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Original Investigation
March 8, 2018

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate CancerThe PREVAIL Randomized Clinical Trial

Author Affiliations
  • 1Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, New York
  • 2Department of Hematology/Medical Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland
  • 3Gustave Roussy, Cancer Campus, Department of Cancer Medicine, University of Paris Saclay, Villejuif, France
  • 4Department of Medical Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 5Divisions of Medical Oncology and Urology, Duke University Medical Center, Duke Cancer Institute, Duke University, Durham, North Carolina
  • 6Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy
  • 7Division of Clinical Studies, Royal Marsden Hospital and Institute of Cancer Research, London, England
  • 8Division of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  • 9Department of Clinical Development, Medivation, LLC, a Pfizer company, San Francisco, California
  • 10formerly with Department of Biostatistics, Medivation, LLC, a Pfizer company, San Francisco, California
  • 11Department of Biostatistics, Astellas Pharma Europe BV, Leiden, The Netherlands
  • 12Department of Medical Oncology, Astellas Pharma, Inc, Northbrook, Illinois
JAMA Oncol. Published online March 8, 2018. doi:10.1001/jamaoncol.2017.5808
Key Points

Question  What is the clinical relevance of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) definition of radiographic progression-free survival (rPFS)?

Findings  In a series of prespecified sensitivity analyses of rPFS in the PREVAIL randomized clinical trial of 1717 men with chemotherapy-naive metastatic castration-resistant prostate cancer, enzalutamide significantly reduced the risk of radiographic progression or death. Using 2 different statistical methods, rPFS and overall survival were found to be positively correlated.

Meaning  The PCWG2 definition of rPFS is a robust end point that is clinically meaningful and associated with overall survival.


Importance  Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients.

Objective  To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS.

Design, Setting, and Participants  PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016.

Interventions  Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.

Main Outcomes and Measures  Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula.

Results  In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ.

Conclusions and Relevance  Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.

Trial Registration  clinicaltrials.gov Identifier: NCT01212991