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Randomized Controlled Trial
. 2018 May 1;4(5):694-701.
doi: 10.1001/jamaoncol.2017.5808.

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

Dana E Rathkopf  1 , Tomasz M Beer  2 , Yohann Loriot  3 , Celestia S Higano  4 , Andrew J Armstrong  5 , Cora N Sternberg  6 , Johann S de Bono  7 , Bertrand Tombal  8 , Teresa Parli  9 , Suman Bhattacharya  10 , De Phung  11 , Andrew Krivoshik  12 , Howard I Scher  1 , Michael J Morris  1
Affiliations
Randomized Controlled Trial

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

Dana E Rathkopf et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rathkopf has received advisory/consulting fees from Janssen and research funding for her institution from AstraZeneca, Astellas Pharma, Celgene, Genentech, Janssen, Medivation, Millenium, Novartis, Pfizer, Roche, and Tracon. Dr Beer owns stock in Salarius Pharma. He has received consulting/advisory fees from AstraZeneca, Churchill Pharma, Dendreon, Janssen Biotech, Janssen Japan, Janssen Oncology, Janssen R&D, and Johnson & Johnson. His institution has received research funding from Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Janssen R&D, Medivation, OncoGenex, Sotio, and Theraclone Sciences. Dr Loriot has received consulting fees and nonfinancial support from Astellas Pharma, Bristol-Myers Squibb, MSD, Pfizer, and Roche. He has received research funding, consulting fees, and nonfinancial support from Sanofi. He has received consulting fees from AstraZeneca. Dr Higano has received consulting/advisory fees from Aptevo, Asana, Astellas Pharma, Bayer, Blue Earth Diagnostics, Churchill, Clovis, Dendreon, Endocyte, Ferring, Medivation, MorphoSys, Orion, and Pfizer. She has received research funding from Aptevo, Aragon, AstraZeneca, Bayer, Dendreon, Exelixis, Genentech, Medivation, Millennium, Pfizer, Sanofi, and Teva. Dr Armstrong has received consulting fees and research funding for his institution from Astellas Pharma, Bayer, Dendreon, Janssen, Medivation, Pfizer, Sanofi, and Valeant. He reports research funding to his institution from Active Biotech, Bristol-Myers Squibb, Genentech, Gilead, Novartis, and Roche. Dr Sternberg has received honoraria from Astellas Pharma, Bayer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, and Sanofi. Dr de Bono has received consulting fees and nonfinancial support from Astellas Pharma, AstraZeneca, Genentech, Roche, and Sanofi. Dr Tombal has received honoraria from Amgen, Astellas Pharma, Bayer, Ferring, Janssen, and Sanofi. He has received consulting/advisory fees from Astellas Pharma, Bayer, Ferring, Janssen, Sanofi, Steba Biotech, and Takeda. He has served on speakers’ bureaus for Amgen and Janssen. He has received research funding from Ferring. He has received funding for travel from Amgen, Astellas Pharma, Bayer, Ferring, Janssen, and Sanofi. Dr Parli is an employee of Medivation, LLC, a Pfizer company. Dr Bhattacharya is a former employee of Medivation, LLC, a Pfizer company. Mr Phung is an employee of Astellas Pharma. Dr Krivoshik is an employee of Astellas Pharma. He owns stock in Abbott and AbbVie. He has a patent with Abbott. Dr Scher is on the Board of Directors for Asterias Biotherapeutics. He is a compensated consultant for Astellas Pharma, BIND Pharmaceuticals, Blue Earth Diagnostics, Clovis Oncology, Med IQ, Merck, OncLive, Physicians Education Resource, Roche, Sanofi Aventis, and WIRB Copernicus Group. He is an uncompensated consultant for Ferring Pharmaceuticals, Medivation, and Pfizer. He has received research funding for his institution from Illumina, Innocrin Pharma, Janssen, and Medivation. Dr Morris is a compensated consultant for Advanced Accelerator Applications. He is an uncompensated consultant for Astellas Pharma, Bayer, Endocyte, Progenics, and Tokai. He has received research funding for his institution from Bayer, Progenics, and Endocyte. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Figure 2.
Figure 2.. Duration of Radiographic Progression-Free Survival (rPFS) in Primary Analysis, Sensitivity Analysis 1 (SA1), and SA2
A, Primary analysis and SA1 (intention-to-treat population, data cutoff May 6, 2012). B, SA2 (intention-to-treat population, data cutoff September 16, 2013).
Figure 3.
Figure 3.. Duration of Radiographic Progression-Free Survival (rPFS) in Sensitivity Analysis 3 (SA3), SA4, SA5, and SA6
All intention-to-treat population; data cutoff, May 6, 2012.
See this image and copyright information in PMC

References

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