In the PREVAIL clinical trial, enzalutamide provided significant improvements vs placebo in radiographic progression-free survival (rPFS) and overall survival (OS) in chemotherapy-naïve men with mCRPC. This post hoc analysis aimed to evaluate the prognostic association between the magnitude of PSA decline from baseline and clinical outcomes in PREVAIL.
Men from the enzalutamide and placebo arms of PREVAIL were grouped into categories of confirmed maximal PSA decline from baseline at month 3 of treatment: no decline/decline < 30% and ≥ 30%, ≥ 50% or ≥ 90% decline. Confirmation required PSA decline on ≥ 1 consecutive visit after month 3. Best overall soft-tissue response (per RECIST v1.1) was determined for patients with measurable disease at baseline (data cutoff: 16 Sep 2013). Time to PSA progression (data cutoff: 16 Sep 2013), rPFS (per PCWG2; data cutoff: 6 May 2012) and OS (data cutoff: 16 Sep 2013) were estimated using the Kaplan-Meier method.
In PREVAIL, men were randomized to enzalutamide (n = 872) or placebo (n = 845). Most men in the placebo arm (66%, 558/845) had no PSA decline/decline < 30%, in contrast to 11% (94/872) in the enzalutamide arm. In the enzalutamide arm, 81% (701/872) of men had a PSA decline of ≥ 30% from baseline at week 13, 73% (639/872) had a PSA decline of ≥ 50% and 35% (307/872) had a PSA decline of ≥ 90%. Key outcomes for the enzalutamide arm are provided by PSA decline category in the Table. PSA flare (rise followed by a fall) after 3 months was rare with enzalutamide (< 1%).Table:
|Outcome||Maximal PSA Decline From Baseline at Month 3 in the Enzalutamide Arm (N = 872)|
|No Decline/ Decline < 30%||≥ 30% Decline||≥ 50% Decline||≥ 90% Decline|
|(n = 94/872)||(n = 701/872)||(n = 639/872)||(n = 307/872)|
|Best objective soft-tissue response (CR or PR), % (95% CI)||12.0 (4.5-24.3)||70.6 (65.1-75.6)||74.8 (69.2-79.9)||89.7 (82.8-95.0)|
|Median (95% CI) time to PSA progression, mo||3.7 (3.7-4.6)||13.8 (11.3-14.0)||13.9 (13.8-16.6)||22.5 (16.8-NYR)|
|Median (95% CI) rPFS, mo||7.9 (3.7-NYR)||NYR (13.8-NYR)||NYR (13.8-NYR)||NYR (13.8-NYR)|
|HR (95% CI) for rPFS||1.0 (ref)||0.20 (0.13-0.31)||0.17 (0.11-0.27)||0.10 (0.05-0.19)|
|Median (95% CI) OS, mo||23.1 (17.8-28.0)||32.4 (31.5-NYR)||NYR (31.5-NYR)||NYR (NYR-NYR)|
|HR (95% CI) for OS||1.0 (ref)||0.31 (0.22-0.42)||0.28 (0.20-0.39)||0.19 (0.12-0.28)|
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; mo, months; NYR, not yet reached; OS, overall survival; PR, partial response; PSA, prostate-specific antigen; ref, reference, rPFS, radiographic progression-free survival.
PSA declines after 3 months of enzalutamide therapy are strongly associated with soft-tissue response and improvements in rPFS and OS. Providing updated prognostic information to chemotherapy-naïve men with mCRPC can be of clinical value given the heterogeneity of long-term outcomes.
Clinical trial identification
Legal entity responsible for the study
This study was sponsored by Medivation, Inc. (which was was acquired by Pfizer, Inc. in September 2016) and Astellas Pharma, Inc., the co-developers of enzalutamide.
This study was sponsored by Medivation, Inc., (which was acquired by Pfizer, Inc. in September 2016) and Astellas Pharma, Inc., the co-developers of enzalutamide.
A.J. Armstrong: Consultant: Bayer, Sanofi, Novartis, Dendreon, Medivation, Janssen Biotech, Eisai Bureau: Dendreon, Sanofi, Medivation, Janssen Biotech Grant/Patent (inst) Dendron, Sanofi, Bayer, Pfizer, Novartis, BMS, Janssen Oncology, Medivation, Astellas, Gilead. P. Lin, T. Parli: Employment: Pfizer, Inc. C.S. Higano: Consulting/Travel: Dendreon, Bayer, Medivation, Ferring, J&J, AbbVie, Genentech, Pfizer, BHR, Orion, Sanofi, Amgen, Ockham, Teva, Astellas. P. Iversen: Consultant/Advisor, Meeting Participant/Lecturer, Scientific Study/Trial and Clinical Research Collaboration: Astellas Pharma, Medivation. C.N. Sternberg: Honoraria: Pfizer, Bristol-Myers Squibb, Novartis, Janssen, Bayer, Astellas Pharma, Sanofi, Eisai, Ipsen, GlaxoSmithKline, MSD. B. Tombal: Consulting: Astella, Bayer, Ferring, Janssen, Takeda, Steba Biotech, Sanofi Speakers Bureau: Amgen, Janssen Travel/Honoraria: Amgen, Astellas, Bayer, Ferring, Janssen, Sanofi. D. Phung: Employment: Astellas Pharma. A. Krivoshik: Employment and Travel/Expenses: Astellas Pharma Stock/Ownership Interests: Abbott Laboratories, AbbVie. T.M. Beer: Consulting: Astellas, Bayer, Dendreon, Janssen Japan, Novartis, AstraZeneca, Churchill, Proacta Stock/Ownership: Salarius.