Karim Fizazi1, Charles G Drake2, Tomasz M Beer3, Eugene D Kwon4, Howard I Scher5, Winald R Gerritsen6, Alberto Bossi7, Alfons J M van den Eertwegh8, Michael Krainer9, Nadine Houede10, Ricardo Santos11, Hakim Mahammedi12, Siobhan Ng13, Riccardo Danielli14, Fabio A Franke15, Santhanam Sundar16, Neeraj Agarwal17, André M Bergman18, Tudor E Ciuleanu19, Ernesto Korbenfeld20, Lisa Sengeløv21, Steinbjorn Hansen22, M Brent McHenry23, Allen Chen23, Christopher Logothetis24. 1. Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: karim.fizazi@gustaveroussy.fr. 2. Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA. 3. Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA. 4. Mayo Clinic, Rochester, MN, USA. 5. Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Weill-Cornell Medical College, New York, NY, USA. 6. Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 7. Institut Gustave Roussy, Villejuif, France. 8. VU University Medical Center, Amsterdam, The Netherlands. 9. Vienna General Hospital (AKH Wien), Wien, Austria. 10. CHU of Nimes, Nimes, France; Montpellier University, Montpellier, France. 11. Centro Médico Austral, Buenos Aires, Argentina. 12. Centre Jean Perrin, Clermont-Ferrand, France. 13. St John Of God Hospital, Subiaco, Australia. 14. University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. 15. Hospital de Caridade de Ijuí, Ijuí, Brazil. 16. Nottingham University Hospitals NHS Trust, Nottingham, UK. 17. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 18. The Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 19. Institute of Oncology Ion Chiricuta, Cluj-Napoca, Romania. 20. Hospital Britanico de Buenos Aires, Buenos Aires, Argentina. 21. Herlev Hospital, Region Hovedstadens Apotek, Herlev, Denmark. 22. Odense University Hospital, Odense, Denmark. 23. Bristol-Myers Squibb Company, Wallingford, CT, USA. 24. The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. OBJECTIVE: To report the final analysis of OS. DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.
RCT Entities:
BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. OBJECTIVE: To report the final analysis of OS. DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.
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