the results from this analysis were nevertheless consistent with the base case NMA (see Appendix D).

Proportionality of hazards was assessed for all outcomes that had a Kaplan–Meier curve available. The assumption held for all cases except CHAARTED, where borderline plausibility was assumed. A sensitivity analysis was therefore performed excluding CHAARTED from the base case, and results were consistent with the base case NMA (see Appendix D).

B.2.10 Adverse reactions

B.2.10.1 Safety summary

Table 21 presents an overview of the safety data from ARASENS up to the data cutoff date (25 October 2021).

The overall incidence of treatment-emergent adverse events (TEAE) was comparable between the treatment groups.[45] At least one TEAE was reported in nearly all patients during the study; 99.5% of patients experienced TEAEs in the darolutamide+docetaxel group and 98.9% in the placebo+docetaxel group. Similar incidences were observed for TEAEs with a worst grade of ≥ 3 in both treatment groups (70.2% versus 67.5%, respectively). The incidences of Grade 5 TEAEs were similar in both treatment groups (4.1% versus 4.0%, respectively). ''''''' Grade 5 TEAEs were considered to be study drug-related by the investigator in the darolutamide+docetaxel group.[44] Overall, treatment-emergent serious adverse events (TESAE) were reported with a similar incidence between the darolutamide+docetaxel and placebo+docetaxel treatment groups (44.8% versus 42.3% of patients, respectively).[45]

TEAEs that resulted in permanent discontinuation of study drug occurred at a comparable incidence in both the darolutamide+docetaxel group and the placebo+docetaxel group (13.5% versus 10.6%, respectively).[45] The incidences of TEAEs that resulted in permanent discontinuation of docetaxel were also comparable between the treatment groups (8.0% versus 10.3%, respectively).

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Table 21: Overview of TEAEs (SAS)

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B.2.10.2 Extent of exposure

B.2.10.2.1 Study drug exposure

Most patients in both treatment groups received the planned dose of study drug (the median was '''''''''% and the mean was above '''''''% in both treatment groups).[44] The median treatment duration at the time of the database cut-off was longer in the darolutamide+docetaxel group (41.0 months) than in the placebo+docetaxel group (16.7 months; Appendix F).[45] The proportion of patients staying on study drug treatment for over 42 months was more than 2-fold higher in the

darolutamide+docetaxel group than in the placebo+docetaxel group (45.9% versus 19.1%, respectively).

After the last dose of docetaxel, patients continued on study drug treatment for a median time of '''''''''' months in the darolutamide+docetaxel group and '''''''''' months in the placebo+docetaxel group.[44]

B.2.10.2.2 Docetaxel exposure

The majority of the patients in both treatment groups, 87.6% in the darolutamide+docetaxel group and 85.5% in the placebo+docetaxel group, received full six cycles of docetaxel (Appendix F).[45] The median total number of cycles was '''''' in both treatment arms.[44] There were '''''' patients ('''''''%) in the darolutamide+docetaxel group and ''''''' patients ('''''''%) in the placebo+docetaxel group who never received docetaxel. These patients were initially assessed by the investigator to be candidates for docetaxel and ADT. After randomization and start of study drug, they were no longer considered to be eligible to receive concomitant docetaxel within six weeks after start of study drug.

B.2.10.2.3 Dose modifications

The full dose of study drug was tolerated by the majority of patients in both treatment groups without any dose modifications during the treatment period.[44] At least one study drug dose modification (interruption/delay or reduction) was reported for ''''''''''% of patients in the darolutamide+docetaxel group and '''''''''''% in the

placebo+docetaxel group (Appendix F). The total number of study drug dose

modifications was higher in the darolutamide+docetaxel group ('''''''') than in the placebo+docetaxel group (''''''''). The number of study drug dose modifications per

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patient was generally similar in both treatment groups, with most patients having either one or two dose modifications; however, there were slightly more patients with ≥ 10 dose modifications per patient in the darolutamide+docetaxel group (''''''''%) than in the placebo+docetaxel group (''''''''%). The most common reason for dose modification was patient error for ''''''''''''% of events in the darolutamide+docetaxel group and ''''''''''% of events in the placebo+docetaxel group. Most patient errors were reported as single dose interruptions; however, the single missed dose did not impact the overall compliance with the study drug. TEAE was a reason for drug dose modification in ''''''''''''% and '''''''''''% of dose modification events, respectively. Study drug dose reductions (for any reason) were reported for ''''''''''% of patients in the darolutamide+docetaxel group and ''''''''% in the placebo+docetaxel group. Study drug dose was re-escalated in '''''''''''% and '''''''''''% of patients with dose reduction, respectively.

Overall, docetaxel dose modifications were reported at a similar level between the treatment groups.[44] At least one docetaxel dose modification (interruption/delay or reduction) was reported for ''''''''''''% of patients in the darolutamide+docetaxel group and '''''''''''% of patients in the placebo+docetaxel group (Appendix F). The primary reason for docetaxel dose modifications was TEAE in '''''''''''% and '''''''''''% of patients in the darolutamide+docetaxel and placebo+docetaxel group, respectively. Docetaxel dose was interrupted or delayed in ''''''''''''% and '''''''''''% of patients in the darolutamide+docetaxel and placebo+docetaxel groups, respectively, and a dose reduction was reported in ''''''''''''% and ''''''''''% of patients, respectively. Docetaxel was withdrawn in ''''''''''% versus ''''''''''% of patients, respectively.

B.2.10.3 Common treatment-emergent adverse events

Table 22 presents the most common TEAEs occurring in ≥ 10% of patients in either treatment group. To adjust for potential differences in study drug treatment duration between the treatment groups, exposure-adjusted incidence rates (EAIRs) per 100 patient year (PY) are also summarized.

The most commonly reported TEAEs were generally comparable between the treatment groups.[44] The most common events (≥ 25% of patients in either treatment group) included alopecia, fatigue, anaemia, arthralgia, oedema peripheral, neutrophil count decreased, and diarrhoea. The most common TEAEs reported with ≥ 3% Company evidence submission template for darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer [ID3971] © Bayer (2022). All rights reserved 86 of 201 RESTRICTED

higher incidence in the darolutamide+docetaxel group than in the placebo+docetaxel group were decreased appetite, hypertension, aspartate aminotransferase (AST) increased, and pain in extremity. When adjusted for the difference in study drug treatment duration, the EAIRs of these events were comparable between the treatment groups. Based on the analysis of common TEAEs over time, the incidences for the majority of events were highest during the first 6 months after the start of study treatment in both treatment groups, corresponding to the docetaxel treatment period.[89] After that, a trend towards lower incidence and reduced severity of TEAEs was observed in both treatment arms for most TEAEs.

Overall, events with a worst grade of ≥ 3 were reported with low incidences within the most common TEAEs, with the exception of the following Grade 3 or 4 TEAEs that occurred in ≥ 5% of patients in either treatment group: neutrophil count decreased, white blood cell count decreased, hypertension, and neutropenia.[44] Many of the common TEAEs in the study (such as alopecia, anaemia, neutropenia) are known to be commonly associated with docetaxel treatment. For the events known to be associated with both darolutamide and docetaxel (such as fatigue, neutrophil count decreased, and neutropenia), the incidences were similar between the treatment groups.

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Table 22: Incidences and exposure-adjusted incidence rates of the most common TEAEs by MedDRA PT occurring in ≥ 10% of patients in either treatment group (SAS)

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B.2.10.4 Treatment-emergent adverse events by severity

Table 23 presents the incidence of worst Grade 3 or 4 TEAEs.

Overall, TEAEs with Grade 3 or 4 as the worst grade were reported at a similar incidence in the darolutamide+docetaxel group (66.1%) and in the placebo+docetaxel group (63.5%).[45] The most common TEAEs with worst Grade of 3 or 4 (≥ 5% of patients in either treatment arm) in the darolutamide+docetaxel and placebo+docetaxel groups, respectively, were neutrophil count decreased (''''''''''% versus ''''''''''''%), WBC count decreased (''''''''''% versus ''''''''''%), neutropenia ('''''''% versus ''''''''''%), febrile neutropenia (7.8% versus 7.4%), hypertension (6.4% versus 3.2%) and anaemia (4.8% versus 5.1%).[44, 45] Hypertension was reported with ≥ 3% higher incidence in the darolutamide+docetaxel group than in the placebo+docetaxel group, which is discussed in more detail in Section B.2.10.6.

Table 23: Incidence of worst Grade 3 or 4 TEAEs by MedDRA PT occurring in ≥ 1.5% of patients in either treatment group (SAS)

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B.2.10.5 Treatment-related adverse events

Overall, TEAEs assessed as study drug-related by the investigator were reported with a slightly higher incidence in the darolutamide+docetaxel group ('''''''''''%) than in the placebo+docetaxel group (''''''''''%; Table 21).[44] Study drug-related TEAEs that were reported in ≥ 5% of patients in either the darolutamide+docetaxel or placebo+docetaxel treatment group included fatigue (''''''''''''% versus '''''''''''%, respectively), hot flush (''''''''% in both groups), ALT increased (''''''''% versus '''''''%), AST increased ('''''''% versus ''''''''%), and anaemia ('''''''% versus ''''''''%). These events were reported mostly with Grade 1 or 2 as the worst grade. Study drugrelated Grade 4 ALT and AST increases were both observed in '''''''''' patient ('''''''%) in the darolutamide+docetaxel group and '''''' Grade 4 events were reported in the placebo+docetaxel group (Table 24).

Overall, TEAEs that were assessed as docetaxel-related by the investigator occurred with a similar incidence between the treatment arms, in ''''''''''% of patients in the darolutamide+docetaxel group and in ''''''''''% of patients in the placebo+docetaxel group (Table 21).[44] Docetaxel-related events reported in ≥ 20% of patients in either the darolutamide+docetaxel or placebo+docetaxel treatment group included alopecia ('''''''''''% versus ''''''''''%, respectively), neutrophil count decreased (''''''''''''% versus ''''''''''''%), fatigue (''''''''''''% versus ''''''''''''%), and WBC count decreased (''''''''''% versus ''''''''''%) (Table 24).

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Table 24: Study drug and docetaxel-related TEAEs by MedDRA and worst CTCAE grade occurring in ≥ 5% of patients (SAS)

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B.2.10.6 Adverse events of special interest

Adverse events of special interest were defined as events/disorders representing potential risks known to be associated with ADT or with anti-androgens. Most of the reported events were comparable in both treatment groups with no major differences (Table 25).[44, 45] The majority of events reported for fatigue/asthenic conditions, bone fractures, fall, vasodilatation and flushing, breast disorders/gynaecomastia, rash, mental impairment disorders, depressed mood disorders, seizure and decreased weight were Grade 1 or 2 in both treatment groups (Appendix F). A general trend of decreasing incidence of TEAEs of special interest was observed in both treatment arms after the first 6 months of study treatment, with the exception of hypertension.

Table 25: Incidences and exposure-adjusted incidence rates of TEAEs of special interest associated with ADT or anti-androgens (SAS)

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The majority of adverse events (AEs) of special interest with incidences slightly higher in the darolutamide+docetaxel group compared to the placebo+docetaxel group exhibited similar EAIRs when adjusted for the difference in study drug treatment duration, demonstrating no increased risk.[44] For other AEs of special interest where the incidence risk ratio for EAIR was > 1 or there was a disproportionality in their incidence between treatment groups:[44]

• Breast disorders/gynaecomastia: the observed slight difference in the incidence of breast disorders/gynaecomastia was not considered clinically relevant. All events of breast disorders/gynaecomastia were either Grade 1 or 2 as the worst grade in both treatment groups. No TESAEs, study drug or docetaxel discontinuations, dose interruptions or dose reductions were reported due to breast disorders/gynaecomastia in the darolutamide+docetaxel group

• Rash: rash events resulting in dose modification or permanent discontinuation of study drug or docetaxel treatment, and events with Grade 3 or 4 as the worst grade were more common in the darolutamide+docetaxel group

• Hypertension: the incidence of Grade 3 events were consistently higher in the darolutamide+docetaxel group regardless of history of hypertension; however, these events did not lead to dose modifications or permanent discontinuation of darolutamide

• '''''''''

• • Coronary artery disorders: fatal events of myocardial infarction were reported in the darolutamide+docetaxel group. In both treatment groups,

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coronary artery disorders were more commonly reported in patients who had a medical history of cardiac disorders. With the known history of patients who experienced cardiac disorders along with the known side effects of ADT causing metabolic changes contributing to these events, no evidence was seen to link the events to darolutamide

• Cerebral haemorrhage: all ''''''' reports of cerebrovascular accident (CVA) in the darolutamide+docetaxel group were confounded by preceding surgery, trauma, and underlying comorbidities. No evidence was found for an increased risk of cerebral and intracranial haemorrhage for patients treated with darolutamide compared with placebo, both in combination with docetaxel and ADT

• Seizure: considering the low number of seizure events reported, with none leading to permanent discontinuation of darolutamide, and confounding factors reported in '''''''' of the patients, it is concluded that there is not sufficient evidence for an increased risk of seizure with darolutamide in combination with docetaxel and ADT

B.2.10.7 Safety overview

The data from ARASENS demonstrated that darolutamide in combination with docetaxel and ADT had an acceptable safety profile in the target indication, characterized by AEs that were mostly predictable and reversible.[44] Treatment with darolutamide did not adversely affect the overall safety of docetaxel and ADT, and it did not add to the toxicity profile that is driven by the six cycles of docetaxel.[89] Discontinuation rates due to AEs with darolutamide plus docetaxel and ADT were similar to those with docetaxel and ADT, highlighting the favourable tolerability profile of darolutamide. Furthermore, adding darolutamide to docetaxel and ADT did not affect the ability of patients to complete the full six cycles of docetaxel treatment.

In general, the incidence, severity, and nature of the most commonly reported TEAEs in patients treated with darolutamide in combination with docetaxel were consistent with those expected of the individual compounds in the target population (patients with advanced age and underlying disease).[44] Importantly, the incidences of these events were similar between the treatment groups; there was a higher incidence of hypertension in the darolutamide+docetaxel group compared with the placebo+docetaxel group, however, the EAIRs were similar when adjusted for the

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difference in study drug treatment duration. The combination of darolutamide with docetaxel did not show an increase in most of the known expected toxicities of either drug, or specific safety concerns which are known to be associated with the currently existing therapeutic options for mHSPC. Based on the analysis of common TEAEs over time, the incidences for the majority of events were highest during the first 6 months after the start of study treatment in both treatment groups, corresponding to the docetaxel treatment period. After that, a trend towards lower incidence and reduced severity of TEAEs was observed in both treatment groups for most TEAEs.

As recommended in the SmPC for docetaxel, patients should be monitored for signs of neutropenia, gastrointestinal toxicity, worsening pulmonary symptoms and tumour lysis syndrome.[90] Hypersensitivity reactions may occur within a few minutes following initiation of the infusion of docetaxel, therefore facilities for the treatment of hypotension and bronchospasm should be available. No additional monitoring is warranted with the addition of darolutamide to docetaxel and ADT.

B.2.11 Ongoing studies

The ARASENS study is complete; no other studies are investigating darolutamide in combination with docetaxel and ADT in mHSPC patients. The primary analysis in ARASENS focused on OS as the primary outcome, the follow-up duration was sufficient to provide mature data and there will be no further data cuts.

B.2.12 Interpretation of clinical effectiveness and safety evidence

B.2.12.1 Principal findings from the clinical evidence

The ARASENS study met its primary objective, showing a statistically significant improvement of OS in patients treated with darolutamide in combination with docetaxel and ADT compared with placebo in combination with docetaxel and ADT.[44, 45] The risk of death was 32.5% lower in the darolutamide+docetaxel group than in the placebo+docetaxel group. This result was observed despite a higher percentage of patients receiving life-prolonging subsequent therapy after discontinuation of study treatment in the placebo+docetaxel group (75.6%) compared with the darolutamide+docetaxel group (56.8%). A consistent OS benefit

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for darolutamide in combination with docetaxel was observed across all pre-specified subgroups, including baseline extent of disease, ALP, age, ethnicity, geographical region, PSA, ECOG PS, Gleason score and metastasis at initial diagnosis. Treatment compliance was high in both treatment groups, where more than ''''''% of patients received planned dose of study drug and more than 85% of patients completed the full 6 cycles of docetaxel.

In addition to the OS improvement, a consistent benefit in secondary endpoints also favoured darolutamide plus docetaxel and ADT.[44, 45] The time to CRPC was significantly longer in the darolutamide+docetaxel group compared to the placebo+docetaxel group (64% reduction in risk), and almost half the amount of patients progressed to CRPC (35% versus 60%, respectively). This significantly reduces the burden on patients, as progression leads to deterioration of HRQL and poorer prognosis (see Section B.1.3.3). Additionally, treatment with darolutamide plus docetaxel and ADT resulted in significantly longer time to pain progression, SSE-FS, time to first SSE and time to first subsequent antineoplastic therapy, all of which are key to maintaining patients HRQL and reducing the burden on both patients and the NHS. Results of the exploratory endpoints further supported the conclusion of clinical benefit for patients in the darolutamide+docetaxel group compared with the placebo+docetaxel group, including a longer time to PSA progression in the darolutamide+docetaxel group. HRQL (measured by NCCNFACT-FPSI-17 and BPI-SF) was maintained in patients from both treatment groups while receiving study treatment.

Darolutamide in combination with docetaxel and ADT is the first multimodal, triplet therapy with demonstrated prolonged survival and delayed disease progression in patients with mHSPC. By delaying progression to mCRPC, darolutamide is likely to reduce the high levels of psychological burden associated with the inevitable progression to a disease state with worse prognosis with current SoC. The added benefit of darolutamide in combination with docetaxel therapy outweighed any additional toxicity, which was transient and did not affect overall HRQL.[44] Darolutamide in combination with docetaxel and ADT has an acceptable safety profile in the target indication, characterized by AEs that are mostly predictable and reversible. Furthermore, darolutamide exhibits fewer pDDIs compared to

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enzalutamide or apalutamide,[43] which may drive clinical decisions in situations where these considerations are clinically important.[37]

Results from NMAs of OS, PFS base and alternative networks reported that darolutamide + docetaxel + ADT is the most efficacious treatment in the evidence base. For OS, darolutamide + docetaxel + ADT had a ''''''''''''''''''''''''''' '''''''''''''''''''''''''' ''''''''''''''

'''''''''''''''''' '''' '''''''''''''' ''''''''''' '''''''''' '''''''''''''' ''''''''' ''''''''' ''''''''''' '''''''''' '''''' ''''''''''' ''''''''''''' and when

compared to '''''''''''''''''''''''''''''' '''''''''' '''''''''''' the HR was in '''''''''''''''' ''''' ''''''''''''''''''''''''''''''' '''

'''''''''''''''''''''''' '''''''' ''''''''''' ''''''''' ''''''''' '''''''''''' '''''''''''' ''''''' '''''''''''' ''''''''''''' This effect was consistent for the progression outcomes (PFS base and alternative networks).

B.2.12.2 Strengths and limitations of the evidence base

ARASENS was a large RCT that investigated the efficacy and safety of the first triplet combination therapy, darolutamide plus docetaxel and ADT, for the treatment of patients with de novo and recurrent mHSPC. It was a high-quality study with an overall low risk of bias, that investigated outcomes that are relevant to clinicians and patients, and are commonly used in clinical practice.[37] It is the only study in mHSPC which included a more active comparator widely used as part of the SoC (docetaxel plus ADT). ARASENS provided robust data directly relevant to the decision problem being addressed, which demonstrated that darolutamide plus docetaxel and ADT significantly improved survival for patients with mHSPC and significantly reduced the time progression to mCRPC in comparison to placebo plus docetaxel and ADT.

There remains an unmet need for a treatment approach that prolongs survival and delays disease progression to mCRPC beyond current SoC, without compromising tolerability or patients’ HRQL. Therefore, darolutamide plus docetaxel and ADT, as demonstrated by ARASENS, has the potential to improve patient outcomes and change the landscape of current clinical practice.

Although the ARASENS study did not capture EQ-5D questionnaire data, HRQL data were reported using validated instruments (NCCN–FACT FPSI–17 and BPISF). The NCCN–FACT FPSI–17 questionnaire assesses symptoms of prostate cancer, symptoms of treatment of prostate cancer, and HRQL of prostate cancer patients, while the BPI-SF is a widely used tool to assess patient-reported levels of pain. The HRQL evaluation in ARASENS demonstrated that HRQL was maintained

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in both treatment groups and the addition of darolutamide to docetaxel and ADT had no detriment to patients HRQL.

A notable limitation of the evidence base is that there are no head-to-head data for darolutamide plus docetaxel and ADT versus enzalutamide and ADT or ADT alone, which are listed as comparators in the scope of this appraisal. The ARASENS study was started before regulatory and NICE approval of enzalutamide and ADT[38] , and therefore did not include it as a comparator. To address this limitation, an ITC was conducted, and the findings demonstrate that darolutamide plus docetaxel and ADT is the most efficacious treatment in the evidence base for OS and PFS (Section B.2.9).

B.2.12.3 Applicability of clinical evidence to practice

As confirmed by clinical experts, ARASENS provides head-to-head data for the relevant comparator used in clinical practice, which is docetaxel and ADT.[37] A realworld treatment pattern study demonstrated that ADT alone and docetaxel plus ADT were the most common initial mHSPC treatments received in the UK in 2020 (47.2% and 40.2%, respectively), while novel hormonal agents plus ADT were used the least (12.6%).[91] However, as part of a clinical advisory board, clinicians noted that the lockdowns caused by the COVID-19 pandemic resulted in a decrease in docetaxel prescribing in a number of centres from April 2020, in some cases falling below 5%. At the same time, some centres also saw an increase in prescribing of enzalutamide+ADT. This is likely due to enzalutamide being easier to manage and requiring less resource use; therefore, the significant staffing issues associated with the pandemic resulting in some clinicians making different treatment choices. It is important to note, however, that there was significant inter-regional variation,[14] with some centres not changing their practice at all during this time. Clinicians estimated that androgen receptor targeting agents (ARTAs) are currently prescribed in > 50% of patients, and therefore could arguably be considered current SOC.[37] However, rapid access data for the UK in 2021 will be available later this year, which will confirm the current situation and how things have changed. It is estimated that with resourcing issues returning more closely to normal approaching the end of the COVID pandemic, prescribing decisions may also have returned to their prepandemic levels, with docetaxel plus ADT remaining as SoC.

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As part of a clinical advisory board, a consensus was gained that the ARASENS population was reflective of other clinical trials and reflective of the population that would be considered suitable for chemotherapy in UK clinical practice.[37] In total, ''''''' patients were enrolled across ''''''''''' UK trial centres in ARASENS, with '''''' patients in the darolutamide+docetaxel group and '''''' patients in the placebo+docetaxel group being included in the FAS.[44] This is a reasonable proportion for an international study, enabling meaningful representation of UK clinical practice in trial outcomes and clinical efficacy results which we would expect in clinical practice in England. The outcomes in ARASENS are relevant to patients and commonly used in clinical practice, and efficacy data for the docetaxel plus ADT group was considered to be in line with other publications and evidence.[37]

The addition of darolutamide to the combination of docetaxel plus ADT is not associated with any significant NHS clinical service changes; darolutamide plus ADT is already reimbursed for the treatment of adult patients with nmCRPC at high risk of developing metastatic disease, and docetaxel plus ADT is reimbursed for mHSPC.[92, ] 93

Darolutamide has been reported to exhibit fewer pDDIs compared to enzalutamide or apalutamide[43] , and limited DDIs have been seen when darolutamide was administered alongside medications commonly used to treat comorbidities in an elderly patient population, such as calcium channel blockers and anticoagulants.[48-50] Enzalutamide and apalutamide are potent enzyme inducers, therefore interaction with many common medicinal products that are substrates of enzymes is expected.[94, 95] This can lead to reduction in plasma concentrations, lost or reduced clinical effect and also increase the risk of formation of active metabolites; all of which may lead to sub-optimal treatment of comorbidities while being treated for mHSPC. This is particularly important as most mHSPC patients are elderly (> 65 years) and a considerable proportion will have comorbidities, some of which may be life limiting.[9, 96] Due to polypharmacy in mHSPC patients, some potential drug-drug interactions could be missed, which is a major concern for clinicians.[37] In this regard, clinicians were reassured by the reduced DDIs observed with darolutamide as it would result in less resource intensive monitoring of any interactions.[37]

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As demonstrated in ARASENS, darolutamide in combination with docetaxel and ADT significantly increases OS, significantly increases the time to mCRPC, maintains patients’ HRQL and has an acceptable safety profile in patients with mHSPC (Section B.2.6).[44] The very positive benefit-risk ratio of this first triple combination therapy reinforces its use early on in this aggressive metastatic pathway.

B.3 Cost-effectiveness

B.3.1 Published cost-effectiveness studies

A systematic literature review (SLR) was conducted to identify cost-effectiveness studies in mHSPC. Full details of the search methods and results are presented in Appendix G. The search identified 30 publications that met the inclusion criteria. As some studies were associated with multiple publications, secondary publications were combined, leaving 23 unique studies. However, for the purpose of this submission, only details from the UK studies are discussed below (Table 26).

Searching the NICE website identified three previous STAs for adults with mHSPC. These appraisals are summarized in Table 27 and include:

• NICE TA712[38] , which assessed the cost-effectiveness of enzalutamide plus ADT for treating mHSPC in the UK

• NICE TA721[42] , which assessed the cost-effectiveness of abiraterone with prednisone or prednisolone and ADT in newly diagnosed high-risk mHSPC

• NICE TA741[88] , which assessed the cost-effectiveness of apalutamide plus ADT for treating mHSPC in the UK

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Table 26: Summary list of published cost-effectiveness studies

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Table 27: Previous NICE TAs

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B.3.2 Economic analysis

As no relevant economic studies investigating the cost-effectiveness of darolutamide+docetaxel+ADT in adult men with mHSPC were identified, a de novo model was developed. The design of this model is described below.

B.3.2.1 Patient population

In line with the ARASENS trial and anticipated marketing authorization for darolutamide, the patient population considered in this analysis is adult men with mHSPC.[46]

Population characteristics in the model are aligned with those of the ARASENS trial population; the mean age at baseline is 66.8 years. Section B.2.3.1 provides further details on the baseline characteristics of patients participating in the ARASENS trial. As discussed in Section B.2.12.3, clinical experts confirmed that the ARASENS population, and therefore the population in the model, was reflective of the population that would be considered suitable for chemotherapy in UK clinical practice.[37] .

B.3.2.2 Model structure

A de novo cost-effectiveness model was developed in Microsoft Excel[®] . A partitioned survival model with three health states (pre-progression, post-progression and death) was selected as the model structure. The three-state partitioned survival model is widely used in oncology modelling, including in previous NICE TAs for mHSPC and the darolutamide model in nmCRPC.[38, 42, 88, 100] In TA660, TA712 and TA741, a partitioned survival model structure was considered most appropriate. In TA721, a more complex, multi-state modelling approach was used initially; however, this was subsequently criticized by the Evidence Review Group (ERG) and the model was rebuilt during the appraisal to follow a partitioned survival structure. A partitioned survival model was therefore deemed most appropriate for NICE decision-making.

The model structure, as shown in Figure 16 below, is fully aligned with the NHS treatment pathway and with the primary objectives of treatment in mHSPC: delaying

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disease progression to progressed mHRPC, and avoiding debilitating symptoms and reduced HRQL, as discussed in Section B.1.3

Figure 16: Model structure

==> picture [492 x 177] intentionally omitted <==

Key: mHRPC, metastatic hormone-relapsed prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; OS, overall survival; PD1, progressed disease – first line; PD2, progressed disease – second line; PD3, progressed disease – third line; PFS, progression-free survival; ToT, time on treatment; Tx, treatment.

The model has three mutually exclusive health states:

• mHSPC, progression-free: all patients enter the model in the mHSPC health state. In this state, the disease is stable and responding to treatment. For the darolutamide and enzalutamide treatment arms, the mHSPC health state is further partitioned into active treatment and no active treatment, based on modelled time on treatment (ToT). In line with current UK clinical practice, background ADT continued indefinitely[37]

• mHRPC, progressed disease : it is assumed patients who have progressed to hormone-relapsed disease to have moved onto subsequent treatment. To model this progression across treatment lines, the mHRPC health state is divided into three lines of treatment (first line [1L], second line [2L] and third line [3L], respectively) that patients subsequently progress through. This reflects the multiple lines of therapy available in the NHS (see Section B.1.3.4)

• Dead : this is an absorbing state

Health state occupancy in a partitioned survival model is dictated by the area under

the curves for the different survival inputs. Progression was modelled using time to

CRPC, which was taken from ARASENS. This was considered to be better aligned

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with UK clinical practice than rPFS, as time to CRPC consists of multiple criteria used to assess disease progression in UK practice and does not rely on a set assessment schedule like rPFS (see Section B.3.3 for more details).[37] However, the definition of time to CRPC used in ARASENS did not include death as an event. To account for patients leaving the pre-progression health state by either progression or death, an additional analysis was conducted to derive an amended secondary endpoint in which death was included as an event to measure all risks in preprogressed patients, as discussed in Section B.2.6.2.1.1. For this analysis, PFS is therefore defined as time to castration resistance or death (TTCROD). This approach was validated by expert clinicians at an advisory board meeting, who agreed that rPFS is more reflective of how progression was assessed in other mHSPC trials rather than clinical practice, and that TTCROD is a more clinically reflective progression endpoint.[37]

OS is based on the ARASENS primary endpoint. TTCROD was used directly to estimate the proportion of patients in the mHSPC, mHRPC and death health states over time, where

• mHSPC = TTCROD

• mHRPC = OS - TTCROD

• Dead = 1 - OS

All post-progression treatment costs are applied as a single weighted lump-sum cost upon progression, based on publicly available data for time to progression or treatment discontinuation. This approach is most aligned with a partitioned survival model structure, which relies on survival curves to model progression, since there are no direct trial data or survival curves to inform progression between the different post-progression health states (PD1-3). This approach is also in line with the approached used in the previous darolutamide model in nmCRPC (TA660).

B.3.2.3 General model settings

The analysis perspective is that of the NHS and Personal Social Services (PSS) in England for costs and direct health effects on individual patients for outcomes, in line with the NICE reference case.[101]

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The model uses a 28-day cycle length. A half-cycle correction is applied throughout the model to both costs and health outcomes to better account for the fact that some costs can occur at any point during the cycle, while other health outcomes are spread across time. The analysis assumes a lifetime time horizon (34 years), which is sufficient to capture the plausible maximum life expectancy for the ARASENS intention-to-treat (ITT) population (mean age 66.8 years). Shorter time horizons are explored in the scenario analysis in Section B.3.11. A discount rate of 3.5% per year is applied to costs and quality-adjusted life years (QALYs), which is also specified in the NICE reference case.[101] All costs are presented in British pounds sterling (GBP) and the cost year is 2021.

General model settings, along with a comparison of settings used in past appraisals in mHSPC and a brief justification for our approach, are summarized in Table 28. Not all previous appraisals are equally representative, as they either cover treatments that were not approved in the UK (abiraterone, TA721)[42] , or approved in a different patient population (apalutamide, TA741).[88] The enzalutamide+ADT appraisal, TA712, is therefore the most relevant source of comparison and validation for this appraisal.[38, 42, 88]

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Table 28: Features of the economic analysis

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