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

Publication ,  Journal Article
Rathkopf, DE; Beer, TM; Loriot, Y; Higano, CS; Armstrong, AJ; Sternberg, CN; de Bono, JS; Tombal, B; Parli, T; Bhattacharya, S; Phung, D ...
Published in: JAMA Oncol
May 1, 2018

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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Published In

JAMA Oncol

DOI

EISSN

2374-2445

Publication Date

May 1, 2018

Volume

4

Issue

5

Start / End Page

694 / 701

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Radiography
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Middle Aged
  • Male
  • Humans
  • Antineoplastic Combined Chemotherapy Protocols
 

Citation

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Rathkopf, D. E., Beer, T. M., Loriot, Y., Higano, C. S., Armstrong, A. J., Sternberg, C. N., … Morris, M. J. (2018). Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol, 4(5), 694–701. https://doi.org/10.1001/jamaoncol.2017.5808
Rathkopf, Dana E., Tomasz M. Beer, Yohann Loriot, Celestia S. Higano, Andrew J. Armstrong, Cora N. Sternberg, Johann S. de Bono, et al. “Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.JAMA Oncol 4, no. 5 (May 1, 2018): 694–701. https://doi.org/10.1001/jamaoncol.2017.5808.
Rathkopf DE, Beer TM, Loriot Y, Higano CS, Armstrong AJ, Sternberg CN, et al. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol. 2018 May 1;4(5):694–701.
Rathkopf, Dana E., et al. “Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.JAMA Oncol, vol. 4, no. 5, May 2018, pp. 694–701. Pubmed, doi:10.1001/jamaoncol.2017.5808.
Rathkopf DE, Beer TM, Loriot Y, Higano CS, Armstrong AJ, Sternberg CN, de Bono JS, Tombal B, Parli T, Bhattacharya S, Phung D, Krivoshik A, Scher HI, Morris MJ. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol. 2018 May 1;4(5):694–701.

Published In

JAMA Oncol

DOI

EISSN

2374-2445

Publication Date

May 1, 2018

Volume

4

Issue

5

Start / End Page

694 / 701

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Radiography
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Middle Aged
  • Male
  • Humans
  • Antineoplastic Combined Chemotherapy Protocols