January Abiraterone pre-docetaxel for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer

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1 LONDON CANCER NEW DRUGS GROUP RAPID REVIEW Abiraterone pre-docetaxel for asymptomatic/minimally symptomatic metastatic castration resistant prostate cancer Abiraterone pre-docetaxel for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer Contents Summary 1 Background 2 Epidemiology 2 Safety 3 Cost 4 Reference 5 Produced for the London New Drugs Group Contact: Angela Bennett Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Tel: Fax: Anegla.bennett@gstt.nhs.uk Further copies of this document are available from URL NeLM-Area/Evidence/Drug- Specific-Reviews/ Produced for use within the NHS. Not to be reproduced for com- Summary Abiraterone has recently received a UK licence extension for the requested indication. The licensed indication states that abiraterone is indicated in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. There is a need to highlight what criteria are required for mildly symptomatic patients and under what circumstances it is deemed that chemotherapy is not yet clinically indicated. The CDF application was for use in metastatic castrate refractory prostate cancer pre-docetaxel. This does not include the additional stipulation that is stated in the license, which is that abiraterone can be used where chemotherapy is not yet indicated. If CDF funding is agreed for abiraterone as per the CDF application, patients would be eligible if they were suitable for chemotherapy, but the clinician decided to treat the patient with abiraterone instead. There is phase III double-blind, randomised data that has recently been published and which the licence extension was based on. The co-primary endpoints were radiographic progression-free survival (assessed by central review), and overall survival. If a trial contains co-primary endpoints both objectives do not need to be clinically significant in order for the trial to be deemed a success. One significant co-primary is sufficient. On the basis of the blinded central radiologic review, at the time of the first interim analysis, treatment with abiraterone plus prednisone, as compared with placebo plus prednisone, resulted in a 57% reduction in the risk of radiographic progression or death (median not reached vs. median of 8.3 months; hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.43; 95% CI ; P<0.001). At the time of the second interim analysis, the median to radiographic progression-free survival on the basis of investigator assessment was 16.5 months in the abiraterone arm and 8.3 months in the prednisone arm (hazard ratio 0.53; 95% CI ; P<0.001). Overall survival was improved with abiraterone prednisone (median not reached, vs months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the pre-specified boundary for significance (P 0.001) at the observed number of events. The study was unblinded by the independent data monitoring committee after the planned second interim analysis that was performed after 43% of the expected deaths had occurred, as the committee felt the results thus far meant it was unethical to continue the study. Grade 3 or 4 adverse events were reported in 48% of patients in the abiraterone arm and 42% of patients in the placebo arm; serious adverse events were reported in 33% and 26% of patients, and adverse events resulting in death were reported in 4% and 2% of patients, respectively. Fatigue, arthralgia, and peripheral oedema were among the adverse events reported more frequently in the abiraterone arm than in the placebo arm. Muscle spasm appeared to be more common in the placebo arm than the abiraterone arm (20% vs. 14%, respectively).

2 Background Prostate cancer is a disease in which tumours develop in the prostate, a gland in the male reproductive system. In England and Wales, there were over 36,900 people newly diagnosed with prostate cancer and over 9,600 deaths from prostate cancer in The incidence of prostate cancer increases with age. The cause of prostate cancer is thought to be multi-factorial, involving both environmental and genetic factors (1). It is estimated that 55% to 65% of people with prostate cancer will go on to develop metastatic disease (that is, the cancer spreads to other parts of the body). In over 90% of people with metastatic prostate cancer, the disease will initially respond to standard hormonal therapy but eventually become resistant to it. This clinical condition is described as castration-resistant prostate cancer, androgenindependent prostate cancer, or hormone-refractory prostate cancer (1). NICE clinical guideline 58 ( Prostate cancer ) states that localised disease should be managed with active surveillance, surgical removal of the prostate (known as prostatectomy) or high-dose radical radiotherapy. However, once the cancer has become metastatic, it is unlikely that it will be able to be cured, though the progression of the cancer can be slowed with treatment. Stopping the body making testosterone can slow the growth of the cancer, or even shrink it. People with prostate cancer may therefore receive hormonal therapy to reduce androgen levels. Standard hormonal treatments for metastatic disease are orchidectomy (surgical removal of the testes, also known as surgical castration ) or use of a gonadotrophin-releasing hormone analogue such as goserelin, leuprorelin or triptorelin (also known as medical castration ) (2). For metastatic castration-resistant prostate cancer, NICE Technology Appraisal No. 101 recommends docetaxel as a treatment option for hormone-refractory prostate cancer associated with a Karnofsky performance-status score of 60% or more (3). Abiraterone Abiraterone acetate (Zytiga, Janssen) is a selective androgen biosynthesis inhibitor. Abiraterone acetate blocks cytochrome P17 (an enzyme thought to play a role in the production of testosterone), thereby stopping the testes and other tissues in the body from making testosterone (1). It is administered orally in combination with prednisone or prednisolone (1). Abiraterone was recently licensed in the UK in combination with prednisolone or prednisone 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 (4). The CDF application for funding was for use in metastatic castrate refractory prostate cancer predocetaxel and doesn t include the additional stipulation that chemotherapy is not yet clinically indicated. If funding for abiraterone is accepted as per the CDF application, clinicians would be able to use abiraterone to treat patients who would otherwise be eligible for docetaxel (i.e. a larger number of patients). NICE are in the process of reviewing abiraterone for the licensed indication and the expected date of publication for the technology appraisal is November 2013 (1). Epidemiology The manufacturer has provided information that approximately 434 patients in London would be eligible for abiraterone according to the licensed indication (personal communication). For this model, it was assumed that the population of London was 8,192,300. This therefore estimates that 5 patients per 100,000 would be eligible for abiraterone if it is used as per the licensed indication. This model assumes that patients are only on the drug for two thirds of the time when compared to the phase III trial (which is in-line with the London audit data). The model does not take in to account any concurrent clinical trials which would mean that fewer patients receive abiraterone. Published data There is one published randomised, double-blind, phase III study evaluating the effects of abiraterone plus prednisone in patients with progressive metastatic castration-resistant prostate cancer who had not received chemotherapy and in whom clinically significant cancer-related symptoms had not developed (5). Eligibility criteria included: Aged 18 years or over Metastatic, histologically or cytologically confirmed adenocarcinoma of the prostate Prostate-specific antigen (PSA) progression according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria or radiographic progression in soft tissue or bone with or without PSA progression Ongoing androgen deprivation with a serum testosterone level of less than 50ng per decilitre ECOG performance status of 0 or 1 No symptoms or mild symptoms, as defined according to the Brief Pain Inventory-Short Form (BPI-SF) Previous therapy with an antiandrogen was required.

3 Patients with visceral metastases who had received previous therapy with ketoconazole lasting more than 7 days were excluded. One thousand and eighty eight patients were randomly assigned to receive abiraterone 1g daily plus prednisone 5mg twice daily (546 patients) or placebo plus prednisone 5mg twice daily (542 patients). Treatment was continued until progression. Patients were stratified according to baseline ECOG performance status. The co-primary endpoints were radiographic progression-free survival and overall survival. Radiographic progression-free survival was determined by an independent radiologist who was unaware of study group assignments. Changes in PSA level were not included in the definition of radiographic progression-free survival. The prespecified secondary endpoints were times to opiate use for cancer-related pain, to initiation of cytotoxic chemotherapy, to a decline in EOG performance status, and to PSA progression. Other endpoints included radiographic progression-free survival as measured by investigators, PSA response rate ( 50% decline in PSA level from baseline), rate of objective response according to RECIST criteria, and healthrelated quality of life. Baseline characteristics were well balanced between the two study groups. The median age was 71 years (range years) in the abiraterone arm and 70 years (range years) in the placebo arm (6). All patients had received previous hormonal treatment for their cancer. Around 46% of patients had received previous surgery and about 54% of patients had received previous radiotherapy for their cancer. About 13% of patients had received other treatment for their cancer. The median PSA at initial diagnosis was 22.3mg/mL in the abiraterone arm (range ng/mL) and 21ng/mL in the placebo arm (range ng/mL). On the basis of the blinded central radiologic review, at the time of the first interim analysis, treatment with abiraterone plus prednisone, as compared with placebo plus prednisone, resulted in a 57% reduction in the risk of radiographic progression or death (median not reached vs. median of 8.3 months; hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.43; 95% CI ; P<0.001). At the time of the second interim analysis, the median to radiographic progression-free survival on the basis of investigator assessment was 16.5 months in the abiraterone arm and 8.3 months in the prednisone arm (hazard ratio 0.53; 95% CI ; P<0.001). Overall survival was improved with abiraterone prednisone (median not reached, vs months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the prespecified boundary for significance (P 0.001) at the observed number of events. The study was unblinded by the independent data monitoring committee after the planned second interim analysis that was performed after 43% of the expected deaths had occurred, as the committee felt the results thus far meant it was unethical to continue the study. Other results were as follows: Median time to initiation of cytotoxic chemotherapy was 25.2 months in the abiraterone arm and 16.8 months in the placebo arm (hazard ratio 0.58; 95% CI ; P<0.001) Median time to PSA progression was 11.1 months in the abiraterone arm and 5.6 months in the placebo arm, a 51% reduction in risk (hazard ratio 0.49; 95% CI ; P<0.001). The median time to a decline in the FACT-P total score was 12.7 months in the abiraterone arm and 8.3 months in the placebo arm (hazard ratio 0.78; 95% CI ; P=0.003). The median time to increase in pain was 26.7 months among patients in the abiraterone arm and 18.4 months among those in the placebo arm (hazard ratio 0.82; 95% CI ; P=0.049). Safety Grade 3 or 4 adverse events were reported in 48% of patients in the abiraterone arm and 42% of patients in the placebo arm; serious adverse events were reported in 33% and 26% of patients, and adverse events resulting in death were reported in 4% and 2% of patients, respectively. Fatigue, arthralgia, and peripheral oedema were among the adverse events reported more frequently in the abiraterone arm than in the placebo arm. Muscle spasm appeared to be more common in the placebo arm than the abiraterone arm (20% vs. 14%, respectively). The frequency of adverse events resulting in treatment discontinuation was similar in the two study groups. A total of 19% of patients in the abiraterone arm and 12% of patients in the placebo arm had adverse events leading to dose modification or interruption of study treatment. The proportions of patients with grade 3 or 4 serious adverse events were similar in the two groups.

4 Adverse events that were classified as cardiac disorders were reported in 19% of patients in the abiraterone arm and 16% of patients in the placebo arm. Mineralocorticoid-related adverse events were more common in the abiraterone arm than in the placebo arm, including hypertension (22% vs. 13%), hypokalemia (17% vs. 13%), and fluid retention or oedema (28% vs. 24%), and were mostly grade 1 or 2 events. Cost The price of abiraterone 250mg, 120-tablet pack is 3516 (including VAT). Abiraterone was continued in the trial until progression, which is reported as 16.5 months for the abiraterone treatment arm. This would mean that the cost for one patient s treatment for 16.5 months would be 58,014. Assuming that there are 5 patients per 100,000 eligible for abiraterone according to the licensed indication, this would mean that the cost per 100,000 population would be 290,070 per 100,000 population. This calculation uses the list price for abiraterone. There is a patient access scheme available for patients, which results in a reduced price. Service implications Abiraterone is an oral medication and as a result it would be expected to have minimal service implications Summary Abiraterone has recently received a UK licence extension for the requested indication. The licensed indication states that abiraterone is indicated in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. There is a need to highlight what criteria are required for mildly symptomatic patients and under what circumstances it is deemed that chemotherapy is not yet clinically indicated. The CDF application was for use in metastatic castrate refractory prostate cancer pre-docetaxel. This does not include the additional stipulation that is stated in the license, which is that abiraterone can be used where chemotherapy is not yet indicated. If CDF funding is agreed for abiraterone as per the CDF application, patients would be eligible if they were suitable for chemotherapy, but the clinician decided to treat the patient with abiraterone instead. that has recently been published and which the licence extension was based on. The co-primary endpoints were radiographic progression-free survival (assessed by central review), and overall survival. If a trial contains co-primary endpoints both objectives do not need to be clinically significant in order for the trial to be deemed a success. One significant coprimary is sufficient. On the basis of the blinded central radiologic review, at the time of the first interim analysis, treatment with abiraterone plus prednisone, as compared with placebo plus prednisone, resulted in a 57% reduction in the risk of radiographic progression or death (median not reached vs. median of 8.3 months; hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.43; 95% CI ; P<0.001). At the time of the second interim analysis, the median to radiographic progression-free survival on the basis of investigator assessment was 16.5 months in the abiraterone arm and 8.3 months in the prednisone arm (hazard ratio 0.53; 95% CI ; P<0.001). Overall survival was improved with abiraterone prednisone (median not reached, vs months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the prespecified boundary for significance (P 0.001) at the observed number of events. The study was unblinded by the independent data monitoring committee after the planned second interim analysis that was performed after 43% of the expected deaths had occurred, as the committee felt the results thus far meant it was unethical to continue the study. Grade 3 or 4 adverse events were reported in 48% of patients in the abiraterone arm and 42% of patients in the placebo arm; serious adverse events were reported in 33% and 26% of patients, and adverse events resulting in death were reported in 4% and 2% of patients, respectively. Fatigue, arthralgia, and peripheral oedema were among the adverse events reported more frequently in the abiraterone arm than in the placebo arm. Muscle spasm appeared to be more common in the placebo arm than the abiraterone arm (20% vs. 14%, respectively). NICE are in the process of reviewing abiraterone for the licensed indication and the expected date of publication for the technology appraisal is November There is phase III double-blind, randomised data

5 Drug Indication Incidence (number of patients per 100,000 eligible for this treatment) Abiraterone 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 Average duration of treatment (taken from trial data) Cost per month/ cycle 5/100, months 3516 per month Cost per 100,000 population per month/ cycle 17,580 per month Cost per 100,000 for average treatment duration 290,070 These calculations use the list price for abiraterone. There is a patient access scheme available for patients, which results in a reduced price. References 1. NICE Health Technology Appraisal. Final Scope. Abiraterone acetate for the treatment of metastatic castration-resistant prostate cancer not previously treated with chemotherapy. Accessed 7/1/13. Available at live/13641/62262/62262.pdf 2. NICE Clinical Guideline 58. Prostate cancer. Diagnosis and treatment. February Available at nicemedia/live/11924/39626/39626.pdf 3. NICE Technology Appraisal 101. Docetaxel for the treatment of hormone-refractory metastatic prostate cancer. June Available at live/11578/33348/33348.pdf 4. NeLM news item. CHMP recommends approval of new indication for abiraterone (Zytiga ) and new contra-indication in severe hepatic impairment. 19 th November Available at 5. Ryan CJ et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New England journal of medicine. Published online 10 th December Supplementary appendix to reference 5. Published online 10 th December 2012.

6 Details of search strategy: NeLM NICE 1. EMBASE; ABIRATERONE/; 374 results. 2. EMBASE; PROSTATE CANCER/; results. 3. EMBASE; 1 AND 2; 246 results. 4. EMBASE; *ABIRATERONE/; 45 results. 5. EMBASE; 2 AND 4; 26 results. 6. MEDLINE; abiraterone.ti,ab; 219 results. 7. MEDLINE; PROSTATIC NEOPLASMS/; results. 8. MEDLINE; 6 AND 7; 159 results. 9. EMBASE,MEDLINE; Duplicate filtered: [2 AND 4], [6 AND 7]; 185 results. 10. EMBASE; 3 [Limit to: Human and English Language]; 224 results. 11. MEDLINE,EMBASE; Duplicate filtered: [6 AND 7], [3 [Limit to: Human and English Language]]; 383 results. The document reflects the views of LCNDG and may not reflect those of the reviewers Please direct any comments to Angela Bennett, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: , Angela.bennett@gstt.nhs.uk