abiraterone acetate, 250mg tablets (Zytiga ) SMC No. (873/13) Janssen-Cilag Ltd

abiraterone acetate, 250mg tablets (Zytiga ) SMC No. (873/13) Janssen-Cilag Ltd 09 January 2015 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in Scotland. The advice is summarised as follows: ADVICE: following a full submission considered under the end of life process abiraterone acetate (Zytiga ) is not recommended for use within NHS Scotland. Indication under review: with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. In a randomised, double-blind phase III study of adult men with metastatic castration-resistant prostate cancer, treatment with abiraterone in combination with corticosteroid was associated with an extended progression-free survival and overall survival when compared with placebo plus corticosteroid. The submitting company did not present a sufficiently robust economic analysis to gain acceptance by SMC and in addition their justification of the treatment s cost in relation to its benefits was not sufficient to gain acceptance by SMC. This advice takes account of the views from a Patient and Clinician Engagement (PACE) meeting. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium Published 09 February 2015 1

Indication With prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Dosing Information The recommended dose is 1,000mg (four 250mg tablets) as a single daily dose that must not be taken with food. Abiraterone is to be taken with low dose prednisone or prednisolone. The recommended dose of prednisone or prednisolone is 10mg daily. Medical castration with luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment in patients not surgically castrated. Product availability date December 2012. Abiraterone acetate meets SMC end of life criteria in this setting. Summary of evidence on comparative efficacy Abiraterone acetate is a prodrug of abiraterone, an androgen biosynthesis inhibitor. It specifically inhibits the enzyme cytochrome P450 17 (CYP17), which is involved in the production of testosterone, and blocks androgen synthesis in the adrenals, testes and prostate tumours. 1 The indication under review is for an extension to abiraterone s licence, to use in males with metastatic castration-resistant prostate cancer (CRPC) in whom chemotherapy is not yet indicated. Abiraterone has previously been accepted for restricted use by SMC for the treatment of males with metastatic CRPC who have progressed on or after docetaxel-based chemotherapy. Evidence for the indication under review is from COU-AA-302, an international, double-blind, randomised, and placebo-controlled phase III study. 2-5 The study recruited adult males with metastatic, histologically- or cytologically-confirmed prostate cancer with a life expectancy of at least six months. Patients were medically or surgically castrated with no or mild symptoms, progressive disease, good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1) and had previous anti-androgen therapy. Castration was defined as serum testosterone <50nanograms/dL (<1.7nanomol/L); symptoms scored using the Brief Pain Inventory-Short Form (BPI-SF) in which a score of 0 or 1 was asymptomatic and scores of 2 or 3 were classed as mild symptoms. Progressive disease was either prostate specific antigen (PSA) progression in accordance with Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria or radiographic progression according to modified Response Evaluation Criteria in Solid Tumours (RECIST). 2 Patients were randomised equally (with stratification for baseline ECOG performance status) to abiraterone 1g daily (n=546) or placebo (n=542). All patients also received open-label corticosteroid (prednisone or prednisolone 5mg twice daily). Cytotoxic, hormonal (with the exception of luteinising hormone releasing hormone [LHRH] agonists) or immuno-therapy was prohibited during the study. LHRH agonists were prescribed to maintain castrate testosterone levels, and bisphosphonates were permitted if taken prior to randomisation. Upon disease progression, patients were switched to alternate treatments at the investigator s discretion. 2 2

The study was designed with two co-primary endpoints: radiographic progression-free survival (PFS) and overall survival. Radiographic PFS was determined by an independent, blinded radiologist and was defined as freedom from death from any cause, freedom from progression in soft-tissue lesions as measured by computed tomography or magnetic resonance imaging in accordance with modified RECIST, or progression on bone scanning according to criteria adapted from PCWG2. Overall survival was defined as the time from randomisation to death from any cause. All efficacy analyses were conducted in the intention-to-treat population, with an overall type 1 error of 0.05 shared between the co-primary endpoints: 0.01 for radiographic PFS and 0.04 for overall survival. Pre-specified interim analyses for overall survival were planned; to control the type 1 error from multiple interim analyses, the significance level was set at <0.0001, 0.0005, and 0.0034 for the analyses when approximately 15%, 40% and 55% total planned events were accrued, respectively. 2 The primary analysis for independent-radiologist-assessed radiographic PFS was based on a data cut-off date in December 2010 at which point there had been 401 events: 150 in the abiraterone group and 251 in the placebo group. The hazard ratio (HR) for radiographic PFS was 0.43 (95% confidence interval [CI]: 0.35 to 0.52), p<0.001. Median radiographic PFS was not reached in the abiraterone plus corticosteroid group and was 8.3 months in the placebo plus corticosteroid group. 2 Investigatorassessed radiographic PFS has been reported at later data cut-offs, the most recent in May 2012 at which point there had been 292 events in the abiraterone plus corticosteroid group and 352 in the placebo plus corticosteroid group. Median radiographic PFS was 16.5 months for abiraterone plus corticosteroid, and 8.2 months for placebo plus corticosteroid; HR 0.52 (95% CI: 0.45 to 0.61), p<0.0001. 3,4 At the first interim analysis of overall survival in December 2010, there were 209 events and median overall survival was not reached in either treatment group. 4 Hazard ratios for overall survival favoured abiraterone plus corticosteroid in the second and third interim analyses, but they did not meet the prespecified statistical significance levels. During the SMC assessment process, results of the final analysis of overall survival were presented at the European Society of Medical Oncology Conference in Madrid, 5 and published in a peer-reviewed journal just prior to publication of this advice. 9 Results are shown in table 1 below. Abiraterone plus corticosteroid (n=546) Placebo plus corticosteroid (n=542) No. of events 147 186 Interim analysis 2 Median overall December 2011 Not reached 27.2 months survival (median follow-up = 22.2 months) HR (95% CI) 0.75 (0.61 to 0.93), p=0.01* No. of events 200 234 Interim analysis 3 Median overall May 2012 35.3 months 30.1 months survival (median follow-up = 27.1 months) HR (95% CI) 0.79 (0.66 to 0.95), p=0.0151* No. of events 741 Final Analysis Median overall (median follow-up = 49.4 months) 34.7 months 30.3 months survival HR (95% CI) 0.80 (0.69 to 0.93), p=0.0027 Table 1: Overall survival in the pivotal study. 2-5 *Not statistically significant (significance levels for 2 nd and 3 rd interim analyses were 0.0005 and 0.0034 respectively). HR=hazard ratio, CI=confidence interval Benefits of abiraterone plus corticosteroid versus placebo plus corticosteroid were demonstrated for secondary outcomes, with delays in the median time to: opioid use for cancer-related pain (HR=0.71, 3

p=0.0002); initiation of chemotherapy (HR=0.61, p<0.0001); deterioration in ECOG performance status by at least one point (HR=0.83, p=0.005); and PSA progression as per the PCWG2 criteria (HR=0.50, p<0.0001). Patient-reported outcomes were measured using the BPI-SF and Functional Assessment of Cancer Therapy-Prostate (FACT-P) tools. Compliance rates for completion were >95% for both treatment groups. There was a consistent pattern of abiraterone delaying the progression of pain scores or in deteriorations in the functional status of patients, although these were not always statistically significant. The median time to a clinically relevant increase in mean pain intensity of at least 30% from baseline was 26.7 months for abiraterone plus corticosteroid and 18.4 months for placebo plus corticosteroid (HR=0.83, p=0.06). Progression of pain interfering with activities of daily living was significantly delayed in the abiraterone plus corticosteroid group: 10.3 months versus 7.4 months respectively, HR=0.8 (p=0.005). Median time to functional status degradation was prolonged for abiraterone plus corticosteroid when evaluated in terms of FACT-P total score, prostate-cancer specific sub-scale scores and all other FACT-P subscales except social/family well-being subscale. 3 The data and safety monitoring committee for the study recommended unblinding the study on the basis of the results of efficacy and safety outcomes from the second interim analysis. Unblinding occurred in early May 2012 and at the time of the third interim analysis, three placebo patients had crossed-over to abiraterone. Subsequent therapy, regardless of treatment sequence, has been reported up to the third interim analysis of overall survival. In both groups the most common treatment was docetaxel given to 44% of abiraterone plus corticosteroid patients versus 56% of placebo plus corticosteroid patients. 3 At the final analysis of overall survival, 44% of placebo plus corticosteroid patients had subsequently received abiraterone. 5 Summary of evidence on comparative safety Adverse events (AE) were reported in almost all patients in the study, 99% of abiraterone plus corticosteroid and 97% of placebo plus corticosteroid patients; grade 3 or 4 AE occurred in 49% and 44% of patients respectively. Similar proportions of patients discontinued treatment due to AEs: 11% in the abiraterone plus corticosteroid group and 10% in the placebo plus corticosteroid group. Interruption to treatment or dose modification occurred in 21% and 12% of patients respectively. Fatigue was the most commonly reported AE (40% of abiraterone plus corticosteroid treated patients and 35% of placebo plus corticosteroid treated patients); however, this was relatively mild in severity with only 2% of patients in either group reporting grade 3 or 4 fatigue. AEs leading to death occurred in 4% (21/542) of abiraterone plus corticosteroid patients and in 3% (16/540) placebo plus corticosteroid patients. In each group, six patients deaths were considered to be treatment-related. 3 The safety profile of abiraterone was considered by the European Medicines Agency (EMA) to be consistent with previous experience (except for four new adverse drug reactions identified dyspepsia, aspartate aminotransferase [AST] increased, rash and haematuria). 4 Summary of clinical effectiveness issues CRPC is defined by disease progression despite androgen deprivation therapy (either surgically or medically with LHRH analogues). Fit patients with metastatic CRPC and symptomatic progression or with rapidly rising PSA levels are usually offered docetaxel-based chemotherapy. In men for whom chemotherapy is not yet indicated, clinical experts consulted by SMC advise that a watchful waiting strategy is employed together with best supportive care options including combination of LHRH analogues with bicalutamide, dexamethasone or diethylstilbestrol. Despite these options, the 4

prognosis of men with metastatic CRPC is still poor. 4 criteria. Abiraterone acetate meets SMC end of life Clinical experts consulted by SMC considered that there is unmet need in this therapeutic area, namely a lack of effective therapies in patients for whom chemotherapy is not yet indicated. The pivotal study provides data relative to a comparator relevant to NHS Scotland, watchful waiting, i.e. use of corticosteroid with continuation of androgen deprivation therapy (LHRH analogue plus corticosteroid). Abiraterone plus corticosteroid when compared with placebo plus corticosteroid significantly prolonged the time to radiographic progression or death by 8.3 months. In the final analysis, median overall survival in the abiraterone plus corticosteroid group was 34.7 months versus 30.3 months in the placebo plus corticosteroid group. These results were statistically significantly different despite confounding due to substantial crossover. Deterioration in markers of health-related quality of life: specifically functional status and clinically significant increases in mean pain were delayed in patients treated with abiraterone. Abiraterone plus corticosteroid was shown to delay the initiation of cytotoxic chemotherapy compared with placebo plus corticosteroid, a benefit of potential value to patients. However, patients commenced on abiraterone will require more frequent follow-up, and monitoring of serum transaminases, blood pressure, serum potassium and fluid retention (initially fortnightly for three months, then monthly thereafter). 1 Clinical experts consulted by SMC considered that abiraterone is a therapeutic advancement, delaying the initiation of chemotherapy and providing a therapeutic option in a patient group where there is no proven therapy. Summary of patient and clinician engagement A patient and clinician engagement (PACE) meeting with patient group representatives and clinical specialists was held to consider the added value of abiraterone in this setting, as an end of life medicine, in the context of treatments currently available in NHS Scotland. The key points expressed by the group were: Currently this patient group has a limited range of options to extend life. Abiraterone not only improves survival but prolongs the period of normal quality of life without imposing unacceptable toxicity. SMC has already accepted this medicine in the post chemotherapy setting and PACE participants felt strongly that it would be more appropriate to use it earlier in the treatment pathway, where the total benefits are likely to be greater. The alternative option of watchful waiting at this stage of the condition has the inherent risk that a life-threatening skeletal event may occur before further treatment has been started. Watchful waiting is associated with significant anxiety knowing that the disease is progressing but nothing is being done. Men can self administer this oral preparation at home allowing them to continue to work or maintain their current level of daily living whilst reducing the anxiety associated with time spent at hospital and travelling for administration. Men can still play an active role in society and the burden on the family is often much reduced as a result. 5

Patients experience relatively few side effects on treatment and there are no external signs of treatment as would occur with chemotherapy e.g. hair loss, nail changes. Men feel they can pass themselves off as not having cancer which is hugely valuable to their sense of wellbeing. The PACE group was very strongly of the view that this medicine should be made available in NHS Scotland. They noted that there is an equity issue that can be distressing for patients and can impact on NHS Scotland s ability to participate in clinical research. Summary of comparative health economic evidence The submitting company provided a cost-utility analysis comparing abiraterone acetate plus prednisolone or prednisone (AAP) to watchful waiting (WW) and best supportive care (BSC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) and in whom chemotherapy (with docetaxel) is not yet clinically indicated. The clinical data used in the economic analysis were individual patient data from the 3 rd interim analysis of study COU-AA-302. The control arm of this study was placebo plus prednisolone, which was used as a proxy for watchful waiting. The model used was a discrete event simulation (DES) in which a set of prediction equations were developed in order to simulate the patient experience, based on their baseline characteristics, through a treatment pathway. The phases of the model consisted of pre-docetaxel treatment with AAP or WW followed by BSC, on docetaxel treatment followed by BSC for both arms, and post docetaxel treatment followed by BSC to death. A lifetime time horizon was used. The prediction equations estimated time to treatment start and discontinuation, and time to death in each phase of the model. In each phase, time in BSC leading to death was estimated. Parametric functions were fitted to each prediction equation to extrapolate the time to event outcomes. The utility of each treatment phase in the model was based on a bespoke UK utility study in 163 metastatic CRPC patients in which EQ- 5D data was collected to correspond to the treatment phases in the economic model. This produced a post-adt baseline utility of 0.83, 0.625 for pre-docetaxel BSC, 0.692 on docetaxel treatment and 0.70 for post-docetaxel treatment. BSC leading to death utility (0.5) was based on published EQ-5D values for Swedish patients with end-of-life prostate cancer. An additional on-treatment utility benefit for AAP over WW for on-treatment benefits such as reduced fatigue and pain (0.021) was included in the utility calculations based on regression analysis of mapped FACT-P to EQ- 5D data, though the disutility estimated for on-treatment grade 3 or 4 adverse events was not taken into account. Drug acquisition costs were based on recommended doses of each medicine. In the base case, it was assumed that post-docetaxel treatment consisted of 50% use of abiraterone and 50% enzalutamide in the WW arm, and 100% use of enzalutamide in the AAP arm. Treatment duration estimates were based on the prediction equations. Docetaxel administration was based on an assumed patient body surface area of 2.01m 2. Resource use data for scheduled hospital and GP visits, nurse visits, diagnostic/imaging and other laboratory tests were estimated using a resource use survey conducted with UK oncologists and urologists. Unscheduled events relating largely to adverse events were based on analysis of data in study clinical experts and analysis of data from the COU-AA- 302 study. Resource use based on clinical opinion/trial data and costs for incremental grade 3 and 4 adverse events associated with docetaxel were estimated, and the costs of terminal care were also included. A patient access scheme (PAS) is already in place for abiraterone in the post-chemotherapy setting and has been assessed by the Patient Access Scheme Assessment Group (PASAG) as acceptable 6

for NHS Scotland for this current submission. Under the PAS, a confidential discount was offered on the list price of abiraterone. The base case result with the PAS was 48,235 per quality adjusted life year (QALY). SMC would wish to present all the with-pas cost-effectiveness estimates that informed the decision but is unable to do so as the company has indicated that the incremental costs, life years gained and incremental QALYs should remain commercial in confidence. The key driver of the results is the additional drug cost of AAP, which makes up 92% of the cost difference. In the pre-docetaxel phase, there are also additional costs for AAP over WW in medical resource utilisation. The life year and QALY benefits are associated with longer time on AAP treatment and progression free pre-docetaxel than WW, although mean survival associated with the on docetaxel treatment phase is greater with WW; this is stated by the company to be due to longer time on docetaxel and being able to receive AAP post docetaxel. Adopting a 10 year time horizon, consistent with the previous SMC submission for abiraterone, increased the ICER to 52.2k/QALY. Varying the treatment effect coefficients in the prediction equations by ±1 standard error resulted in an ICER range of 41k-61k/QALY, and in further requested analysis, applying ±1.5 SE variation (corresponding to the 87% confidence interval around the mean treatment effect) produced an ICER range of 39k-69k/QALY. This is likely to represent a relatively pessimistic upper estimate as the survival benefit was below the median trial based estimate of 4.3 months OS benefit (with 44% patient cross-over to AAP) at the final analysis. Key limitations in the economic analysis were as follows: The trial data used in the model are not mature, and more recent final analysis results based on 49.4 months follow-up have been presented at the 2014 ESMO meeting. These show a lower median survival benefit for AAP than that based on the interim analysis, but is likely to be confounded by much larger cross-over of patients from the placebo plus corticosteroid arm to AAP than at interim. The company was requested to use the final analysis data in the model if at all possible, but responded this was not possible in the time available. Hence, the use of the interim data in the model based on only 27.1 months follow-up represents a limitation as a source for extrapolation via the prediction equations in the model. The discrete event simulation (DES) model used has some advantages over a standard cancer economic model based on a Markov structure; however, it does add uncertainty in terms of being able to assess the robustness of the extrapolations due to the added complexity of the model. Not all the data were used for the prediction equations as those with missing baseline characteristics data were excluded, although evidence submitted by the company suggests that any bias introduced would not have favoured abiraterone. There was some lack of transparency in the choice of final parametric functions for the time to event prediction equations. The Weibull was used to replace the best fitting exponential function, but best fitting log-logistic functions were retained for some prediction equations (AAP/WW start to end, and docetaxel start to death). The company was asked to explore the use of the Weibull function instead for these equations, which resulted in an ICER of 53,745/QALY based on lower incremental costs and lower incremental LYG/QALY gained estimates for AAP vs. WW than in the base case. The company was requested to explore the impact of using radiographic PFS instead of time to treatment discontinuation as a proxy of PFS, but stated this was not possible with the DES model structure. There is some uncertainty over the utility increment estimated for on treatment with AAP based on the FACT-P to EQ 5D mapping, as the robustness of the mapping exercise is unclear. The base case value of 0.83 for post ADT baseline utility appears to be high relative to other advanced cancers although prostate cancer patients may be somewhat fitter and in better quality of life than patients with some other cancers. 7

As well as the limitations above, the ICERs are above acceptable levels with the current data and after a range of scenario and sensitivity analyses. The Committee considered the benefits of abiraterone in this setting in the context of its decision modifiers that can be applied when encountering high cost-effectiveness ratios and concluded that the criterion for a substantial increase in life expectancy was met. After considering all the available evidence, the output from the PACE process, and after application of the appropriate modifiers, the Committee was unable to accept abiraterone for use in NHS Scotland. It was noted that abiraterone was likely to be effective and increase quality of life but as there remained some uncertainty about the long-term benefits relative to the current treatment pathway it could not be considered a cost effective use of NHS resources. Summary of patient and public involvement The following information reflects the views of the specified Patient Interest Groups. Submissions were received from Prostate Cancer UK, Prostate Scotland, and Edinburgh and Lothian Prostate Cancer Support Group (ELPCSG), all of which are registered charities. Prostate Cancer UK has received funding from several pharmaceutical companies in the past two years, including from the submitting company. Prostate Scotland and ELPCSG have not received any pharmaceutical company funding in the past two years. Advanced prostate cancer is incurable and patients often experience slowly deteriorating health leading to greater reliance on family and carers, along with urinary symptoms, reduced mobility, fatigue, anxiety and depression. Current treatment options are limited. When hormone therapy is no longer working, chemotherapy may be offered. However, this is associated with considerable side-effects. Advantages of the new medicine include: ease of administration - it is an oral treatment which can be taken at home thereby increasing the time patients can spend with their families, and reduces the reliance on medical professionals. It is thought to increase survival whilst improving symptoms for patients such as pain, fatigue, mobility and numbness in the legs. Whilst there are side-effects associated with abiraterone, they are generally regarded by patients as less of a burden than the side-effects of chemotherapy. Additional information: guidelines and protocols The European Association of Urology updated its prostate cancer management guidelines in 2014. 6 The defining characteristics of CRPC are: Castrate levels of serum testosterone (<50nanograms/dL or <1.7nanomol/L) plus either 8

1. Biochemical progression: Three consecutive increases in PSA (7 days apart) resulting in two 50% increases over the nadir, with PSA>2nanograms/mL or 2. Radiological progression: The appearance of at least two bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST. The gold-standard treatment outcome in CRPC is overall survival, with other commonly used outcomes of improvements in quality of life, PFS and prostate cancer specific survival. Nearly all studies of treatments for CRPC have been conducted with ongoing androgen suppression, so this should be continued in these patients. In patients with metastatic CRPC, good performance status, mildly symptomatic or asymptomatic with no evidence of visceral disease, the following are suggested as 1 st -line non-chemotherapy-based therapeutic options: abiraterone, Sipuleucel T, enzalutamide. The recommendations are made on the basis of the results of placebo-controlled studies of abiraterone (COU-AA-302), enzalutamide (PREVAIL) and Sipuleucel T (phase III study supporting registration). Due to a lack of head to head studies or data for different sequencing options, it is not clear how to choose the most appropriate therapeutic option. Enzalutamide was granted a marketing authorisation pre-docetaxel in November 2014 and Sipuleucel T has not yet been launched in the UK. The National Institute for Health and Care Excellence published prostate cancer; diagnosis and treatment clinical guideline number 175, in 2014. 7 The goals of treatment in hormone-relapsed disease are: improvement of survival and quality of life with control of symptoms. Hormone-relapsed disease may be defined as such when there is radiological progression, loss of PSA control or development of disease-related symptoms. LHRH analogues are usually continued in hormone-relapsed disease since the androgen receptors on the cancer cells can remain active, and the disease may still respond to alternative agents such as corticosteroids, oestrogens and abiraterone that also act on the androgen pathway. It is recommended that corticosteroid is offered to patients with hormone-relapsed prostate cancer as a 3 rd -line hormonal therapy after androgen deprivation therapy and anti-androgen therapy. Chemotherapy (docetaxel plus prednisolone) is recommended in men with symptomatic progression and in asymptomatic patients with rapidly rising PSA. The European Society for Medical Oncology published its guidance in 2013. 8 It recommended that patients who develop CRPC should continue androgen suppression and be considered for further hormone treatments. In those with poor initial hormone response or severe symptoms, chemotherapy may be preferable. Patients who progress following docetaxel should be considered for treatment with abiraterone or enzalutamide. Additional information: comparators Treatment options for men with metastatic CRPC include combination of LHRH analogues with: bicalutamide, corticosteroid (dexamethasone) or diethylstilbestrol (sometimes with low-dose aspirin). 9

Cost of relevant comparators Drug Dose Regimen Cost per year ( ) Abiraterone plus prednisolone Abiraterone 1,000mg orally once daily 35,602 Prednisolone 5mg orally twice daily Diethylstilbestrol 1 to 3mg orally once daily 1,279 to 3,836 Dexamethasone 500 micrograms orally once daily 624 Bicalutamide 50mg orally once daily 30 Doses are for general comparison and do not imply therapeutic equivalence. Costs from evadis on 03 September 2014 except abiraterone from www.mims.co.uk (30 September 14). Dose of dexamethasone as per NICE guidelines. Costs do not take any patient access schemes into consideration. Additional information: budget impact The submitting company estimated the population eligible for treatment to be 514 in year 1 and 525 in year 5 with an estimated uptake of 80% in year 1 (411 patients) declining to 55% by year 5 (289 patients). The company has requested that both the with and without PAS budget impact estimates based on these patient numbers should remain confidential. Other data were also assessed but remain commercially confidential.* 10

References The undernoted references were supplied with the submission. Those shaded in grey are additional to those supplied with the submission. 1. Janssen-Cilag Ltd. Summary of product characteristics Zytiga 250mg tablets. www.medicines.org.uk [Last updated 21 Aug 2014] 2. Ryan CJ, Smith MR, de Bono JS et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138-48 (plus online Supplementary Appendix and Study Protocol) 3. Rathkopf DE, Smith MR, de Bono JS et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Article In Press.EurUrol 2014. http://dx.doi.org/10.1016/j.eururo.2014.02.056(plus online Supplementary Appendix) 4. European Medicines Agency. Assessment report Zytiga (abiraterone). Procedure no. EMEA/H/C/002321/II/0004/G. 15 November 2012. www.ema.europa.eu 5. Ryan C, Smith M, Fizazi K et al. Final overall survival (OS) analysis of COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mcrpc) patients (pts) without prior chemotherapy. Paper 7530 presented at ESMO 2014, Madrid (28 September 2014). 6. Mottet N, Bastian PJ, Bellmunt J et al. Guidelines on prostate cancer (update April 2014) European Association of Urology. www.uroweb.org 7. National Institute for Health and Care Excellence. Prostate cancer: diagnosis and treatment. NICE clinical guideline 175 (January 2014). www.nice.org 8. Horwich A, Parker C, de Reijke T&Kataja V, on behalf of the ESMO Guidelines Working Group. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2013; 24 (Supplement 6): vi106 14. 9. Ryan CJ, Smith MR, Fizazi K, Saad F et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncology (published online 16 January 2015; doi:10.1016/s1470-2045(14)71205-7 ) This assessment is based on data submitted by the applicant company up to and including 14 November 2014. *Agreement between the Association of the British Pharmaceutical Industry (ABPI) and the SMC on guidelines for the release of company data into the public domain during a health technology appraisal: http://www.scottishmedicines.org.uk/about_smc/policy_statements/policy_statements 11

Drug prices are those available at the time the papers were issued to SMC for consideration. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC. Patient access schemes: A patient access scheme is a scheme proposed by a pharmaceutical company in order to improve the cost-effectiveness of a drug and enable patients to receive access to cost-effective innovative medicines. A Patient Access Scheme Assessment Group (PASAG, established under the auspices of NHS National Services Scotland reviews and advises NHS Scotland on the feasibility of proposed schemes for implementation. The PASAG operates separately from SMC in order to maintain the integrity and independence of the assessment process of the SMC. When SMC accepts a medicine for use in NHS Scotland on the basis of a patient access scheme that has been considered feasible by PASAG, a set of guidance notes on the operation of the scheme will be circulated to Area Drug and Therapeutics Committees and NHS Boards prior to publication of SMC advice. Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. 12