Dana E Rathkopf1, Matthew R Smith2, Johann S de Bono3, Christopher J Logothetis4, Neal D Shore5, Paul de Souza6, Karim Fizazi7, Peter F A Mulders8, Paul Mainwaring9, John D Hainsworth10, Tomasz M Beer11, Scott North12, Yves Fradet13, Hendrik Van Poppel14, Joan Carles15, Thomas W Flaig16, Eleni Efstathiou4, Evan Y Yu17, Celestia S Higano17, Mary-Ellen Taplin18, Thomas W Griffin19, Mary B Todd20, Margaret K Yu19, Youn C Park20, Thian Kheoh19, Eric J Small21, Howard I Scher22, Arturo Molina23, Charles J Ryan21, Fred Saad24. 1. Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: rathkopd@mskcc.org. 2. Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA. 3. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK. 4. MD Anderson Cancer Center, Houston, TX, USA. 5. Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA. 6. University of Western Sydney School of Medicine, Penrith, Australia. 7. Institut Gustave Roussy, University of Paris Sud, Villejuif, France. 8. Radboud University Medical Centre, Nijmegen, The Netherlands. 9. Hematology & Oncology Clinics of Australia, Brisbane, Australia. 10. Sarah Cannon Research Institute, Nashville, TN, USA. 11. Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA. 12. Cross Cancer Institute, Edmonton, Alberta, Canada. 13. Laval University, Québec City, Québec, Canada. 14. University Hospital Leuven, Leuven, Belgium. 15. Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 16. University of Colorado Cancer Center and University of Colorado School of Medicine, Aurora, CO, USA. 17. University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 18. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 19. Janssen Research & Development, Los Angeles, CA, USA. 20. Janssen Research & Development, Raritan, NJ, USA. 21. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. 22. Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. 23. Janssen Research & Development, Menlo Park, CA, USA. 24. CRCHUM, University of Montréal, Montréal, Québec, Canada.
Abstract
BACKGROUND:Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. OBJECTIVE: Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. DESIGN, SETTING, AND PARTICIPANTS: Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). INTERVENTION: Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively. RESULTS AND LIMITATIONS: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. CONCLUSIONS: The updated IA of study COU-AA-302 in patients with mCRPC without priorchemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo. TRIAL REGISTRATION: Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. PATIENT SUMMARY: The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.
RCT Entities:
BACKGROUND:Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. OBJECTIVE: Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. DESIGN, SETTING, AND PARTICIPANTS: Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). INTERVENTION: Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively. RESULTS AND LIMITATIONS: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. CONCLUSIONS: The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo. TRIAL REGISTRATION: Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. PATIENT SUMMARY: The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.
Authors: Ethan Basch; Karen Autio; Charles J Ryan; Peter Mulders; Neal Shore; Thian Kheoh; Karim Fizazi; Christopher J Logothetis; Dana Rathkopf; Matthew R Smith; Paul N Mainwaring; Yanni Hao; Thomas Griffin; Susan Li; Michael L Meyers; Arturo Molina; Charles Cleeland Journal: Lancet Oncol Date: 2013-09-25 Impact factor: 41.316
Authors: Axel Heidenreich; Patrick J Bastian; Joaquim Bellmunt; Michel Bolla; Steven Joniau; Theodor van der Kwast; Malcolm Mason; Vsevolod Matveev; Thomas Wiegel; Filiberto Zattoni; Nicolas Mottet Journal: Eur Urol Date: 2013-11-12 Impact factor: 20.096
Authors: Daniel P Petrylak; Catherine M Tangen; Maha H A Hussain; Primo N Lara; Jeffrey A Jones; Mary Ellen Taplin; Patrick A Burch; Donna Berry; Carol Moinpour; Manish Kohli; Mitchell C Benson; Eric J Small; Derek Raghavan; E David Crawford Journal: N Engl J Med Date: 2004-10-07 Impact factor: 91.245
Authors: Ian F Tannock; Ronald de Wit; William R Berry; Jozsef Horti; Anna Pluzanska; Kim N Chi; Stephane Oudard; Christine Théodore; Nicholas D James; Ingela Turesson; Mark A Rosenthal; Mario A Eisenberger Journal: N Engl J Med Date: 2004-10-07 Impact factor: 91.245
Authors: C Parker; S Nilsson; D Heinrich; S I Helle; J M O'Sullivan; S D Fosså; A Chodacki; P Wiechno; J Logue; M Seke; A Widmark; D C Johannessen; P Hoskin; D Bottomley; N D James; A Solberg; I Syndikus; J Kliment; S Wedel; S Boehmer; M Dall'Oglio; L Franzén; R Coleman; N J Vogelzang; C G O'Bryan-Tear; K Staudacher; J Garcia-Vargas; M Shan; Ø S Bruland; O Sartor Journal: N Engl J Med Date: 2013-07-18 Impact factor: 91.245
Authors: Stephen Harland; John Staffurth; Arturo Molina; Yanni Hao; Dennis D Gagnon; Cora N Sternberg; David Cella; Karim Fizazi; Christopher J Logothetis; Thian Kheoh; Christopher M Haqq; Johann S de Bono; Howard I Scher Journal: Eur J Cancer Date: 2013-08-22 Impact factor: 9.162
Authors: Atish D Choudhury; Kathryn P Gray; Jeffrey G Supko; Lauren C Harshman; Mary-Ellen Taplin; Amanda F Pace; Matthew Farina; Katherine A Zukotynski; Brandon Bernard; Philip W Kantoff; Mark Pomerantz; Christopher Sweeney Journal: Prostate Date: 2018-06-07 Impact factor: 4.104
Authors: Matthew R Smith; Dana E Rathkopf; Peter F A Mulders; Joan Carles; Hendrik Van Poppel; Jinhui Li; Thian Kheoh; Thomas W Griffin; Arturo Molina; Charles J Ryan Journal: J Urol Date: 2015-07-04 Impact factor: 7.450
Authors: Dana E Rathkopf; Emmanuel S Antonarakis; Neal D Shore; Ronald F Tutrone; Joshi J Alumkal; Charles J Ryan; Mansoor Saleh; Ralph J Hauke; Rajesh Bandekar; Edna Chow Maneval; Carla J de Boer; Margaret K Yu; Howard I Scher Journal: Clin Cancer Res Date: 2017-02-17 Impact factor: 12.531
Authors: Fred Saad; Kim N Chi; Antonio Finelli; Sebastien J Hotte; Jonathan Izawa; Anil Kapoor; Wassim Kassouf; Andrew Loblaw; Scott North; Ricardo Rendon; Alan So; Nawaid Usmani; Eric Vigneault; Neil E Fleshner Journal: Can Urol Assoc J Date: 2015 Mar-Apr Impact factor: 1.862
Authors: Emma L Simpson; Sarah Davis; Praveen Thokala; Penny R Breeze; Peter Bryden; Ruth Wong Journal: Pharmacoeconomics Date: 2015-11 Impact factor: 4.981