Therapies currently available for castrate-refractory prostate cancer (CRPC) provide only modest clinical benefit. Expression of the programmed death 1 (PD-1) receptor and its ligand, PD-L1, has been reported in CRPC. Pembrolizumab, an anti–PD-1 antibody, blocks the interaction between PD-1 and PD-L1. KEYNOTE-028 (NCT02054806) is a nonrandomized, phase 1b trial to evaluate the safety and efficacy of pembrolizumab in 20 advanced solid tumor cohorts. Herein are the results from the prostate adenocarcinoma cohort of this study.
Key eligibility criteria included advanced adenocarcinoma of the prostate, failure of standard therapy, measurable disease per RECIST v1.1, ECOG PS 0-1, and PD-L1 expression in ≥1% of tumor or stroma cells by immunohistochemistry. Pembrolizumab 10 mg/kg was administered every 2 weeks (wk) for up to 24 months (mo) or until disease progression (PD), intolerable toxicity, death, or withdrawal of consent. Stable patients (pts) with PD could remain on treatment until PD was confirmed by a follow-up scan. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator review. As an exploratory objective, a NanoString platform was used to assess baseline tumor tissue for the gene expression profile (GEP) of an 18-gene panel hypothesized to be associated with a Th1-derived IFN-ɣ immune response.
Of the 23 pts enrolled in this cohort, median age was 65 years, 74% had an ECOG PS of 1 (1 pt had an ECOG PS of 2), and 74% received ≥2 prior therapies for metastatic disease. As of February 17, 2016, median follow-up duration was 33 wk (range, 6-79 wk). Fourteen pts (61%) had treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13%). Three pts (13%) had grade 3-4 TRAEs; 1 pt had grade 3 fatigue, 1 pt had grade 3 peripheral neuropathy, and 1 pt had grade 3 asthenia and grade 4 lipase increase. No pts died or discontinued pembrolizumab because of a TRAE. Three pts had a confirmed PR, for an ORR of 13% (95% CI, 3%-34%); median duration of response was 59 wk (range, 28-62 wk). Stable disease rate was 39% (n = 9; 95% CI, 20%-61%). Median OS was 8 mo, and the 6-mo PFS rate was 39%. Two pts remained on treatment at data cutoff. Exploratory assessment of the relationship between GEP score and clinical outcome revealed the putative T cell inflamed signature to be associated with better clinical outcome, consistent with pembrolizumab findings published previously.
Pembrolizumab produced durable responses among heavily pretreated pts with advanced PD-L1–positive prostate cancer. Treatment was associated with a favorable side-effect profile.
Clinical trial identification
Legal entity responsible for the study
Merck & Co. Inc.
Merck & Co., Inc.
C. Massard: Advisory Board Member: Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi, Orion, MedImmune, New Oncology, DebioPharm.
M. Gould, P. Qiu, S. Saraf, S. Keefe: Employee, stock ownership Merck & Co., Inc.
S.A. Piha-Paul: Corporate-sponsored research: GlaxoSmithKline, Novartis, Puma Biotechnology, Inc., Merck, Sharp and Dohme, BioMarin Pharmaceutical, Inc., Principia Biopharma, Inc., Abbvie, XuanZhu Biopharma, Helix BioPharma Corp., Incyte, Inc., Curis.
All other authors have declared no conflicts of interest.