Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer

The PREVAIL randomized clinical trial

Dana E. Rathkopf, Tomasz (Tom) Beer, Yohann Loriot, Celestia S. Higano, Andrew J. Armstrong, Cora N. Sternberg, Johann S. De Bono, Bertrand Tombal, Teresa Parli, Suman Bhattacharya, De Phung, Andrew Krivoshik, Howard I. Scher, Michael J. Morris

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)694-701
    Number of pages8
    JournalJAMA oncology
    Volume4
    Issue number5
    DOIs
    StatePublished - May 1 2018

    Fingerprint

    Castration
    Disease-Free Survival
    Prostatic Neoplasms
    Randomized Controlled Trials
    Survival
    Research Personnel
    Placebos
    Clinical Trials
    Disease Progression
    Drug Therapy
    Pharmaceutical Preparations
    MDV 3100

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer : The PREVAIL randomized clinical trial. / Rathkopf, Dana E.; Beer, Tomasz (Tom); Loriot, Yohann; Higano, Celestia S.; Armstrong, Andrew J.; Sternberg, Cora N.; De Bono, Johann S.; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I.; Morris, Michael J.

    In: JAMA oncology, Vol. 4, No. 5, 01.05.2018, p. 694-701.

    Research output: Contribution to journalArticle

    Rathkopf, DE, Beer, TT, 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 2018, 'Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer: The PREVAIL randomized clinical trial', JAMA oncology, vol. 4, no. 5, pp. 694-701. https://doi.org/10.1001/jamaoncol.2017.5808
    Rathkopf, Dana E. ; Beer, Tomasz (Tom) ; Loriot, Yohann ; Higano, Celestia S. ; Armstrong, Andrew J. ; Sternberg, Cora N. ; De Bono, Johann S. ; Tombal, Bertrand ; Parli, Teresa ; Bhattacharya, Suman ; Phung, De ; Krivoshik, Andrew ; Scher, Howard I. ; Morris, Michael J. / Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer : The PREVAIL randomized clinical trial. In: JAMA oncology. 2018 ; Vol. 4, No. 5. pp. 694-701.
    @article{fe008f170534445c9b39526a18b52051,
    title = "Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer: The PREVAIL randomized clinical trial",
    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.",
    author = "Rathkopf, {Dana E.} and Beer, {Tomasz (Tom)} and Yohann Loriot and Higano, {Celestia S.} and Armstrong, {Andrew J.} and Sternberg, {Cora N.} and {De Bono}, {Johann S.} and Bertrand Tombal and Teresa Parli and Suman Bhattacharya and De Phung and Andrew Krivoshik and Scher, {Howard I.} and Morris, {Michael J.}",
    year = "2018",
    month = "5",
    day = "1",
    doi = "10.1001/jamaoncol.2017.5808",
    language = "English (US)",
    volume = "4",
    pages = "694--701",
    journal = "JAMA oncology",
    issn = "2374-2437",
    publisher = "American Medical Association",
    number = "5",

    }

    TY - JOUR

    T1 - Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer

    T2 - The PREVAIL randomized clinical trial

    AU - Rathkopf, Dana E.

    AU - Beer, Tomasz (Tom)

    AU - Loriot, Yohann

    AU - Higano, Celestia S.

    AU - Armstrong, Andrew J.

    AU - Sternberg, Cora N.

    AU - De Bono, Johann S.

    AU - Tombal, Bertrand

    AU - Parli, Teresa

    AU - Bhattacharya, Suman

    AU - Phung, De

    AU - Krivoshik, Andrew

    AU - Scher, Howard I.

    AU - Morris, Michael J.

    PY - 2018/5/1

    Y1 - 2018/5/1

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85047477475&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85047477475&partnerID=8YFLogxK

    U2 - 10.1001/jamaoncol.2017.5808

    DO - 10.1001/jamaoncol.2017.5808

    M3 - Article

    VL - 4

    SP - 694

    EP - 701

    JO - JAMA oncology

    JF - JAMA oncology

    SN - 2374-2437

    IS - 5

    ER -