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Single Technology Appraisal

Abiraterone for treating newly diagnosed metastatic hormone-naive prostate cancer [ID945]

Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Abiraterone for treating newly diagnosed metastatic hormone-naive prostate cancer [ID945]

Contents:

Final Scope and Final Matrix of Consultees and Commentators

1. Pre-Meeting Briefing

2. Company submission from Janssen

• Company submission

• Company evidence submission - IA2 addendum

3. Clarification letters

• NICE request to the company for clarification on their submission ’

• Company response to NICE s request for clarification

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

• British Association of Urological Surgeons (BAUS)

• British Uro-oncology Group (BUG) The Royal College of Physicians endorsed the BUG statement

• Prostate Cancer UK

• Tackle Prostate Cancer

• NHS England

5. Expert statements from:

• Brian John Davies – patient expert, nominated by Prostate Cancer UK

• Professor Nicholas James – clinical expert, nominated by Janssen

6. Evidence Review Group report prepared by the Aberdeen HTA Group

7. Evidence Review Group report – factual accuracy check

8. Evidence Review Group report – erratum

9. Evidence Review Group report – addendum

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

Pre-meeting briefing Abiraterone for treating newly diagnosed metastatic hormone-naïve prostate cancer

This slide set is the pre-meeting briefing for this appraisal. It has been prepared by the technical team with input from the committee lead team and the committee chair. It is sent to the appraisal committee before the committee meeting as part of the committee papers. It summarises:

• the key evidence and views submitted by the company, the consultees and their nominated clinical experts and patient experts and

• the Evidence Review Group (ERG) report

It highlights key issues for discussion at the first appraisal committee meeting and should be read with the full supporting documents for this appraisal

Please note that this document includes information from the ERG before the company has checked the ERG report for factual inaccuracies The lead team may use, or amend, some of these slides for their presentation at the Committee meeting

1

Prostate cancer disease background

• 46,700 people diagnosed with prostate cancer in UK (2014)

• ~18% new diagnoses present with metastases

• Newly diagnosed patients have poorer prognosis than primary progressive metastatic prostate cancer (people who present with localised disease but develop metastases later)

  • 30% 5-year survival

• ≥50% of patients experience pain, fatigue and drowsiness. Bone pain often the most distressing & dominant

• ≤75% of patients develop bone disease that can result in skeletal-related events (SREs) including spinal cord compression and pathological fracture (associated with loss of mobility/further impaired quality of life/significant healthcare costs)

• Urological complications often lead to abdominal pain, urinary retention and dysuria

2

Prostate cancer disease background

• Prostate cancer is an androgen dependent disease. Inhibition of testosterone (androgen deprivation therapy, ADT) is the key initial treatment strategy

• ADT consists of a luteinising hormone-releasing hormone (LHRH) agonist. Surgical castration (orchidectomy) and bicalutamide monotherapy are less commonly used options

• Most people respond to ADT  but vast majority develop progressive disease within 1 to 2 years

• Note on terminology:

  • Hormone sensitive metastatic prostate cancer (mHSPC): people with metastatic disease who have not yet received hormone therapy, or have received ADT but have not become resistant to it

  • Hormone naïve metastatic prostate cancer (mHNPC): people with metastatic disease who have not yet received hormone therapy

  • Castrate resistant metastatic prostate cancer (mCRPC, sometimes also referred to as hormone refractory prostate cancer (mHRPC): metastatic prostate cancer which has progressed and is resistant to ADT

3

Patient experience

Experience of current treatments

• although life expectancy with prostate cancer has improved, all treatments can decrease quality of life

• Problems with current treatments include fatigue, “chemo fog” (an inability to concentrate for long periods of time) and loss of libido

• Stressful for patients (+ carers) to know their treatment will eventually fail. Patients may worry about what may be the next treatment may be, its side effects and whether they can cope with it.

Patient experience/ thoughts on having option of abiraterone + androgen deprivation therapy (ADT)

• No curative treatments so all new life-extending treatment options welcomed.

• Particular unmet need for life-extending treatments for people who cannot have docetaxel +ADT, either because they are not fit enough to tolerate it, or docetaxel is contraindicated

• Patient on abiraterone reported: After almost 4 years of treatment I have very few problems. I am very active….. [and] busy around the house and garden. I don’t have, or need a carer.

• There is the worry that if all of the advanced treatments are given at the beginning of treatment there will be nothing left in reserve, but the benefits outweigh the disadvantages of this

4

Abiraterone (Zytiga, Janssen)

5

Abiraterone: licensed indications

Indication under appraisal (MA gained Nov 2017)

• the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT).

• In trials, high risk prognosis defined as having ≥2 of the following 3 risk factors:

  • (1) Gleason score of ≥8; ( range 6 to 10. Cells taken from a biopsy are assessed for how quickly they are likely to grow)

  • (2) presence of 3 or more lesions on bone scan;

  • (3) presence of measurable visceral (excluding lymph node disease) metastasis

Indication appraised in TA387

• the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated

• Indication appraised in TA259

• the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

6

Treatment pathway NICE/NHSE guidance HORMONE CASTRATE RESISTANT Metastatic SENSITIVE Metastatic

ADT, androgen deprivation therapy; TA, technology appraisal; Chemotx, chemotherapy

Use of off-license docetaxel with ADT for hormone naïve prostate cancer

• Marketing Docetaxel in combination with prednisone or prednisolone is authorisation indicated for the treatment of patients with hormone refractory metastatic prostate cancer (when used for this indication eo le have u to 10 c cles of docetaxel p p p y )

• NHS En land off-label use in combination with ADT g ( )

• Clinical NHS England will commission ( up to 6 cycles ) docetaxel for commissioning the treatment of hormone naive metastatic prostate cancer ) policy statement if: •

• (2016) have newly diagnosed metastatic, prostate cancer; • are either commencing, or who have commenced within 12 weeks, long-term hormone therapy (Androgen Deprivation Therapy) for metastatic disease for the first time; and

• • have sufficient performance status to be treated with 6 cycles of docetaxel chemotherapy

• (dose same as label, prednisolone for first 3 weeks)

ADT, Androgen Deprivation therapy

8

Decision problem ERG agrees with company’s comparators

Clinical trial evidence: overview

Abiraterone + prednisolone + ADT vs. ADT

• Direct comparison (newly diagnosed, high-risk mHSPC) with ADT – LATTITUDE: AAP (abiraterone + prednisolone) + ADT vs. ADT

• – STAMPEDE* (UK MRC trial, but included wider population than indicated for abiraterone + ADT because included people with localised disease)

Abiraterone + prednisolone + ADT vs. Docetaxel + ADT

• Direct comparison

  • STAMPEDE

• Indirect comparison for comparison with Docetaxel + ADT • LATTITUDE: AAP + ADT vs. ADT

  • GETUG-AFU15 (Docetaxel + ADT vs ADT),

  • CHAARTED (Docetaxel + ADT vs. ADT)

• Supporting direct randomised comparison data from STAMPEDE*

  • AAP + ADT vs. ADT

  • STAMPEDE metastatic disease subgroup

  • – Sensitivity analyses around indirect comparison)

10

LATITUDE: overview

abiraterone + ADT vs. ADT

Patients

• Adults

• Newly diagnosed (<3 months) adults

• • high risk mHSPC (1) Gleason score of ≥8

(2) ≥3 lesions on bone scan;

(3) measurable visceral

(excluding lymph node disease) metastasis

• with ECOG

performance status 0,1,or 2

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n=597

Abiraterone 1000 mg once daily + Prednisolone 5 mg once daily + ADT*

Double-blinded 1:1 randomisation

Treatment until disease progression, withdrawal of consent or unacceptable toxicity 60 months follow up

ADT alone* n=602

Endpoints

• 1°

• Overall survival

• • Radiographic progression free survival (investigatorassessed)

• 2°

• Time to:

  • Starting chemotherapy

  • • Next SRE

• Pain progression

• • Next therapy

• • PSA progression

• • Qol (including EQ-5D5L)

• Safety

*LHRH or bilateral orchidectomy

11

LATITUDE: statistical analysis plan

• Pre-randomisation stratification by presence/absence visceral disease and performance status (0,1 or 2)

• Intention to treat (ITT) used for all analyses (excluding 10 patients removed from ITT population because of Good Clinical Practice non-compliance at 1 study site)

• Safety population: all randomised patients who received study drug, except those from non-compliant site

• Statistical significance for co-primary endpoint 0.05: OS (0.049) and rPFS (0.001)

• • Planned statistical analyses:

Interim Number (%) of required Date met In company analysis events (deaths) for statistical model power Interim 1 426 (50%) 31[st] Oct 2016 (30.4 Yes months follow up) Study ended early; unblinded + crossover permitted 12[th] Jan 2017 Interim 2 554 (65%) 2[nd] Oct 2017 (41.4 No months follow up) Final 852 (100%) Not met No 12

Baseline Characteristics

LATITUDE: investigator-assessed radiographic progression free survival (rPFS)

• AAP + ADT delayed disease progression compared with ADT alone

• Median rPFS 33.0 months with AAP + ADT and 14.8 months with ADT

• Hazard ratio, 0.47 (95% CI 0.39 to 0.55)

Reference: Fizazi et al. 2017 NEJM 377:352-360

14

LATITUDE: Overall survival

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----- Start of picture text -----
•
At interim anal sis 1 30.4 months follow u
y ( p)
ADT AAP + ADT
Deaths n (%) 237 (39%) 169 (28%)
Median survival months 34.7 Not reached
(95% CI) (33.0, not reached)
Hazard ratio 0.62, 95% CI 0.51 to 0.76 p<0.001
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15

Reference: Fizazi et al. 2017 NEJM 377:352-360

LATITUDE: adjustment for subsequent treatments

• More people on ADT (40.9%) had subsequent treatments than AAP + ADT (20.9%)

• Company used the Inverse Probability Censoring Weighted (IPCW) analyses to adjust for subsequent treatment

  • adjusted hazard ratio for overall survival 0.48 (95% CI 0.36 to 0.63)

• Company “Due to small sample sizes across sequences of interest, limited follow-up and an imbalance in patient characteristics across switchers versus non-switchers in the current dataset, these analyses are not robust enough to present or take forward to subsequent

• modelling at this time , but were all in favour of AAP + ADT”

16

Second interim analysis unadjusted for crossover *** of patients had crossed over from ADT to AAP +ADT (median time on AAP + ADT after ADT was *** months). The presented results are unadjusted for crossover.

NR, not reached

17

Trials included in the network metaanalysis

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ERG agree that STAMPEDE does not provide sufficiently comparable data for the considered patient population to be included in the indirect treatment comparison

However, STAMPEDE investigators have performed a direct randomised comparison of abiraterone (+ prednisone + ADT) to docetaxel (+ ADT)

Key: AAP, abiraterone acetate + prednisolone; ADT, androgen deprivation therapy; DOC, docetaxel. Notes:[a] , Continuous lines in this network represent the trials contributing to the primary analyses and is meant to depict the greatest number of trials that can be included in the analyses. One trial (STAMPEDE) was not considered in the base case ITC 18 due to differences in patient population. Dotted lines represent the trials contributing to the sensitivity analyses.

Description of trials included in the network meta-anal sis NMA y ( )

STAMPEDE: comparison of abiraterone + ADT with ADT

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SOC , standard of care; RT, radiotherapy; M1,
metastatic prostate cancer; E+A, enzalutamide
+ abiraterone; E2 transdermal oestradiol
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20

Summary: differences in populations included in clinical trials in the NMA

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NDx, newly diagnosed 21

Definition of high risk (and high volume disease

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LATITUDE
HIGH RISK (at least 2 of 3)
Three or more Visceral Gleason
bone lesions metastasis score ≥8
HIGH VOLUME (1 of 2)
CHAARTED and GETUG-AFU 15
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22

Further differences between trials included in network meta-analysis

ADT, Androgen deprivation therapy; AAP abiraterone + prednisolone; Doc, docetaxel; RECIST, Response Evaluation Criteria in 23 Solid Tumours; PCWG2, Prostate Cancer Working Group 2; rPFS, radiographic Progression Free Survival

Baseline characteristics across trials red boxes show notable differences to LATITUDE

a metastatic subgroup; b, High-volume disease defined as visceral metastases and/or ≥4 bone metastases with at least one metastasis beyond the pelvis or vertebral column;[c] , High-volume disease was retrospectively defined in the GETUG-AFU 15 trial following the CHAARTED definition (visceral metastases 24 and/or ≥4 bone metastases with at least one metastasis beyond the pelvis or vertebral column)

Network meta-analysis: results

Similar overall survival and progression free survival with AAP + ADT vs. docetaxel + ADT

AAP, abiraterone; ADT, androgen deprivation therapy; ITT, intention to treat; NDx new diagnosis; HV, high volume; HR, hazard 25 ratio; CI, confidence interval; CrI, credible interval; PAA-Doc , Bayesian pairwise probability of abiraterone + ADT being more effective than docetaxel + ADT

PFS: estimates from LATITUDE and metastatic sub rou from STAMPEDE g p

Definitions of progression outcomes in STAMPEDE. Failure free survival: radiologic, clinical, PSA progression or death from prostate cancer. PFS[b] defined as radiologic or clinical progression 26 or death from prostate cancer

Overall survival results from LATITUDE compared with STAMPEDE For abiraterone vs. docetaxel, STAMPEDE directly randomised results differ from company’s indirect comparison

LATITUDE: Adverse events

EPAR, “the safety profile of AAP is well characterised. In this new setting, no new unexpected events have been reported.” In addition, whilst it “cannot be excluded that a lower dose of prednisone did not impact the incidence of hypertension in (LATITUDE), AEs (including hypertension) were generally manageable and the benefits outweigh the risks for the claimed indication.”

28

LATITUDE: types of adverse event

29

STAMPEDE: adverse events grade 3-5 abiraterone + ADT and docetaxel + ADT arms

Network meta-analysis safety results

31

LATTITUDE: Quality of life summary

Quality of life measure Results

EQ-5D-5L visual analogue scale and utility score Functional Assessment of Cancer TherapyProstate (FACT-P)

Sustained improvements with AAP + ADT vs ADT until disease progression

Functional Assessment Time to FACT-P score worsening: • of Cancer TherapyAAP + ADT: 12.9 months (95% CI 9.0, 16.6) • Prostate (FACT-P) ADT: 8.3 ( 95% CI 7.4, 11.1) HR (time to worsening QoL) 0.85 (95% CI 0.74, 0.99) Brief Fatigue Inventory AAP + ADT  35% reduction in the time to BFI (BFI) worse fatigue intensity compared with ADT (HR= 0.65 [95% CI: 0.53 to 0.81]) • Median time to pain AAP + ADT: not reached • progression measured ADT: 16.6 months by Brief Pain Inventory HR (pain progression) short form 0.70 [95% CI: 0.583-0.829]

Median time to pain progression measured by Brief Pain Inventory short form

32

Network meta-analysis, quality of life results: FACT-P

CI, confidence interval; CrI, credible interval; ITC, indirect treatment comparison 33

Network meta-analysis, quality of life results: Brief Pain Inventory

CI, confidence interval; CrI, credible interval; ITC, indirect treatment comparison 34

ERG comments on NMA

• Bayesian network meta-analysis a reasonable approach

• Preferred random effects model to company’s fixed effect model

  - Using random effects model for OS resulted in a lower HR but wider credible intervals. **HR 0.894, 95% CrI 0.258 to 2.979** 
  

• Not possible to use random effects for PFS (only 2 studies with PFS)

• • In comparison including docetaxel +ADT trials :

  • Heterogeneity between studies: patient characteristics (newly diagnosed, and/or primary progressive; high volume/high risk); variable ADT and docetaxel doses between studies; varying previous and subsequent treatments; reporting variations; different definitions of progression free survival; length of studies

  • ERG have “huge reservations for taking [indirect comparison of AAP + ADT vs. docetaxel + ADT] forward to economic modelling …”

  • ERG confirm that abiraterone at least equivalent to docetaxel  but estimates might not be robust

35

Key Issues: clinical

• Are there people who can take:

  • ADT, but not abiraterone + ADT? Who are they?

  • abiraterone + ADT but not docetaxel + ADT ? Who are they?

• For abiraterone + ADT vs. ADT, are estimates for overall survival from LATITUDE robust? If not, is this accounted for in part by:

  • Differences in follow-on treatments in LATITUDE vs. NHS?

  • Differences in when treatment stops in LATITUDE vs. NHS?

• For abiraterone +ADT vs. docetaxel + ADT, which estimate of clinical effectiveness is most robust?

  • Direct, randomised, evidence from STAMPEDE for broader population?

  • Indirect non-randomised, unadjusted evidence from network meta analysis?

• How is quality of life on and after:

  • Abiraterone + ADT? /Docetaxel + ADT?

• Is there any further data from STAMPEDE that would support the company submission?

36

Cost effectiveness model

Health States

• First 5 months: Company used Kaplan Meier data from LATITUDE.

• 5 months + Multi-state Markov model, cycle length 1 week for first year, every 28 days thereafter

Hormone sensitive before progression

• Modelled cohort based on LATITUDE mean age 67 years

• Time horizon 20 years

• Company: used this approach rather than a partitioned survival semi Markov model (used in TA259, 391, 316, 377) “to allow flexibility to explore assumptions around subsequent therapy and post ”

• progression survival 1L = 1[st] line; 2L = 2[nd] line; 3L = 3[rd] line

Castrate resistant Further (‘subsequent’) treatment options

37

Overview: transitions between health states

Transition probabilities

38

Company’s rationale for using Kaplan Meier data for first 5 months

Log cumulative hazard plots of OS (left) and rPFS (right) show proportional hazards after 5 months  company used Kaplan Meier data in its model for the first 5 months and then used multi-state modelling, assuming proportional hazards, thereafter

Overall Survival rPFS

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Figure 26 + 27 company submission page 118 (cumulative hazard plots)

39

Transitions for subsequent therapies in mCRPC health states

• Company: PFS data for subsequent treatment from LATITUDE were not used

  • Low number of patients receiving subsequent therapies within the trial & use of non-UK standard treatments

• Modelled survival outputs from model for TA387 (AAP for mCRPC before chemotherapy). Data extrapolated from COU-AA-302 (see slides 40 + 41)

• All active treatments were assumed to have equal clinical effectiveness* The weighted average survival (and treatment costs) was calculated based upon the expected market share of each treatment in UK practice (see slide 42)†

• Transition probabilities after the 1[st] line mCRPC health state (to 2[nd] and 3[rd] line treatments for mCRPC) estimated by using mean health state durations from TA387 and assuming a constant probability over time

• Using survival outputs from TA387 model overestimates survival in all treatment arms compared with LATITUDE overall survival Kaplan Meier curves ‡

  • Company used a “calibration factor” to adjust the modelled overall survival to reflect LATITUDE (see slides 43 + 44 )¥

40

Summary: modelling of castrate resistant states using TA387 modelled survival

• The choice of survival curves from TA387 to apply in current model dependent on 1[st] treatment for castrate resistant prostate cancer

• Market share estimates also used to estimate % of people receiving active treatments or best supportive care for 2[nd] and 3[rd] treatments. But active/non active 2[nd] and 3[rd] treatments don’t affect survival in model

41

Recap: clinical evidence informing TA387 modelling from COU-AA-302

42

Recap: TA387 company’s discrete event simulation model[[st]]

‘1[[st]] treatment’

Abiraterone Docetaxel Best supportive care Compared with: Best supportive care Docetaxel Abiraterone

Model in ut Com an p p y Prediction equations 17 prediction equations Include baseline covariates Population 83% of intention-to-treat (ITT) population with data on covariates (‘full covariate subgroup’) Distribution for time on first Log-logistic in base case; Weibull in sensitivity treatment analyses

43

Subsequent treatment market shares for mCRPC used in current model

Modelled overall survival estimates MSM modelling using TA387 model outputs

2. 1. Without calibration With calibration Predicted OS higher than Using calibration factor of HR 2.62 Kaplan-Meier data

45

Company’s alternative approach for modelling mCRPC health state transitions

• Alternative approach using multi state modelling analysis of LATITUDE data for all states including the castrate resistant health states

  • ERG refers to this as the “MSM model”

• Despite the transition probabilities in the model being based on LATITUDE data, 1[st] line mCRPC treatment discontinuation was estimated from mean times spent on 1[st] line mCRPC treatment during the COU-AAP-302 trial

46

Comparison of MSM/TA387 and MSM model Time spent (weeks) in each health state

The red boxes show key differences between the modelled outcomes using these 2 approaches

47

Comparison of MSM/TA387 and MSM model

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----- Start of picture text -----
time spent (weeks) in each health state
MSM/TA387
Doc +
ADTDoc + ADT PFS (mHSPC)
ADT ADT Pre-1 [st] line
mCRPC
AAP + 1 [st] line mCRPC
AAP + ADT
ADT
on-treatment
0 50 100 150 200 250 300 1 [st] line mCRPC
MSM
off-treatment
Doc +
Doc + ADT
ADT 2 [nd] line mCRPC
ADT ADT 3 [rd] line mCRPC
AAP +
AAP + ADT
ADT
0 50 100 150 200 250 300
0 50 100 150 200 250 300
48
modelled time (weeks)
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Recap: proportion of people receiving different mCRPC treatment options

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----- Start of picture text -----
Radium-223
cabazitaxel
AAP
enzalutamide
docetaxel
BSC
AAP ADT Doc + ADT AAP ADT Doc + ADT AAP ADT Doc + ADT
1 [st] line mCRPC 2 [nd] line mCRPC 3 [rd] line mCRPC
AAP ADT Doc AAP ADT Doc + AAP ADT Doc
+ + + ADT + +
ADT ADT ADT ADT ADT
Drug + admin *** *** *** *** *** *** *** ***
(£1000s)
----- End of picture text -----*

49

ERG comments on the modelling approach for mCRPC health states 1/2

Co mpany’s base case approach

• Base case using multistate modelling with some input from TA387 discrete event simulation modelled (ERG refers to as MSM/TA387 model) coupled with a ‘calibration factor’ is a complicated, non-statistical way of fitting curves to LATITUDE data

  • Fitting of the MSM/TA387 model OS curves to LATITUDE OS curves seems to negate the reason for adopting the MSM/TA387 modelling approach.

  • Instead, the company could have used the usual well-established statistical methods to fit curves to the Kaplan Meier data from LATITUDE

• Uncertainty about what 1[st] line mCRPC treatment proportions should be

• applied to subsequent AAP + ADT, ADT and docetaxel + ADT treatments for mHSPC

• Not clear whether NICE approval of abiraterone for mHSPC would, over time, lead to mHSPC patients receiving more than one novel agent for their metastatic prostate cancer

50

ERG comments on the modelling approach for mCRPC health states 2/2

Comparison of base case MSM/TA387 modelling approach and company’s alternative MSM approach

• Base case MSM/TA387 model and alternative MSM models differ in the proportion of mCRPC survival spent on 1[st] line mCRPC treatment and time spent on 3[rd] line mCRPC treatment

  • 1[st] line mCRPC treatment options include more costly active treatments

  • 3[rd] line mCRPC treatment option mostly best supportive care

• MSM model estimates a smaller survival gain for AAP + ADT vs. ADT compared with MSM/TA387 model

• Concerned that both the MSM/TA387 model and the MSM model do not accurately reflect costs and benefits of the 1[st] treatment for mCPRC after a person’s cancer has progressed on their initial treatment for mHSPC

  • For the ADT and Docetaxel + ADT arms the first treatment for mCPRC includes more expensive treatment options like abiraterone or enzalutamide, whereas a greater proportions people receiving AAP + ADT may receive cheaper options like docetaxel or have best supportive care for mCRPC

51

Sources of utility data

Modelled utility value by health state

• Baseline utility (EQ-5D-3L) for people with newly diagnosed MHSPC from LATITUDE was ***

• Effect of being on- or off-treatment from regression analysis of LATITUDE, were applied to this value for AAP + ADT and ADT.

• Data from the time trade off study was applied for docetaxel

ERG comments on the time trade off study

ERG extracted the key differences in the health state descriptions of experience on ADT, on doctaxel + ADT and on ADT after docetaxel (table 60 ERG report)

54

ERG comments utility values for docetaxel

Plausibility that quality of life is worse after docetaxel

• Assumption that quality of life worse after docetaxel (+ ADT) compared with ADT alone not consistent observations reported in literature:

  • GETUG-AFU 15 (Joly et al., 2010): EORTC-ALA-C30 questionnaire. Docetaxel + ADT is associated with an initial deterioration [in quality of life], at 12 months there is no difference in overall quality of life between docetaxel + ADT and ADT

  • CHAARTED (Morgans et al., 2018): FACT-P. Docetaxel + ADT FACT-P scores were significantly lower than ADT at 3 months (difference -3.09, p=0.02), but significantly higher than ADT at 12 months (difference + 2.85, p=0.04), but differences did not exceed the minimum clinically meaningful change at any time point. Authors concluded “[results suggestive that] ADT + Docetaxel is not associated with a greater long-term negative impact on QOL [than ADT]”

• The utility decrement assumed for while a person is on docetaxel is not applied when docetaxel is taken after abiraterone + ADT

55

ERG comments on company’s utility values based on EQ-5D from LATITUDE

• Quality of life estimates collected every 3 months possibly confounded by a greater proportion of people progressing earlier with ADT monotherapy

• Regression analysis from LATITUDE is only partially applied in the model

  • utility decrements for serious adverse events (SAEs) and skeletal related events (SRE’s) were derived from the literature

• Utility decrement for SAEs and SREs was an order of magnitude lower than the decrements derived from the LATITUDE regression analyses.

The quality of life values in the model are therefore above those observed in LATITUDE

56

Drug costs used in the model

• Commercial access agreement for abiraterone is used Confidential patient access schemes (PAS) are in place for some of the 2[nd] , 3[rd] and 4[th] line treatments in the model  ERG provide results in confidential appendix.

57

Drug and admin costs used in the model

ADT use is assumed to be equally balanced between goserelin, leuprorelin and triptorelin with 30% of these patients also receiving bicalutamide

58

Company’s estimate of treatment compliance on abiraterone

ratio

Area under progression free survival KM curve:

Figure is confidential

Area under time to treatment discontinuation curve

• ---

• – The areas under the curves are around months for the rPFS KM curve and months for TTD KM curve, which results in a ratio of *** time on treatment compared to time in rPFS. This ratio was applied to the abiraterone drug costs in the model

59

ERG comments on treatment compliance assumptions

• Treatment compliance estimate for abiraterone for mHSPC seems low compared the Clinical Study Report data on compliance

• ---

• • ERG estimated treatment compliance of % for AAP + ADT and % for ADT based on the Clinical Study Report for LATITUDE

• The treatment compliance estimate for docetaxel for mHSPC is not applied to the same range of costs as the compliance estimate for abiraterone (i.e did not adjust admin costs for docetaxel for treatment compliance)

• The treatment compliance estimates do not take into account that they reflect discontinuations during the relevant trials. This mainly affects mCRPC treatments in the AAP + ADT arm

60

Resource use

• Scheduled resource use includes visits and frequency in mHSPC and mCRPC from 5 clinicians. For abiraterone costs of blood test + oncologist visit every 2 weeks for first 3 months included

• Unscheduled resource use includes frequency of hospitalisations, imaging and radiotherapy from LATITUDE for mHSPC, trial data from COU-AA-302 used for mCRPC health states. Docetaxel assumed to be equivalent to abiraterone

• Costs of hospital visits from UK National Schedule of Reference costs

• Model implemented one-off cost of terminal care of £7,583 ( UK study Round et al., 2015 inflated to 2018 costs)

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CONFIDENTIAL

ERG comments resource costs

• ---

• • Company model assumes a bone scan at weeks and every weeks thereafter at a cost of £292 for people in the modelled docetaxel + ADT arm.

  • Costs of bone scans are not included for people receiving AAP + ADT or ADT

• ERG cannot find evidence that mHSPC patients who have finished their course of docetaxel and are only receiving ADT in the docetaxel + ADT arm have more routine bone scans than mHSPC patients on AAP + ADT

• No data in the Summary of Product Characteristics for abiraterone or docetaxel to support this company assumption

62

Adverse event costs

• Included costs of managing grade 3 or 4 adverse events

• Frequency of adverse events came from trial data

• Unit costs for each adverse event same as TA387

• The annual probability and cost by treatment arm of diarrhoea, neuropathy, neutropenia, febrile neutropenia, thrombocytopenia, anaemia, oedema, hypokalaemia, hypertension, arthralgia, asthenia, dyspnoea, nausea, vomiting and skeletal events are reported in table 30 page 143 company submission

63

Cost effectiveness results

• All results are shown for the modelled cost effectiveness estimates when the list prices for enzalutamide, cabazitaxel and radium-233 are used in the modelling.

• The results, when the patient access schemes for these technologies have been applied in the model by the ERG, are shown in a confidential appendix to this pre-meeting briefing

64

Company base case results

Probabilistic

65

Deterministic sensitivity analysis

AAP + ADT vs. ADT. Company submission figure 39 page 155

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66

Deterministic sensitivity analysis

AAP + ADT vs Docetaxel + ADT. Company figure 40 page 155

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67

Company’s scenario analyses selected scenarios that had an impact on ICERs

68

Comparison of MSM/TA387 and MSM results

Company base case (MSM/TA387 model)

N.B. the results using the MSM modelling approach were prepared by the ERG using current practice estimates for the proportion of people receiving each subsequent treatment (rather than using subsequent treatment proportions from LATITUDE as the company had done in its scenario analysis using the MSM approach). These data are reported in table 48 ERG report

69

ERG exploratory analyses

• The ERG have presented their exploratory analyses using the MSM/TA387 modelling approach and the MSM modelling approach separately

70

ERG sensitivity analyses on treatment se uences in mCRPC states q

ERG’s exploratory analyses changes made to company base case

ERG change Slide for reference 1) Apply all LATITUDE quality of life regression results (for mHSPC 55 and mCRPC health states) i.e regression disutility values for adverse events not literature values

• 2. No post-docetaxel utility decrement in mHSPC health state 54 3) Compliance estimates for abiraterone costs in mHSPC from clinical 59 study report compliance data, using mid-point values. Apply compliance percentages in the DOC + ADT arm in the same manner as the AAP + ADT arm
• 4. Same number of bone scans in docetaxel + ADT arm (pre- and post 61 docetaxel) as in AAP +ADT arm
• 5. Revised treatment proportions mCRPC 1[st] line that do not 42 differentiate the ro ortions of eo le receivin BSC between arms p p p p g none
• 6. Apply corrections for minor modelling errors (described on pages 137-138 ERG re ort p )

base case included all of these chan es The ERG exploratory g

72

ERG exploratory base case results

Deterministic results using MSM/TA387 model structure

Deterministic results using MSM model structure

73

ERG scenario analyses 1/2 around ERG exploratory base case

• 1. Use Kaplan Meier data for 4 or 7 months (rather than 5) and multi-state modelling transition probability matrices thereafter
• 2. Apply same probability of receiving 1[st] line mCRPC treatment for people who had AAP + ADT or Docetaxel + ADT as their treatment for mHSPC (in company base case, the proportion of people receiving treatment for mCRPC after docetaxel + ADT depended on the hazard ratio for rPFS for Docetaxel + ADT compared with AAP + ADT. This resulted in fewer people having 1[st] line treatment for mCRPC after docetaxel + ADT than after AAP +ADT)
• 3. 1[st] line mCRPC treatment effectiveness estimates from company’s indirect treatment comparison of 1[st] line mCRPC treatments (i.e. better rPFS with enzalutamide than abiraterone rather than assuming equal clinical effectiveness of active treatments)
• 4. Scenario 3 + all people receive enzalutamide rather than abiraterone for mCRPC
• 5. Apply a quality of life increment for ADT (after docetaxel) compared with ADT of half the quality of life increment for AAP + ADT (compared with ADT from the LATITUDE regression analyses

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ERG scenario analyses 2/2 around ERG exploratory base case

6. Apply a quality of life decrement for after docetaxel compared with ADT of ***** as per the company base case (reverse change 2 in ERG base case)

7. Use the utility decrements for SAEs and SREs from literature (as in company base case) rather than LATITUDE regression values (reverse change 1 in ERG base case)

• 8. Apply the LATITUDE quality of life regression that does not differentiate the SAE coefficient between modelled treatment arms
• 9. Apply the company base case assumptions on the proportion of people who receive each 1[st] , 2[nd] and 3[rd] line mCRPC treatment (reverse change 5 in ERG base case)

10. Apply the treatment compliance for abiraterone from company base case that is derived by the company from the LATITUDE rPFS and time to treatment discontinuation Kaplan Meier curves (reverse change 3 in ERG base case)

11. Apply the company’s assumptions on the number of bone scans whilst on docetaxel and after docetaxel (that is, more scans needed on and after treatment with docetaxel with abiraterone + ADT) (reverse change 4 in ERG base case)

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ERG scenario analyses results MSM/TA387 model

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ERG scenario analyses results MSM model (no cPAS)

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Key Issues: cost effectiveness

• Survival model outputs : Is survival after disease progression dependent on:

  • 1[st] treatment received?

  • Follow-on treatments in castrate resistant disease?

  • Is it plausible that post progression survival same across modelled treatment arms

• Survival -MSM/TA387 vs. MSM approach : Which data best model survival in mCRPC after progressing in mHSPC?

  • LATITUDE for hormone sensitive disease extrapolated?

  • or trial (COU-AA-302) for castrate resistant disease before chemotherapy TA387

    • Do the patient groups/ treatment pathways match?

• Utility : Are the values plausible by treatment and adverse events plausible? Can STAMPEDE provide quality of life data?

• Costs : Do the follow-on treatment reflect NHS reality?

• Costs : What is the expected frequency of bone scans for mHSPC cancer, does this differ by treatment?

• Costs : What is the expected compliance to treatment on abiraterone? Should this be included in model?

• Model outputs : Are they valid?

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Authors

• Mary Hughes Technical Lead

• Jasdeep Hayre Technical Adviser

• with input from the Lead Team ( William Turner, Nigel Westwood, Nicholas Latimer )

79

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

Abiraterone for treating newly diagnosed metastatic hormone-naïve prostate cancer [ID945]

Document A

Company evidence submission summary for committee

Janssen confirm that all information in the submission summary is an accurate summary or replication of evidence in the main submission and accompanying appendices and that wherever possible a cross reference to the original source is provided.

6[th] February 2018

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Instructions for companies

This is the template you should use to summarise your evidence submission to the National Institute for Health and Care Excellence (NICE) as part of the single technology appraisal (STA) process. This document will provide the appraisal committee with an overview of the important aspects of your submission for decisionmaking.

This submission summary must not be longer than 25 pages, excluding the pages covered by this template. If it is too long it will not be accepted. Please submit a draft summary with your main evidence submission. The NICE technical team may request changes later.

When cross referring to evidence in the main submission or appendices, please use the following format: Document, heading, subheading (page X).

For all figures and tables in this summary that have been replicated, cross refer to the evidence from the main submission or appendices in the caption in the following format: Table/figure name – document, heading, subheading (page X).

Companies making evidence submissions to NICE should also refer to the NICE guide to the methods of technology appraisal and the NICE guide to the processes of technology appraisal.

Highlighting in the template (excluding the contents list)

Square brackets and grey highlighting are used in this template to indicate text that should be replaced with your own text or deleted. These are set up as form fields, so to replace the prompt text in [grey highlighting] with your own text, click anywhere within the highlighted text and type. Your text will overwrite the highlighted section.

To delete grey highlighted text, click anywhere within the text and press DELETE.

Grey highlighted text in the footer does not work as an automatic form field, but serves the same purpose – as prompt text to show where you need to fill in relevant details. Replace the text highlighted in [grey] in the header and footer with appropriate text. (To change the header and footer, double click over the header or footer text. Double click back in the main body text when you have finished.)

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Contents

Instructions for companies ......................................................................................... 2 Tables and figures ...................................................................................................... 4 Submission summary ................................................................................................. 5 Background ..................................................................................................... 5 Health condition ............................................................................................... 6 Clinical pathway of care ................................................................................... 7 Equality considerations .................................................................................... 8 The technology ................................................................................................ 9 Decision problem and NICE reference case .................................................. 11 Clinical effectiveness evidence ...................................................................... 12 Key results of the clinical effectiveness evidence .......................................... 13 Progression-free survival ......................................................................... 13 Overall survival ........................................................................................ 15 Health-related quality of life ..................................................................... 18 Secondary Endpoints ............................................................................... 20 Evidence synthesis ........................................................................................ 22 Safety Outcomes ..................................................................................... 25 Key clinical issues ......................................................................................... 26 Overview of the economic analysis ............................................................... 27 Incorporating clinical evidence into the model ............................................... 27 Health-related quality of life data ................................................................... 29 Cost and healthcare resource ........................................................................ 29 Key model assumptions and inputs ............................................................... 30 Base-case ICER (deterministic) ..................................................................... 32 Probabilistic sensitivity analysis ..................................................................... 33 Key sensitivity and scenario analyses ........................................................... 34 Innovation ...................................................................................................... 35 Budget impact ................................................................................................ 36 Interpretation and conclusions of the evidence.............................................. 37 References .................................................................................................... 38

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Tables and figures

Table 1: Technology being appraised – B.1.2 (p10-11).............................................. 9 Table 2: The decision problem – B.1.1 (p8-9) .......................................................... 11 Table 3: Summary of evidence for clinical effectiveness .......................................... 12 Table 4: Summary of Key Clinical Data – B.2.6 (p46) .............................................. 17 Table 5: Trials used for evidence synthesis – B.2.10 (p75-78) ................................. 23 Table 6: Base case Bayesian ITC of AAP + ADT vs docetaxel + ADT ..................... 25 Table 7: Over of the model approach ....................................................................... 27 Table 8: Key model assumptions and inputs – B.3.6 (p147-149) ............................. 30 Table 9: Base case results – B.3.7 (p151) ............................................................... 33 Table 10: PSA results - B.3.8 (p151) ........................................................................ 33 Table 11: Key scenario analyses – B.3.8 (p157) ...................................................... 34 Table 12: Budget impact – Budget Impact submission (p23) ................................... 36 Figure 1: Use of AAP in prostate cancer .................................................................... 6 Figure 2: Current management of newly diagnosed high-risk mHSPC in the UK ....... 7 Figure 3: Metastatic prostate cancer clinical pathway of care .................................... 8 Figure 4: Radiographic progression-free survival of AAP + ADT vs ADT alone ....... 13 Figure 5: Overall Survival of AAP + ADT vs ADT alone ........................................... 15 Figure 6: PRO measures for EQ-5D-5L, FACT-P and BFI – B.2.6 (p48-53) ............ 20 Figure 7: Time to event analyses for subsequent treatment, initiation of chemotherapy, PSA progression and first SRE – B.2.6 (p54-59) ............................. 22 Figure 8: Comparison of trial populations – B.2.10 (p73) ......................................... 24 Figure 9: Comparison of trial populations and ITC network – B.2.10 (p80) .............. 24 Figure 10: Scatterplots of probabilistic results for AAP + ADT vs. ADT alone and vs. docetaxel + ADT B.3.8 (p152) .................................................................................. 33 Figure 11: Tornado diagrams for AAP + ADT vs. ADT alone - B.3.8 (p155) ............ 34

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Submission summary

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Background

The treatment landscape in metastatic prostate cancer has significantly evolved over the past six years. In 2012, NICE first recommended abiraterone acetate with prednisone/prednisolone (AAP) for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC), post-chemotherapy [TA259].[1] In 2016, NICE recommended AAP for the treatment of men pre-chemotherapy in mCRPC [TA387],[2] acknowledging the benefit of earlier treatment with novel agents. Other new treatments (such as enzalutamide, cabazitaxel and radium-223) also gained NICE recommendation during this time period.

Subsequently, a study known as CHAARTED shifted the paradigm once more.[3] These data showed that giving docetaxel (i.e. chemotherapy) in addition to androgen deprivation therapy (ADT) to men who are newly diagnosed with metastatic hormone sensitive prostate cancer (mHSPC) (i.e. before they have become resistant to hormone therapy) improved health outcomes further still. Results from a landmark UKbased study (STAMPEDE)[4] reaffirmed this and, although docetaxel + ADT is unlicensed in this specific setting, NHS England released a clinical commissioning policy to support its use in newly diagnosed mHSPC in response to these data.[5]

As illustrated Figure 1, AAP received its third licensed indication from the European Medicines Agency in November 2017 for the treatment of adult men with newly diagnosed high-risk mHSPC, in combination with ADT.[6] AAP + ADT is now the only licensed treatment in mHSPC, capable of delaying the initiation of chemotherapy and disease progression, prolonging survival and, importantly, maintaining patients’ quality of life.[7] AAP has an established safety profile with over six years of clinical experience in the NHS. A series of published data have shown that AAP + ADT will most likely become the treatment of choice for patients with mHSPC to maximise health outcomes and prolong quality of life.[8-11]

In September 2022, AAP will go off-patent in the UK and its price will inevitably decrease significantly due to generic entry. Loss of exclusivity already occurred in 2017 in other countries (such as the US), so launch of generics in the UK in 2022 will

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be rapid, meaning AAP (+ ADT) will thereafter become even more cost-effective across all indications.

Figure 1: Use of AAP in prostate cancer

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Notes:[a] Cancer Research UK Incidence Statistics

Key: AAP; abiraterone acetate with prednisone/prednisolone; ADT, androgen deprivation therapy; L, line of therapy; mCRPC, metastatic castrate resistant prostate cancer; mHSPC, metastatic hormone sensitive prostate cancer

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Health condition

Men with newly diagnosed high-risk mHSPC represent an orphan-sized patient population in the UK, equating to 4,400 new cases per year (see Appendix M).[12] These men experience a high clinical, psychological and economic burden of disease.

Prostate cancer is the most common male cancer in the UK, with over 46,700 men diagnosed in 2014.[12] Approximately 18% of new cases present with metastases at first diagnosis, meaning the cancer is diagnosed too late for curative treatment to be possible and has already spread through the body.[12] A typical man diagnosed at this stage is in his mid-to-late sixties and, often, only diagnosed after developing worrying symptoms, such as urinary problems, bone pain, tiredness or unexpected weight loss.[13] Symptoms can be highly debilitating and impactful on quality of life.[13] The psychological burden of receiving such a diagnosis is hard to quantify.[14]

Men with newly diagnosed mHSPC have a poorer prognosis than those who were originally diagnosed with localised disease whose cancer which since spread beyond the prostate.[15, 16] For men classified ‘high-risk’ at diagnosis, the outlook is even worse as their life expectancy is generally less than three years on conventional hormone

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therapy.[17-19] This is because high-risk disease is an aggressive cancer which is likely to advance more quickly.[17] As well as impacting survival, quicker progression to mCRPC is associated with reduced health-related quality of life (HRQL), increased healthcare costs and greater medical resource use (MRU), affecting both patients and the wider NHS.[20, 21] A man with high-risk disease is defined as having two of the following three poor prognostic factors: a Gleason score of ≥8 (describing the aggressiveness of the tumour), the presence of ≥3 lesions on a bone scan, or the presence of visceral metastases (both describing the extent of tumour spread).[22] Approximately 50% of men with newly diagnosed mHSPC are likely to have high-risk prognostic factors at diagnosis.[22, 23]

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Clinical pathway of care

Historically, ADT has been the standard of care (SOC) in mHSPC and it is still used as monotherapy to treat 50–60% of these men in the UK today.[24-26] Although most men initially respond to ADT, the vast majority develop progressive disease within one to two years.[27] Docetaxel + ADT is also now used in this setting because of its reported survival benefits,[3, 28] although real-world data suggest usage has plateaued at 40% of the mHSPC population.[24, 29] Whilst ADT alone does not elicit comparable survival benefits, docetaxel chemotherapy is associated with greater toxicity. As a result, some patients in the UK prefer to delay chemotherapy and would choose to receive ADT alone.

Figure 2: Current management of newly diagnosed high-risk mHSPC in the UK

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Key: ADT, androgen deprivation therapy; RCT, randomised controlled trial.

The current management of men with newly diagnosed high-risk mHSPC in the NHS is shown in Figure 2 and has been validated by clinical experts.[30] This also acknowledges the significant proportion of men who are enrolled into randomised controlled trials (RCTs) in the UK.[31]

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For the 18% of men (see Figure 1) whose prostate cancer is diagnosed after their disease has already metastasised, the care pathway has evolved quite considerably and thus treatment in metastatic prostate cancer can now be considered in terms of sequential lines of therapy (i.e. first-line treatment for mHSPC followed by a sequence of suitable regimens [1L, 2L, etc.] for mCRPC). Several novel agents are now available and the order in which a patient may receive them is determined by prior treatment, NICE recommendation and NHS policy. The clinical pathway of care is thus illustrated by Figure 3.

Figure 3: Metastatic prostate cancer clinical pathway of care

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Key: ADT, androgen deprivation therapy; BSC, best supportive care; mCRPC, metastatic castrationresistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; NDx, newly diagnosed; NHSE, National Health Service England. Notes:[1] , If docetaxel is contraindicated or not suitable;[2] , Use of abiraterone or enzalutamide in mCRPC is dependent on the prior use of docetaxel and/or prior abiraterone or enzalutamide, as per respective NICE guidance.

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Equality considerations

Even though docetaxel is a generic, inexpensive drug with reported survival benefits, not all men with newly diagnosed high-risk mHSPC in the UK undergo treatment. Indeed, 20% of men are considered clinically unsuitable for chemotherapy at diagnosis[30] and others are simply unable to receive it for reasons beyond clinical

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prognostic factors. In clinical practice, the overarching decision to undertake early chemotherapy lies between a patient and their clinician. It is essential a clinician can also account for psychological, social and economic factors in making informed judgement regarding which treatment is best suited to an individual patient. As substantiated by UK clinical experts,[30] these commonly include, but are not limited to:

• The presence of a carer or loved one for support, both for attending chemotherapy clinics and managing potential side effects.

• Where a man lives, be it isolated or accessible by public transport to attend chemotherapy clinics, with or without a carer.

• The emotional state required to endure the toxicity of chemotherapy, which is often understated.

• Religious beliefs that can prevent a man from pursuing chemotherapy due to the alcohol content in docetaxel.

• Being unwilling to undertake treatment.

These factors could realistically prevent a man with newly diagnosed high-risk mHSPC from undertaking treatment with docetaxel + ADT and thus compromise their survival in the absence of any alternative life-prolonging therapy.

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The technology

Table 1: Technology being appraised – B.1.2 (p10-11)

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

Key: AA, abiraterone acetate; CYP17, 17α-hydroxylase; DHEA, dehydroepiandrosterone; EPAR, European Public Assessment Report; LHRH, luteinising-hormone-releasing hormone; PAS, patient access scheme; SPC, summary of product characteristics.

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Decision problem and NICE reference case

The company submission is broadly consistent with the final NICE scope and the NICE reference case, as detailed and justified in Table 2.

Table 2: The decision problem – B.1.1 (p8-9)

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Clinical effectiveness evidence

Table 3: Summary of evidence for clinical effectiveness

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STAMPEDE was not used to inform the base case of the economic model because it includes a population of patients broader than the licensed indication for AAP + ADT; it was instead included in sensitivity analysis where appropriate. Clinical data from STAMPEDE provide strong supporting evidence for the benefit of AAP + ADT; it represents the single largest evidence base investigating AAP + ADT in the mHSPC setting, and data are specific to UK clinical practice.

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Key results of the clinical effectiveness evidence

A summary of key clinical data from LATITUDE and STAMPEDE is provided in Table 4, at the end of this section.

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Progression-free survival

LATITUDE

At the first interim analysis (IA1), median radiographic progression-free survival (rPFS) was 33.0 months in the AAP + ADT group and 14.8 months in the ADT group. As illustrated by Figure 4, treatment with AAP + ADT was associated with a 53% reduction in the risk of radiographic progression or death compared with ADT alone (HR=0.47 [95%CI: 0.39–0.55]; p<0.001).

Figure 4: Radiographic progression-free survival of AAP + ADT vs ADT alone

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Key: CI, confidence interval; ITT, intention-to-treat; KM, Kaplan–Meier; rPFS, radiographic progression-free survival. Source: Fizazi et al. 2017[7]

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STAMPEDE

While rPFS was not an endpoint specified in STAMPEDE, and the subgroup of patients with metastatic disease in the study was broader than the licensed indication for abiraterone in mHSPC, the results for the comparable endpoint of failure-free survival (FFS) (defined as biochemical [PSA] failure, radiologic or clinical progression, or death from prostate cancer) provide strong supporting evidence for the benefit of AAP + ADT over ADT. In the metastatic subgroup, compared to ADT alone, treatment with AAP + ADT was associated with:

• a 57% reduction in the risk of progression or death from prostate cancer (HR=0.43 [95%CI: 0.36–0.52]; p=NR).

• a 69% reduction in the risk of biochemical failure, progression or death from prostate cancer (HR=0.31 [95%CI: 0.26–0.37]; p<0.0001).

The post-hoc analysis from STAMPEDE comparing AAP + ADT with docetaxel + ADT was conducted for the population of patients who were recruited contemporaneously within the STAMPEDE trial. Of note, this analysis was pre-specified, and thus not statistically powered to detect clinical differences between treatments. Even so, results from the metastatic subgroup showed that, compared to docetaxel + ADT, treatment with AAP + ADT was associated with:

• a 31% reduction in the risk of progression or death from prostate cancer (HR=0.69 [95%CI: 0.50–0.95]; p=NR).

• a 44% reduction in the risk of biochemical failure, progression or death from prostate cancer (HR=0.56 [95%CI: 0.42, 0.75]; p<0.001).[35]

These significant results were also observed in the STAMPEDE ITT population, further supporting the superiority of AAP + ADT in delaying disease progression in men with newly diagnosed high-risk mHSPC.

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Overall survival

LATITUDE

At IA1, a total of 406 deaths were observed; 169 (28%) in the AAP + ADT group and 237 (39%) in ADT group. Median OS was 34.7 months in ADT group and not reached in the AAP + ADT group, indicating that more than 50% of this patient group were still alive after a median follow-up of 30.4 months. As shown in Figure 5, treatment with AAP + ADT was associated with a 38% reduction in the risk of death compared with ADT alone (HR=0.62 [95%CI: 0.51–0.76]; p<0.001).

Of note and worth emphasising, the results show a patient’s total life expectancy on treatment with ADT alone (34.7 months) is of similar magnitude to the median time a patient spent progression-free on treatment with AAP + ADT (33 months [median rPFS]). Such data are particularly important for those men who are unable to receive chemotherapy in mHSPC.

Figure 5: Overall Survival of AAP + ADT vs ADT alone

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Key: AAP, abiraterone acetate + prednisolone; ADT, androgen deprivation therapy; CI, confidence interval. Source: Fizazi et al. 2017[7]

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STAMPEDE

In the metastatic subgroup from STAMPEDE, 150 deaths had occurred in the AAP + ADT group, and 218 (43%) deaths had occurred in the ADT group at the time of the analysis. Treatment with AAP + ADT was associated with a 39% reduction in the risk of death compared with ADT alone (HR=0.61 [95%CI: 0.49–0.75]; p<0.0001). Although this subgroup is broader than the licensed indication for abiraterone, these survival data strongly support the OS results from LATITUDE.

The post-hoc analysis of AAP + ADT versus docetaxel + ADT did not show a statistically significant difference in OS in the metastatic subgroup (HR=1.13 [95%CI: 0.77–1.66]), although these data should be interpreted with caution; this analysis was not pre-specified and thus not statistically powered to detect differences in survival.

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Table 4: Summary of Key Clinical Data – B.2.6 (p46)

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Health-related quality of life

When patients progress to develop mCRPC, their HRQL is severely impacted and evidence has shown this is significantly worse for men with aggressive, high-volume (or similarly high-risk) disease.[16] As such, providing access to a treatment which can improve and/or delay deterioration in their quality of life is of upmost importance.

Several quality of life questionnaires were used in LATITUDE to investigate how high risk mHSPC patients’ HRQL changed over time, when treated with AAP + ADT versus ADT alone: EQ-5D-5L,[38] Functional Assessment of Cancer Therapy – Prostate (FACT-P),[39] Brief Fatigue Inventory (BFI)[40] and Brief Pain Inventory - Short Form (BPISF).[41]

Results consistently demonstrated that treatment of AAP + ADT significantly delayed the deterioration in HRQL for patients with high-risk mHSPC, versus ADT alone, as measured by both the EQ-5D-5L and FACT-P questionnaires (EQ-5D-5L, HR=0.81 [p=0.0038]; FACT-P, HR=0.85 [p=0.0322])[11] This meant patients who were treated with AAP + ADT benefited from a higher quality of life, for a longer time, compared to those given ADT alone.

 EQ-5D-5L

Patients’ responses to the Visual Analogue Scale (VAS) and their utility scores were significantly improved (p<0.05) when treated with AAP + ADT in LATITUDE, resulting in a utility increment for AAP + ADT of '''''''''''''. These results indicate that patients treated with AAP + ADT believed their abilities to walk about, wash and dress themselves, perform their usual activities, and function with less pain/discomfort and less anxiety/depression had increased over time; patients also sustained these improvements until progression. (Figure 6A).

 Functional Assessment of Cancer Therapy – Prostate (FACT-P)

Patients treated with AAP + ADT in LATITUDE reported consistent delays in pain and prostate cancer symptom progression, as well as degradation of functional status, compared with ADT alone (HR=0.75 [95%CI: 0.65–0.87]; p=0.0001) (Figure 6B).[11] More patients treated with AAP + ADT reported less severe level of pain, less

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burdensome symptoms and more energy, allowing them to enjoy their time as they wish, be it with their family or just day-to-day activities.

 Brief Fatigue Inventory (BFI)

Treatment with AAP + ADT significantly reduced the risk of BFI worst fatigue intensity progression by 35% compared with ADT (HR=0.65 [95%CI: 0.53–0.81]; p=0.0001).[11] Significant improvements in fatigue were observed early and maintained throughout with AAP + ADT, meaning patients generally feel less tired, less lethargic and more able to spend time doing the things of value to them, regardless of their disease and treatment. (Figure 6C).

 Brief Pain Inventory-Short Form (BPI-SF)

Time to pain progression was defined as the time interval from randomisation to the first date a patient experienced a ≥30% increase from baseline in the BPI-SF worst pain intensity observed at two consecutive evaluations ≥4 weeks apart. Treatment significantly delayed the progression of pain compared to ADT alone by 31% (HR=0.70 [95% CI: 0.58–0.83], p<0.0001).[11]

Mean changes from baseline in worst pain intensity, pain interference, and average pain progression improved with AAP + ADT versus ADT alone at most time points evaluated (Figure 6D).[11] These improvements were observed as early as Cycle 2 and maintained through Cycle 33, meaning patients on AAP + ADT reported reduction in pain as early as two months after starting treatment.

Since patients treated with AAP + ADT consistently reported less severe pain, treatment allowed them to go on with their lives more comfortably and enjoy time as they wish, be it spending time with the family, doing day-day-chores, or activities elsewhere.[11]

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Figure 6: PRO measures for EQ-5D-5L, FACT-P and BFI – B.2.6 (p48-53)

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A = EQ-5D-5L, B =FACT-P, C =BFI, D= BPI-SF Key: BFI, Brief Fatigue Inventory; CI, confidence interval; EQ-5D-5L, EuroQoL 5-Dimension 5-Level; VAS, visual analogue score; FACT-P, Functional Assessment of Cancer Therapy – Prostate Cancer Source: Chi et al. 2018.[11]

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Secondary Endpoints

In addition to meeting both co-primary endpoints in LATITUDE, AAP + ADT showed consistently significant benefit in all pre-specified secondary endpoints. Indeed, compared with ADT alone, treatment with AAP + ADT:

• Significantly delayed time to subsequent therapy for prostate cancer

Median time to subsequent therapy was not reached in the AAP + ADT group versus

21.6 months for the ADT group (HR=0.42 [95%CI: 0.35–0.50], p<0.0001) (Figure 7A).

• Significantly delayed time to life-extending subsequent therapy

At IA1, twice as many patients from the ADT group had required life-extending subsequent therapy versus the AAP + ADT group (40.9% vs 20.9%, respectively). AAP + ADT significantly delayed the time to initiating life-extending subsequent

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therapy (HR=0.37 [95%CI: 0.29–0.45]; p<0.0001). Docetaxel was the most common treatment after AAP + ADT or ADT alone (17.8% and 31.1%, respectively).

 Significantly delayed time to initiation of chemotherapy

The median time to initiation of chemotherapy was not reached in the AAP + ADT group and was 38.9 months in the ADT group (HR=0.44 [95%CI: 0.35–0.56]; p<0.0001). This translated to a 56% reduction in risk of initiating chemotherapy and represents an endpoint of considerable value to patients (Figure 7B).

 Significantly delayed time to PSA progression [PCWG2 criteria][42]

Median time to PSA progression with AAP + ADT was 33.2 months, and only 7.4 months with ADT (HR=0.30 [95% CI: 0.26–0.35], p<0.0001) (Figure 7C).

 Significantly reduced the risk of skeletal-related events (SREs)

Although the median time to SRE was not reached for either treatment group, AAP + ADT showed a significant reduction in the risk of SREs versus ADT (HR=0.70 [95%CI: 0.54–0.92], p=0.0086), which is beneficial for patients given SREs are associated with both increased pain and significant healthcare costs to patients (Figure 7D).

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Figure 7: Time to event analyses for subsequent treatment, initiation of chemotherapy, PSA progression and first SRE – B.2.6 (p54-59)

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Key: CI, confidence interval; PSA, prostate specific antigen; SRE, skeletal related event. Source: LATITUDE CSR (2017)[36]

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Evidence synthesis

Four trials were identified that provided relevant evidence for consideration in this submission. Table 5 provides a summary of the trials used to derive estimates of comparative effectiveness.

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Table 5: Trials used for evidence synthesis – B.2.10 (p75-78)

1. Evidence synthesis: AAP + ADT versus ADT alone

The LATITUDE trial provides randomised, robust head-to-head evidence of AAP + ADT versus ADT alone in newly diagnosed high-risk mHSPC and is therefore the most appropriate source of data to inform this comparison. LATITUDE also provides the direct safety data relevant to this comparison.

2. Evidence synthesis: AAP + ADT versus docetaxel + ADT

Indirect treatment comparison (ITC) was used to derive estimates of relative effectiveness between AAP + ADT and docetaxel + ADT in newly diagnosed high-risk mHSPC. Four studies had potentially comparable trial populations, study design and

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outcomes. As illustrated in Figure 9, the newly diagnosed high-volume subgroups from CHAARTED and GETUG-AFU 15 were most comparable to the ITT population from LATITUDE and therefore used in the base case; the metastatic population from STAMPEDE is broader than the licensed indication for abiraterone and thus reserved for scenario analysis.

Figure 8: Comparison of trial populations – B.2.10 (p73)

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The network of trials is illustrated in Figure 9. As discussed in B.2.10, there was heterogeneity between the measures used to determine disease progression across all four trials in the network. GETUG-AFU 15 was the only other trial to utilise rPFS as an endpoint, thus enabling a like-for-like comparison with LATITUDE.

Figure 9: Comparison of trial populations and ITC network – B.2.10 (p80)

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Key: AAP, abiraterone acetate + prednisolone; ADT, androgen deprivation therapy; DOC, docetaxel, Notes: Continuous lines represent trials contributing to the base case. Dotted lines represent the addition of STAMPEDE in sensitivity analyses.

The results of the base case Bayesian ITC for PFS and OS are detailed in Table 6.

Results showed a positive trend towards AAP + ADT having the highest probability of being the optimal treatment for delaying disease progression and extending survival

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(93% and 72% probability, respectively). This holds true for all ITC iterations tested in scenario analyses presented in B.2.10 (p81).

Table 6: Base case Bayesian ITC of AAP + ADT vs docetaxel + ADT

While not used to inform the economic model, it is important to highlight two additional independent ITCs which have been published (Vale et al, 2017[9] and Wallis et al, 2017).[10] Both strongly support the consistent trend in benefit with AAP + ADT over docetaxel + ADT for extending survival and delaying disease progression (see B.2.10).

Bayesian ITCs were also conducted for FACT-P (i.e. functional status) and BPI-SF (i.e. pain) scores to assess the relative difference in PROs between AAP + ADT and docetaxel + ADT. Results showed that treatment with AAP + ADT elicited benefits in patients’ HRQL versus docetaxel + ADT from three months and were sustained for at least one year after treatment.[43] Results are further detailed in B.2.10 (p86).

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Safety Outcomes

AAP has an established safety profile with over six years of clinical experience in the NHS. No new safety signals were identified in LATITUDE compared to those already characterised through previous trials in mCRPC. AAP + ADT was well tolerated, with a comparable incidence of TEAEs to ADT alone. In line with its known safety profile, the most frequently reported grade 3/4 TEAEs were mineralocorticoid-associated AEs. All events were however medically manageable, only rarely required treatment discontinuation, and seldom led to serious consequences. These findings were further supported by results from STAMPEDE.

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Comparison of safety outcomes between AAP + ADT and docetaxel + ADT was only possible through Bayesian ITC of the LATITUDE and GETUG-AFU 15 trials. The results, detailed in B.2.10 (p82-84), showed a ''''''''''''''''''''''''''''' '''''''''''''''''' ''''''''''''' ''''' '''''''''''''' '''''

'''''''''''' ''' ''''''''''' '''''''''' '''''''''''''''''''''' '''' '''''''''''' . These findings are supported by real-world experience data with docetaxel + ADT, reporting that the rates of grade ≥3 neutropenia and febrile neutropenia were as high as 36.3% and 18.2%, respectively. Although populations may vary, these same AEs were only reported in 0.5% and 0.2% of patients treated with AAP + ADT in the LATITUDE study.

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Key clinical issues

All analyses are based on clinical data from LATITUDE IA1, at which the median follow-up of patients was 30.4 months follow-up. Whilst the median OS was not reached in the AAP + ADT group, compared to 34.7 months in the ADT group, these data show more than half of the treatment group were still alive at IA1. A second interim analysis (IA2) of the study is due imminently. Indeed, additional data from IA2 could reaffirm long term predictions, after appropriate adjustments have been made for crossover permitted following the independent data and safety monitoring committee’s unanimous recommendation to unblind the trial based on compelling IA1 results.[7]

Most patients in LATITUDE went on to receive subsequent therapies upon progression to mCRPC; 40% of patients treated with ADT alone received life-extending subsequent therapy whilst only 20% of patients treated with AAP + ADT did. Given the study follow-up period was not long enough to capture the entire treatment pathway for the majority of patients, there is still uncertainty around the impact of subsequent therapy on survival, and minimal data to inform survival analysis adjusted for nonpermitted sequences in the UK.

The newly diagnosed high-volume mHSPC subgroups from CHAARTED and GETUGAFU 15 and the ITT population from LATITUDE informed the base case ITC. The comparability of these populations has been validated by both published literature and post-hoc analysis of LATITUDE.[22] Full details on the Bayesian ITC methods are presented in B.2.10.

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Overview of the economic analysis

An overview of the modelling approach is provided in Table 7 with full details and justifications presented in B.3.2.

Table 7: Over of the model approach

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Incorporating clinical evidence into the model

AAP + ADT vs ADT alone: The Kaplan-Meier data from LATITUDE for rPFS, TTST and OS were applied directly into the model for the first five months, after which the transition probabilities estimated through the MSM analysis were applied.

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AAP + ADT vs docetaxel + ADT: HRs derived from the Bayesian ITC for docetaxel + ADT versus AAP + ADT were applied to the estimated transition probabilities for AAP + ADT; the mean HRs for rPFS and OS were 0.76 and 0.92, respectively.

Time on treatment: LATITUDE data were used to conduct a restricted means analysis to estimate the mean time on treatment relative to the mean time spent in rPFS (ratio of '''''''''''' for AAP + ADT).

Post-progression survival: The mean treatment-free interval (TFI) was estimated for both treatment arms to give the average time between rPFS and the start of subsequent therapy. A constant transition probability was estimated by applying an exponential distribution to the mean TFI values for each treatment arm.

• In the base case, survival during the mCRPC phase was estimated in three steps:

1. Survival curves were taken from the base case analysis in the previous appraisal of AAP and BSC in mCRPC [TA387], which were extrapolated from the COU-AA302 study. All life-extending subsequent therapies in mCRPC were assumed to have the same relative effectiveness as AAP, as validated by clinical experts in prostate cancer.[30]

2. The weighted average survival was calculated based upon the expected market share of each treatment in UK practice, as validated by clinical experts.[30]

3. The curves were then calibrated to adjust for the population differences between LATITUDE and COU-AA-302. Extrapolated curves were validated by a UK clinical expert in prostate cancer with all deemed to project clinically plausible estimates, as illustrated in B.3.3.

The model also explored a scenario where the long-term survival from LATITUDE was estimated by the transition probabilities from the MSM analysis alone, without the inclusion of external survival data. Subsequent therapies were costed as per LATITUDE in line with the effectiveness data.

Time on treatment was modelled in a time-dependent manner during 1L mCRPC to accurately capture treatment costs. Transition probabilities after the 1L mCRPC health

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state were estimated by using mean health state durations from the previous submission of AAP [TA387], and assuming a constant probability over time.

Safety: The frequencies with which patients were assumed to experience a range of grade 3/4 AEs and SREs were taken from the literature for each comparator in mHSPC and subsequent therapy in mCRPC. The frequencies were estimated as annual probabilities from the relevant clinical trial data for each treatment.

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Health-related quality of life data

In the LATITUDE trial, HRQL was measured using the EQ-5D-5L; the crosswalk algorithm by van Hout et al.[44] was used to map values to the EQ-5D-3L scale in line with NICE DSU guidance. Full detail on how utilities for the model were derived from LATITUDE is provided in in B.3.4 (p130-136).

A HRQL treatment effect was applied to patients receiving AAP in mHSPC and, in line with past appraisals, the AAP treatment effect from TA387 was applied to those who received AAP in mCRPC. As docetaxel was not an intervention investigated within LATITUDE, values derived from the Time-Trade Off (TTO) utility study were used which included an on- and off-treatment effect associated with docetaxel. The ontreatment effect was applied for the time patients received docetaxel, and the offtreatment effect was applied for the remainder of the pre-progression period.

The utility of patients in the 2L and 3L mCRPC states was estimated by using utility values from TA387 to estimate the relative utility decline of patients over time. These relative values were then applied to the utility value of progressed patients estimated from the LATITUDE utility analysis. AE disutilities from the literature were applied in the base case. A summary of the utility values included in the model is presented in B.3.4 (p136).

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Cost and healthcare resource

Costs for drug acquisition, administration, AEs, and monitoring (scheduled and unscheduled MRU) were all considered; full detail on costs and healthcare resource use is provided in B.3.5 and a summary of all cost parameters included in the model is presented in Appendix R.

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Key model assumptions and inputs

Table 8: Key model assumptions and inputs – B.3.6 (p147-149)

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Base-case ICER (deterministic)

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Results show that, under the confidential CAA, AAP + ADT is a highly cost-effective use of NHS resources in men with newly diagnosed high-risk mHSPC, regardless of the comparator treatment considered. ''''''''' '''' ''''''''''''''''''' '''''''' '''''''''''''''''' '''''''''''''''''' ''''' ''''''''''''''''''''''' ''''''' '''''''''' '''' ''''''''''' '''' ''''''''''''''''''' ''''' ''''''' '''''''''''''''''''' ''''''''''''''''''' '''''''''''''''''''''' ''''''''' '''''''' '''''''' '''''''''''''' ''''''' '''''''''''''' '''''''' ''''''''''''''''' ''''''''' ''''' '''''''''''''''''' ''''''''''' '''''''''''' '''' ''''''''''''''''' ''''''''' '''''''''' ''''''''''''''''''''''''''''' ''''''''' '''''''''' ''''' '''''''''' '''''''''''' ''''''' ''''''' ''''''''''''''''''' '''''' '''''''''''''''''''''''' '''''''''' '''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''''''''''''' ''''''''''''''''''' ''''''''''''''''' ''''' ''''''''''''''' '''''''''' '''''''''''''''''' ''''''''''''' '''''''''''' ''''''''''''''' ''''''''''''''' '''''''''''''''''' '''''''' ''''''''''''''''' '''''''''''''' '''' ''''''''''''''''''''''' '''''' ''''''''''''''' ''''''''' '''''''''''''''''''''' '''''''''''''''''''''' ''''''''''''''''''''''''

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Table 9: Base case results – B.3.7 (p151)

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Probabilistic sensitivity analysis

Table 10: PSA results - B.3.8 (p151)

Figure 10: Scatterplots of probabilistic results for AAP + ADT vs. ADT alone and vs. docetaxel + ADT B.3.8 (p152)

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AAP + ADT vs. ADT alone AAP + ADT vs. docetaxel + ADT
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Key: AAP, abiraterone acetate + prednisolone; ADT, androgen deprivation therapy; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year.

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Key sensitivity and scenario analyses

Figure 11: Tornado diagrams for AAP + ADT vs. ADT alone - B.3.8 (p155)

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AAP + ADT vs. ADT alone
AAP + ADT vs. Docetaxel + ADT
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Key: AAP, abiraterone acetate + prednisolone; ADT, androgen deprivation therapy; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; KM, Kaplan–Meier; OS, overall survival; QALY, qualityadjusted life year; rPFS, radiographic progression-free survival; TFI, treatment free interval

Table 11: Key scenario analyses – B.3.8 (p157)

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Innovation

Abiraterone was discovered in the UK and it is the first novel agent to be licensed in mHSPC in combination with ADT.[6] It has been described by the Chief Executive of the Institute of Cancer Research in London as a “highly innovative treatment that not only improves survival rates but has lower rates of side-effects than conventional therapies ”.[47] AAP already has an established efficacy and safety profile in mCRPC, and these new trial data strongly support its earlier use in the treatment pathway to optimise health outcomes and prolong patients’ HRQL.[7, 11, 34] Results from LATITUDE and STAMPEDE have excited the clinical community, and the Chief Investigator of STAMPEDE was quoted saying “these are the most powerful results I’ve seen from a prostate cancer trial – it’s a once in a career feeling. This is one of the biggest reductions in death I’ve seen in any clinical trial for adult cancer.”[47]

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These data give patients with newly diagnosed metastatic disease hope for the future and should not be underestimated, especially for those who cannot receive chemotherapy. AAP + ADT is an innovative regimen that not only demonstrates gains in survival, but improves quality of life and delays progression to mCRPC, a disease state which is associated with increased healthcare costs and further reduced HRQL.[20, 21]

Patients’ preferences are exceedingly important to acknowledge, although challenging to quantify and rarely accounted for in cost-effectiveness analysis. Many men cannot access chemotherapy, and others are not willing to undertake the course of chemotherapy at this stage in their lives;[30] AAP + ADT significantly delays the time to chemotherapy and provides these men with the only alternative life-prolonging treatment option.[7]

Lastly, AAP is an oral treatment taken at home, alongside the required routine monitoring, while the uptake of docetaxel in early prostate cancer is likely to have increased the burden on chemotherapy clinics which are already overstretched. As such, uptake of AAP + ADT in the NHS will benefit both patients and their carers/loved ones currently faced with the choice between undergoing docetaxel + ADT through chemotherapy clinics, or continued ADT monotherapy with fewer survival benefits.

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Budget impact

The net budget impact described in Table 12 is based upon the assumption that AAP + ADT will be funded by the NHS from October 2018.

Table 12: Budget impact – Budget Impact submission (p23)

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Interpretation and conclusions of the evidence

AAP + ADT offers significant survival benefit to those men currently treated with ADT alone.

AAP + ADT is associated with a clinically and statistically significant survival benefit compared to ADT alone, demonstrating a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death . Results from the STAMPEDE metastatic subgroup demonstrated comparable significant benefit.

AAP + ADT offers benefit in PFS and at least comparable, but likely superior, benefit in survival benefit to those men currently treated with docetaxel + ADT.

Results from Bayesian ITC demonstrated AAP + ADT had a 71.8% and 92.9% probability of superiority with regards to OS and rPFS , respectively, compared to docetaxel + ADT. The direct comparison of AAP + ADT versus docetaxel + ADT from STAMPEDE supported such findings, showing AAP + ADT significantly reduced the risk of FFS by 44% and the risk of PFS by 31% compared to docetaxel + ADT. Results of two independent NMAs both provided further support for AAP + ADT likely being the optimal treatment option in this patient cohort.

AAP + ADT significantly improves pain, fatigue and patients’ HRQL, sustaining these benefits at least until disease progression.

Compared to ADT alone, AAP + ADT showed a significant reduction in the risk of pain progression, risk of fatigue progression, and worsening of HRQL. Results of the ITC showed treatment with AAP + ADT was ''''''''''''''''''''''''' ''''''''' ''''''''''''''''' ''''''''''''''''''''' '''' '''''''''' '''''''''''''''''''' '''''''' '''''''''''''''' '''''''''''''''''''''''' ''''' '''''''''''''''''''''''' ''' '''''''''''

AAP + ADT offers a favourable benefit–risk profile to those men currently treated with ADT alone.

AAP + ADT has an established safety profile with six years of clinical experience in the NHS. Treatment with AAP + ADT was well tolerated with comparable incidence of TEAEs to ADT alone.

AAP + ADT offers an alternative treatment option, with favourable long-term safety profile, to those men currently treated with docetaxel + ADT.

Data published on real-world experience with docetaxel + ADT, since it became routinely available through the NHS, reported the rates of grade ≥3 neutropenia and febrile neutropenia to be as high as 36.3% and 18.2%, respectively. While there are potential variations in populations, these same AEs were only reported in 0.5% and 0.2% of patients treated with AAP + ADT in the LATITUDE study.

AAP + ADT provides the option to delay chemotherapy in those men who do wish to undertake immediate treatment with docetaxel + ADT.

This is particularly relevant to patients wishing to delay exposure to the potential toxicities associated with chemotherapy. Indeed, these benefits are particularly important for men who are either unsuitable for, or unable to receive, chemotherapy at diagnosis. Acknowledging the importance of patient preference, AAP + ADT provides the only efficacious alternative to ADT alone for these men.

Under the confidential CAA, AAP + ADT provides a cost-effective use of NHS resources regardless of the comparator considered.

Cost-effectiveness analyses have showed AAP + ADT is cost-effective, regardless of the comparator considered. AAP + ADT is associated with an ICER of £17,828/QALY when compared to docetaxel + ADT and an ICER of £17,418/QALY when compared to ADT alone.

Under the confidential CAA, AAP + ADT provides an affordable treatment option to the NHS in all patients with newly diagnosed high-risk mHSPC.

When all costs associated with the treatment pathway are considered over a three-year period, AAP + ADT results in a net budget impact of '''''''''''''''''''''''''''' '''''''''''''''''''''''''''' ''''''''' '''''''''''''''''''''''''''''' in Year 1, 2 and 3, respectively. These figures account for the full licensed indicated population of AAP + ADT, acknowledging the distribution of comparator treatments currently used to manage these patients.

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References

1. National Institute for Health and Care Excellence. TA259: Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxelcontaining regimen. 2012.

2. National Institute for Health and Care Excellence. TA387: Abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. 2016.

3. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. The New England journal of medicine . 2015; 373: 737-46.

4. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet (London, England) . 2016; 387: 1163-77.

5. National Health Service. Clinical Commissioning Policy Statement: Docetaxel in combination with androgen deprivation therapy for the treatment of hormone naïve metastatic prostate cancer. 2016.

6. Janssen-Cilag Ltd. Abiraterone acetate (Zytiga®). Summary of Product Characteristics . 2017.

7. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. The New England journal of medicine . 2017; 0: null.

8. Feyerabend S, Saad F and Li T. Indirect Comparison of Abiraterone Acetate and Docetaxel for Treatment of Metastatic “Hormone-Sensitive” Prostate Cancer. ESMO . Madrid: Spain, 2017.

9. Vale CL, Fisher DJ, Carpenter J, et al. LBA33What are the optimal systemic treatments for men with metastatic, hormone-sensitive prostate cancer? A STOPCaP systematic review and network meta-analysis. Annals of oncology : official journal of the European Society for Medical Oncology . 2017; 28: mdx440.026mdx440.026.

10. Wallis CJD, Klaassen Z, Bhindi B, et al. Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naive Prostate Cancer: A Systematic Review and Network Meta-analysis. European urology . 2017.

11. Chi KN, Protheroe A, Rodríguez-Antolín A, et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. The Lancet Oncology . 2018.

12. Cancer Research UK. Prostate cancer incidence statistics. 2017.

13. National Institute for Health Research. Abiraterone (Zytiga) for hormone-naïve metastatic prostate cancer – first line. 2015.

14. Mehnert A, Lehmann C, Graefen M, Huland H and Koch U. Depression, anxiety, post-traumatic stress disorder and health-related quality of life and its association with social support in ambulatory prostate cancer patients. European journal of cancer care . 2010; 19: 736-45.

15. Frees S, Akamatsu S, Lynch K, et al. Timing of the development of metastasis and initiation of treatment are important prognostic factors in prostate cancer. European Urology Supplements . 2016; 15: e845.

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16. Sweeney C, Chen YH, Liu G, et al. Long term efficacy and QOL data of chemohormonal therapy (C-HT) in low and high volume hormone naïve metastatic prostate cancer (PrCa): E3805 CHAARTED trial. Annals of oncology : official journal of the European Society for Medical Oncology . 2016; 27: 720PD-PD.

17. Cancer.net. Prostate Cancer: Stages. 2018. 18. Koo KC, Park SU, Kim KH, et al. Prognostic Impacts of Metastatic Site and Pain on Progression to Castrate Resistance and Mortality in Patients with Metastatic Prostate Cancer. Yonsei Medical Journal . 2015; 56: 1206-12.

18. Mottet N, De Santis M, Briers E, et al. Updated Guidelines for Metastatic Hormone-sensitive Prostate Cancer: Abiraterone Acetate Combined with Castration Is Another Standard. European urology . 2017.

19. Albertsen PC, Aaronson NK, Muller MJ, Keller SD and Ware JE, Jr. Healthrelated quality of life among patients with metastatic prostate cancer. Urology . 1997; 49: 207-16; discussion 16-7.

20. Krahn MD, Bremner KE, Zagorski B, et al. Health care costs for state transition models in prostate cancer. Medical decision making : an international journal of the Society for Medical Decision Making . 2014; 34: 366-78.

21. Buelens S, Poelaert F, Dhondt B, et al. Metastatic burden in newly diagnosed hormone-naive metastatic prostate cancer: Comparing definitions of CHAARTED and LATITUDE trial. Urologic oncology . 2018.

22. Janssen Research & Development. Incidence statistics. 2018.

23. Rulach RJ, McKay S, Neilson S, et al. Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer. BJU international . 2017.

24. European Association of Urology. Prostate Cancer. 2017.

25. National Comprehensive Cancer Network. Prostate Cancer. 2017. 27. Aly A, Mullins CD and Hussain A. Understanding heterogeneity of treatment effect in prostate cancer. Curr Opin Oncol . 2015; 27: 209-16.

26. James ND, Spears MR, Clarke NW, et al. Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). European urology . 2015; 67: 1028-38.

27. Janssen Research & Development. Clinical Validation. 2018. 30. Janssen Research & Development. Advisory Board Report. 2017.

28. National Cancer Research Institute. NCRI Prostate Cancer Clinical Studies Group: Annual Report 2016-17. 2017.

29. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England journal of medicine . 2011; 364: 1995-2005.

30. Chen Y, Clegg NJ and Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. The Lancet Oncology . 2009; 10: 981-91.

31. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. The New England journal of medicine . 2017; 0: null.

32. Sydes MR, Mason MD, Spears MR, et al. Adding abiraterone acetate plus prednisolone (AAP) or docetaxel for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): directly randomised data from STAMPEDE. European Society for Medical Oncology . Madrid: Spain, 2017.

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36. Janssen Research & Development. A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC). Clinical Study Report . Data on File2017.

37. Rydzewska LHM, Burdett S, Vale CL, et al. Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis. European journal of cancer (Oxford, England : 1990) . 2017; 84: 88-101.

38. van Reenen M and Janssen B. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L instrument. 2015.

39. The Radiation Therapy Oncology Group. Functional Assessment of Cancer Therapy-Prostate Version 4 (FACT-P) 2010.

40. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer . 1999; 85: 1186-96.

41. Cleeland CS. The Brief Pain Inventory: User Guide 2009.

42. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2008; 26: 1148-59.

43. Feyerabend S, Saad F, Li T, Ito T and Diels J. Indirect treatment comparison (ITC) of abiraterone acetate (AA) plus prednisone (P) and docetaxel (DOC) on patient-reported outcomes (PROs) in metastatic castration-naïve prostate cancer (mCNPC). 2018.

44. van Hout B, Janssen MF, Feng Y-S, et al. Interim Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L Value Sets. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research . 2012; 15: 708-15.

45. Halabi S, Vogelzang NJ, Ou SS, Owzar K, Archer L and Small EJ. Progression-free survival as a predictor of overall survival in men with castrateresistant prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2009; 27: 2766-71.

46. Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I and Eisenberger M. Prediction of Survival following First-Line Chemotherapy in Men with CastrationResistant Metastatic Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research . 2010; 16: 203-11.

47. The Institute of Cancer Research. ASCO 2017: Adding abiraterone to standard treatment improves prostate cancer survival by almost 40%. 2017.

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal Abiraterone for treating newly diagnosed metastatic hormone-naïve prostate cancer [ID945]

Document B

Company evidence submission IA2 addendum

March 2018

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Instructions for companies

This is the template for submission of evidence to the National Institute for Health and Care Excellence (NICE) as part of the single technology appraisal (STA) process. Please note that the information requirements for submissions are summarised in this template; full details of the requirements for pharmaceuticals and devices are in the user guide.

This submission must not be longer than 150 pages, excluding appendices and the pages covered by this template. If it is too long it will not be accepted.

Companies making evidence submissions to NICE should also refer to the NICE guide to the methods of technology appraisal and the NICE guide to the processes of technology appraisal.

In this template any information that should be provided in an appendix is listed in a box.

Highlighting in the template (excluding the contents list)

Square brackets and grey highlighting are used in this template to indicate text that should be replaced with your own text or deleted. These are set up as form fields, so to replace the prompt text in [grey highlighting] with your own text, click anywhere within the highlighted text and type. Your text will overwrite the highlighted section.

To delete grey highlighted text, click anywhere within the text and press DELETE.

Grey highlighted text in the footer does not work as an automatic form field, but serves the same purpose – as prompt text to show where you need to fill in relevant details. Replace the text highlighted in [grey] in the header and footer with appropriate text. (To change the header and footer, double click over the header or footer text. Double click back in the main body text when you have finished.)

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Contents

Instructions for companies ......................................................................................... 2 Tables and figures ...................................................................................................... 4 Clinical effectiveness results of the relevant trials................................................... 5 Subgroup analysis ................................................................................................ 15 Exploring adjustments to survival ......................................................................... 16 Comparative effectiveness estimates ................................................................... 17 Conclusion ............................................................................................................ 17 References ............................................................................................................... 19

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Tables and figures

Table 1: Subsequent therapy for prostate cancer [LATITUDE, ITT population] ....... 10 Table 2: Life-extending subsequent therapy [LATITUDE, ITT population] ............... 12 Table 3: Hazard ratios in IA1 versus IA2 .................................................................. 17

Figure 1: KM plot of OS [LATITUDE, ITT population] ................................................. 6 Figure 2: KM plot of time to pain progression [LATITUDE, ITT population] ................ 8 Figure 3: KM plot of time to subsequent prostate cancer therapy [LATITUDE, ITT population] .................................................................................................................. 9 Figure 4: KM plot of time to life-extending subsequent prostate cancer therapy [LATITUDE, ITT population] ..................................................................................... 11 Figure 5: KM plot of time to initiation of chemotherapy [LATITUDE, ITT population] 13 Figure 6: KM plot of time to next SRE [LATITUDE, ITT population] ......................... 14 Figure 7: Subgroup analyses of OS [LATITUDE, ITT population] ............................ 15 Figure 8: KM plot of OS vs predicted model survival ................................................ 18

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Clinical effectiveness results of the relevant trials

This document provides updated key efficacy data from the pre-planned second interim analysis (IA2) of the LATITUDE trial. The objective of this IA2 was to obtain results of updated overall survival (OS) and other secondary endpoints. All data presented herein are taken from the updated clinical study report (CSR), which is based on a cut-off date of 2[nd] October 2017, at which point median follow-up was 41.36 months.[1] Of note, the final analysis of radiographic progression-free survival (rPFS) was planned after 565 events and was therefore reached at the first interim analysis (IA1) and presented in the pivotal CSR provided to NICE at time of original submission; as such, results for this endpoint have not been updated and are not presented in this document.

Consistent with the results presented at IA1, the significant benefit of adding abiraterone acetate plus prednisolone (AAP) to androgen deprivation therapy (ADT) was maintained with longer follow-up for both OS and secondary endpoints; this was despite ''''''' out of 602 patients ('''''''''') in the ADT alone group having crossed over to receive open-label treatment with AAP + ADT. As such, the results of IA2 confirm the value of AAP + ADT in men with newly diagnosed high-risk metastatic hormone sensitive prostate cancer (mHSPC).

Patient disposition

A total of 597 patients in the AAP + ADT group and 602 patients in the ADT alone group were included in both the intention-to-treat (ITT) and safety populations. At the time of IA2, treatment was ongoing for 205 (''''''''''%) patients in the AAP + ADT group and 70 (''''''''''%) patients in the ADT alone group. The most common reasons for discontinuation remained progressive disease, reported for ''''''''''% and '''''''''''% of patients in the AAP + ADT and ADT alone groups, respectively. Adverse events (AEs) led to treatment discontinuation for '''''''% of patients in the AAP + ADT group and '''''''% of patients in the ADT alone group.

Treatment exposure

The median total treatment duration was '''''''''''' months for patients in the AAP + ADT group and ''''''''''' months for the ADT group, with a total of '''''''''''% patients in the AAP + ADT group and ''''''''''''% of patients in the ADT alone group having received ≥24

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cycles of treatment. As of 2[nd] October 2017, ''''''/602 ('''''''''') patients in the ADT alone group had crossed over to receive AAP + ADT at IA2, with a median duration of exposure to subsequent AAP + ADT of '''''''''' months.

Overall survival

At the time of IA2, '''''''''' deaths were observed; ''''''''' in the AAP + ADT group and '''''''' in the ADT alone group. As shown in Figure 1, median OS was ''''''' '''''''''''''''''' '''''''''''' in the AAP + ADT group (95% confidence interval [CI]: ''''''''''''''''''') and was '''''''''' months (95% CI: '''''''''''''''''''''''') in the ADT alone group. Treatment with AAP + ADT resulted in a '''''% reduction in the risk of death compared with ADT alone (hazard ratio [HR]=''''''''''' [95%CI: ''''''''''''''''''''''''']; p''''''''''''''''''). At four years, the majority ('''''''%) of patients in the AAP + ADT group were still alive, compared to only ''''''% of patients in the ADT alone group, reaffirming the sustained survival benefit of AAP + ADT.

Figure 1: KM plot of OS [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier; OS, overall survival. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

As illustrated by the comparison of Kaplan-Meier (KM) plots presented in Figure 2, the significant survival benefit associated with AAP + ADT over ADT alone was

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sustained after a longer duration of follow-up, thus substantiating the robustness of results.

Figure 2: KM plot of OS at IA1 vs. IA2 [LATITUDE, ITT population]

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Secondary endpoints

Treatment with AAP + ADT was '''''''''''''''''''''''''''' '''''''''''''''''''' to ADT alone for all secondary efficacy endpoints.

Time to pain progression

As shown in Figure 2, median time to pain progression was '''''''''' months in the AAP + ADT group and '''''''''' months in the ADT alone group, resulting in a ''''''% reduction in the risk of pain progression (HR='''''''''' [95% CI: '''''''''''''''''''''''']; p''''''''''''''''''). The 48month event-free rate was ''''''% for AAP + ADT and ''''''% for ADT alone. These results indicate that treatment with AAP + ADT prolonged the time before patients’ pain got worse, suggesting it would allow men to carry on with their lives more comfortably.

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Figure 3: KM plot of time to pain progression [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

Time to subsequent therapy for prostate cancer

As shown in Figure 3, treatment with AAP + ADT significantly extended the time to subsequent therapy for prostate cancer. While the median time to subsequent therapy was '''''''' ''''''''''''''''''' in the AAP + ADT group, it was '''''''''' months in the ADT alone group (HR='''''''''' [95% CI: '''''''''''''''''''''']; p''''''''''''''''''''').

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Figure 4: KM plot of time to subsequent prostate cancer therapy [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier.

Source: LATITUDE IA2 CSR Addendum, 2018.[1]

A summary of subsequent therapy received is presented in Table 1. A total of ''''''''''% of AAP + ADT patients and ''''''''''''% of ADT alone patients received subsequent therapy for prostate cancer. The most common subsequent therapy was docetaxel, received by ''''''''''''% of patients in the AAP + ADT arm and ''''''''''% of patients in the ADT alone arm, followed by bicalutamide (received by ''''''''% and ''''''''''''% of patients, respectively) and enzalutamide (received by ''''''''% and '''''''''''%, respectively).

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Table 1: Subsequent therapy for prostate cancer [LATITUDE, ITT population]

Time to life-extending subsequent therapy for prostate cancer

As shown in Figure 4, the median time to life-extending subsequent therapy was '''''''' '''''''''''''''''' in the AAP + ADT group but was '''''''''' months in the ADT alone group, demonstrating that AAP + ADT delayed the need for initiation of life-extending subsequent therapy (HR=''''''''''' [95% CI: '''''''''''''''''''''''''']; p'''''''''''''''''').

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Figure 5: KM plot of time to life-extending subsequent prostate cancer therapy [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

Table 2 provides an updated summary of life-extending subsequent therapy for prostate cancer. Life-extending therapy was reported for '''''''''''% of patients in the AAP + ADT group compared with ''''''''''''% of patients in the ADT alone group. The most frequently used life-extending therapy was docetaxel (''''''''''% AAP + ADT and '''''''''''% ADT alone), followed by enzalutamide ('''''''% and ''''''''''%, respectively) and AAP ('''''''% and ''''''''''''%, respectively). Of note, Table 2 only shows subsequent therapy use after treatment discontinuation had occurred. As such, the '''''' patients who had crossed over to AAP at time of IA2 are not counted here as this is not considered subsequent therapy.

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Table 2: Life-extending subsequent therapy [LATITUDE, ITT population]

Time to initiation of chemotherapy

As shown in Figure 5, the median time to initiation of chemotherapy was '''''''' ''''''''''''''''''' in the AAP + ADT group but was '''''''''' months in the ADT alone group, demonstrating that treatment with AAP + ADT significantly delayed the time until patients required chemotherapy (HR='''''''''''' [95% CI: '''''''''''''''''''''']; p'''''''''''''''''''''). This translated to a ''''''% reduction in the risk of initiation of chemotherapy, a particularly important endpoint for those men who would prefer to choose not to undertake chemotherapy in mHSPC. As detailed in Table 1, the majority of patients who received subsequent therapy for their prostate cancer received docetaxel chemotherapy, suggesting that treatment with AAP in this setting does not impair men’s ability to receive chemotherapy later in their disease course.

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Figure 6: KM plot of time to initiation of chemotherapy [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

Time to next skeletal-related event (SRE)

As shown in Figure 6, treatment with AAP + ADT significantly reduced the risk of SREs by '''''''% (HR=''''''''''' [95% CI: ''''''''''''''''''''''], p''''''''''''''''''), although the median time to SRE was '''''''' '''''''''''''''''''' in either arm. The 48-month event-free rate was ''''''% for AAP + ADT and ''''''% for ADT alone.

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Figure 7: KM plot of time to next SRE [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; ITT, intentionto-treat; KM, Kaplan–Meier. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

Exploratory endpoints

Progression-free survival following subsequent therapy

Progression-free survival following subsequent therapy (PFS2) was defined as the time from randomisation to the second disease progression during follow-up after systemic subsequent therapy, or death from any cause. Among the ''''''''' (''''''''''''''') patients in the AAP + ADT group and ''''''''' (''''''''''''''''') patients in the ADT alone group who received systemic subsequent therapy, ''''''''' ('''''''''''%) and '''''''' (''''''''''%) experienced PFS2 events, respectively.

The median PFS2 was longer with initial AAP + ADT treatment (''''''''''' months) compared with initial ADT alone treatment ('''''''''''' months), however this did not reach statistical significance (HR=''''''''''' [95% CI: '''''''''''''''''''''''']; p''''''''''''''''''). It should be noted that PFS2 was based on investigator-assessed progression (defined as clinical, radiographic or prostate specific antigen [PSA] progression) after first subsequent

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therapy, and this progression was not based on a protocol-defined criterion definition.

Subgroup analysis

Subgroup analyses for OS are presented in Figure 7. Consistent with the results for IA1, the point estimates of treatment effect of AAP + ADT on OS were favourable for all subgroups (HRs ranging from '''''''''' ''''' ''''''''''') and consistent with the overall study results, except for the subgroup of patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 (HR='''''''''''). For this subgroup, nine additional death events were reported; however, the small sample size (n=40) precludes drawing any meaningful conclusion.

Figure 8: Subgroup analyses of OS [LATITUDE, ITT population]

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ITT, intention-to-treat; LDH, lactate dehydrogenase; NE, not evaluable; PSA, prostate specific antigen. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

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Exploring adjustments to survival

Since the results reported at IA1 provided strong evidence for the clinical effectiveness of AAP + ADT, the independent data and safety monitoring committee (IDMC) unanimously recommended the trial be unblinded to allow patients from the control arm to crossover to receive active treatment with AAP + ADT.

Indeed, at the time of IA2, '''''' out of the 602 patients in the ADT alone arm had crossed over to receive AAP + ADT; however, the median duration of exposure to subsequent AAP + ADT in these patients was only ''''''''''' months. While within-trial crossover may impact estimates of OS in some cases, and hence necessitate subsequent statistical adjustments in survival, the level of exposure to AAP + ADT experienced at IA2 in these '''''' patients is insufficient to warrant further adjustment at this stage. As highlighted in Document B (p43), the cross-over adjustment conducted at IA1 using the IPCW method demonstrated that any treatment switching biases against AAP + ADT. Therefore, by not conducting further analyses, the incremental survival benefit of AAP + ADT is likely underestimated and hence the results presented are conservative.

Furthermore, since LATITUDE was an international trial, some patients had access to subsequent therapies that would not be available to patients in UK clinical practice. To attempt to make these results more applicable to the UK setting, posthoc analyses were conducted to explore the use of various methods described in the NICE TSD 16 guidance.[2] Aligned with that discussed in Document B (p43), the 2- Stage method, the rank preserving structural failure time (RPSFT) method and inverse probability censoring weighting (IPCW) were considered for adjusting OS data for patients who switched to other therapies which are not permitted in sequence in the NHS.

Given the issues that exist with the 2-Stage method and RPFST, previously discussed in Document B (p43), the IPCW approach was again used to adjust for treatment switching at IA2. While sample sizes were slightly greater than at IA1 (''''''' rather than '''''' for AAP + ADT, and '''''' rather than ''''''' for ADT alone), they remain small for the relevant treatments of interest, with limited follow-up and an imbalance in patient characteristics between switchers and non-switchers. As such, these

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analyses are still not robust enough to consider of additional value at this time. This analysis again demonstrates that a disproportionate number of patients in the ADT arm went on to receive active subsequent treatments which are not available in UK clinical practice; therefore, in not conducting further analyses, the incremental survival benefit of AAP + ADT is likely underestimated and are hence the results presented are conservative.

Comparative effectiveness estimates

Importantly, all HRs remained stable from IA1 to IA2. It should be noted that the impact of cross-over and the fact that more patients from the ADT alone arm received life-extending subsequent therapy, and started earlier, than those in the AAP + ADT arm, has not been corrected explaining the slight increase in HR. A comparison of these HR between IA1 and IA2 is presented in Table 3. The consistency in these results further substantiates the clinical benefit of AAP + ADT vs. ADT alone. Furthermore, because there is little change in the HRs between IA1 to IA2, there is likely to be minimal impact on the indirect treatment comparison (ITC) of AAP + ADT vs. docetaxel + ADT. As such, the ITC results are expected to be similar.

Table 3: Hazard ratios in IA1 versus IA2

Conclusion

As the HRs for OS and secondary endpoints remained consistent between IA1 and IA2, it is reasonable to infer that the cost-effectiveness estimates for AAP in this setting are also likely to remain consistent, with no need to change the key

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conclusions that were made in Janssen’s original submission for this appraisal. As such, it was felt that updated economic analyses were not warranted at this point in time. Figure 8 presents the IA2 KM plot of OS against the predicted OS from the cost-effectiveness model, utilising the scenario where the model estimates survival using LATITUDE data. This graph demonstrates that the model still provides a good prediction of OS when the updated IA2 data is used, further demonstrating that the cost-effectiveness estimates will likely remain consistent.

Figure 9: KM plot of OS vs predicted model survival

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Key: AAP, abiraterone acetate plus prednisolone; ADT, androgen deprivation therapy; KM, Kaplan– Meier; OS, overall survival. Source: LATITUDE IA2 CSR Addendum, 2018.[1]

In summary, the results from IA2 reaffirm the conclusions previously drawn in Document B, that treatment with AAP + ADT is an efficacious and cost-effective use of NHS resources in men with newly diagnosed high-risk mHSPC, when utilised under the confidential commercial access arrangement (CAA), regardless of the comparator treatment considered.

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References

1. Janssen Research & Development. Report of Updated Data from Study 212082PCR3011: Interim Analysis #2. (Clinical Study Report) 12 January 2018 2018. Data on File.

2. Latimer NR and Abrams KR. NICE DSU Technical Support Document 16: Adjusting survival time estimates in the presence of treatment switching. 2014. Available at:

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0088914/pdf/PubMedHealth_PMH0 088914.pdf. Accessed: 26 January 2018.

3. Janssen Research & Development. A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC). (Clinical Study Report) 2017. Data on File.

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10 Spring Gardens London SW1A 2BU United Kingdom

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+44 (0)300 323 0140

Single technology appraisal

Abiraterone for treating newly diagnosed metastatic hormone-naïve prostate cancer ID945

Dear xxxxxx,

The Evidence Review Group, Aberdeen HTA group, and the technical team at NICE have looked at the submission received on 5[th] February 2018 from Janssen. In general they felt that it is well presented and clear. However, the ERG and the NICE technical team would like further clarification on the clinical and cost effectiveness data (see questions listed at end of letter).

The ERG and the technical team at NICE will be addressing these issues in their reports.

Please provide your written response to the clarification questions by 5pm on 8[th] March 2018. Your response and any supporting documents should be uploaded to NICE Docs.

Two versions of your written response should be submitted; one with academic/commercialin-confidence information clearly marked and one with this information removed.

Please underline all confidential information, and separately highlight information that is submitted as commercial in confidence in turquoise, and all information submitted as academic in confidence in yellow.

If you present data that are not already referenced in the main body of your submission and that are academic/commercial in confidence, please complete the attached checklist for confidential information.

Please do not embed documents (PDFs or spreadsheets) in your response because this may result in them being lost or unreadable.

If you have any queries on the technical issues raised in this letter, please contact Mary Hughes, Technical Lead (mary.hughes@nice.org.uk). Any procedural questions should be addressed to Jeremy Powell, Project Manager (Jeremy.Powell@nice.org.uk).

Yours sincerely

Jasdeep Hayre Technical Adviser – Appraisals Centre for Health Technology Evaluation

Encl. checklist for confidential information

www.nice.org.uk

10 Spring Gardens London SW1A 2BU United Kingdom

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Section A: Clarification on effectiveness data

• A1. PRIORITY QUESTION: Please provide a list of all included studies from the clinical effectiveness review. Please indicate which are primary and secondary references. In particular, please clarify whether Gravis 2013 (referenced in Document B) or Gravis 2016 (referenced in Appendix D) is the primary one.

• A2. PRIORITY QUESTION: Please clarify date limits of the systematic searches. Table 4 in Appendix D specifies ‘Sept 2015 - Present’ and specifically excluded studies published before 2015. Updated searches were conducted in July 2017. However, the included studies listed on pages 13-16 of the appendices include some that are published prior to 2015.

• A3. PRIORITY QUESTION: There are references to 2018 citations as data sources in the company submission (i.e., Fizazi 2018 in Table 6, pages 31-32 and Chi 2018 page 47 onwards - Document B). Please clarify how these were identified and why they were included when searching ended in July 2017.

• A4. PRIORITY QUESTION: Document B pages 40 and 44, Figures 8 (KM plot of FFSAAP + ADT vs. ADT [STAMPEDE, M1 only]) and 11 (KM plot of OS- AAP + ADT [STAMPEDE, M1 only]): Please indicate if these are ITT results

• A5. PRIORITY QUESTION: Document B page 65, Table 14 (Treatment emergent Grade 3-4 AEs reported in at least 1% of patients in either treatment) and Appendix F page 37 (post-hoc analyses of LATITUDE): The TEAE are split up between the two documents. Please provide a table including all data from the submission and appendices for all grades.

• A6. Document B page 63 (treatment exposure in LATITUDE) refers to treatment duration in terms of cycles. What was the ‘average’ (mean, median and range) cycle time for abiraterone plus ADT and ADT?

• A7. PRIORITY QUESTION: Appendix Q (mCRPC ITC methods) page 133 states that it was necessary to assume that mitoxantrone and /or prednisolone are approximately equivalent to placebo/SOC. Please provide a statement on the clinical plausibility of this assumption.

• A8. PRIORITY QUESTION: Appendix K (Baseline characteristics) page 97 states “Of note, specific patient characteristics were not reported for each treatment arm and are therefore not included in Table 38”.: Please clarify which patient characteristics are not included in this table.

• A9. PRIORITY QUESTION: Appendix K (Baseline characteristics) page 106, Table 40 (Summary of subsequent therapies, AAP + ADT vs. ADT alone, [STAMPEDE trial, ITT]): The proportions (%) provided do not correspond to the numerators and denominators given. Please check these.

www.nice.org.uk

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• A10. Appendix Q (mCRPC ITC methods) page 136: Did the results of APP versus Radium 223 and AAP versus Enzalutamide include an adjustment for treatment switching?

The ERG have requested that the company provide its responses to questions A11 to A20 in a separate Excel workbook. Please provide the response to each question in a separate worksheet.

• A11. PRIORITY QUESTION: Please expand the Kaplan Meier data of the KM_data worksheet of the model: columns BP:BQ, BV:BW, CE:CF, CK:CL, CT :CU, CZ :DA, DI :DJ, DO :DP to Timepoint, N at risk, N events and N censoring events sufficient to reconstruct the Kaplan Meier curves. Please supply these as a separate workbook rather than adding it to the KM_data worksheet of the model (8 tables).

• A12. PRIORITY QUESTION: Please supply the Kaplan Meier data split by arm for OS and treatment discontinuations (i.e., the parallels to columns C, D, G and H of the 1L_mCRPC_Efficacy worksheet) of COU-AAP-302: Timepoint, N at risk, N events, N censoring events sufficient to reconstruct the Kaplan Meier curves (4 tables).