Charles J Ryan1, Matthew R Smith2, Karim Fizazi3, Fred Saad4, Peter F A Mulders5, Cora N Sternberg6, Kurt Miller7, Christopher J Logothetis8, Neal D Shore9, Eric J Small10, Joan Carles11, Thomas W Flaig12, Mary-Ellen Taplin13, Celestia S Higano14, Paul de Souza15, Johann S de Bono16, Thomas W Griffin17, Peter De Porre18, Margaret K Yu17, Youn C Park19, Jinhui Li19, Thian Kheoh17, Vahid Naini17, Arturo Molina20, Dana E Rathkopf21. 1. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. Electronic address: ryanc@medicine.ucsf.edu. 2. Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA. 3. Institut Gustave Roussy, University of Paris Sud, Villejuif, France. 4. University of Montréal, Montréal, Québec, Canada. 5. Radboud University Medical Centre, Nijmegen, Netherlands. 6. San Camillo and Forlanini Hospitals, Rome, Italy. 7. Charité Berlin, Berlin, Germany. 8. MD Anderson Cancer Center, Houston, TX, USA. 9. Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA. 10. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. 11. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain. 12. University of Colorado Cancer Center and University of Colorado School of Medicine, Aurora, CO, USA. 13. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 14. University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 15. University of Western Sydney School of Medicine and Ingham Institute, Liverpool, Australia. 16. The Institute of Cancer Research and the Royal Marsden Hospital, Sutton, United Kingdom. 17. Janssen Research & Development, Los Angeles, CA, USA. 18. Janssen Research & Development, Beerse, Belgium. 19. Janssen Research & Development, Raritan, NJ, USA. 20. Janssen Research & Development, Menlo Park, CA, USA. 21. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract
BACKGROUND:Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]). INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. FUNDING: Janssen Research & Development.
RCT Entities:
BACKGROUND:Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]). INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. FUNDING: Janssen Research & Development.
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