Michael J Morris1, Arturo Molina2, Eric J Small2, Johann S de Bono2, Christopher J Logothetis2, Karim Fizazi2, Paul de Souza2, Philip W Kantoff2, Celestia S Higano2, Jinhui Li2, Thian Kheoh2, Steven M Larson2, Shannon L Matheny2, Vahid Naini2, Tomasz Burzykowski2, Thomas W Griffin2, Howard I Scher2, Charles J Ryan2. 1. Michael J. Morris, Steven M. Larson, and Howard I. Scher, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Arturo Molina, Thian Kheoh, Shannon L. Matheny, Vahid Naini, and Thomas W. Griffin, Janssen Research & Development, Los Angeles; Eric J. Small and Charles J. Ryan, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; Johann S. de Bono, Institute for Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom; Christopher J. Logothetis, MD Anderson Cancer Center, Houston, TX; Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Paul de Souza, University of Western Sydney School of Medicine, Ingham Institute, Liverpool, New South Wales, Australia; Philip W. Kantoff, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Celestia S. Higano, University of Washington, Seattle, WA; Jinhui Li, Janssen Research & Development, Raritan, NJ; and Tomasz Burzykowski, International Drug Development Institute, Louvain-la-Neuve, Belgium. morrism@mskcc.org. 2. Michael J. Morris, Steven M. Larson, and Howard I. Scher, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Arturo Molina, Thian Kheoh, Shannon L. Matheny, Vahid Naini, and Thomas W. Griffin, Janssen Research & Development, Los Angeles; Eric J. Small and Charles J. Ryan, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; Johann S. de Bono, Institute for Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom; Christopher J. Logothetis, MD Anderson Cancer Center, Houston, TX; Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Paul de Souza, University of Western Sydney School of Medicine, Ingham Institute, Liverpool, New South Wales, Australia; Philip W. Kantoff, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Celestia S. Higano, University of Washington, Seattle, WA; Jinhui Li, Janssen Research & Development, Raritan, NJ; and Tomasz Burzykowski, International Drug Development Institute, Louvain-la-Neuve, Belgium.
Abstract
PURPOSE:Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC. PATIENTS AND METHODS: rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation. RESULTS: A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72. CONCLUSION:rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.
RCT Entities:
PURPOSE: Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC. PATIENTS AND METHODS: rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation. RESULTS: A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72. CONCLUSION: rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.
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