KEYNOTE-199 cohorts 4 and 5: Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC)

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Conference Proceeding

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European Urology Open Science


Introduction & Objectives: The mechanisms of action of enza and pembro, a PD-1 inhibitor, may be synergistic, suggesting that pembro + enza combination therapy may be a promising treatment option. KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study. Cohort (C) 4 (RECIST-measurable disease) and C5 (bone-predominant disease) consist of chemotherapy-naive patients (pts) with mCRPC treated with enza + pembro after progression with enza. Results for C4 and C5 are presented.

Materials & Methods: Pts with or without prior abiraterone treatment had to have clinically meaningful response to/benefit after enza, initiated ≥4 wk before first dose of pembro, followed by disease progression. Failure of enza was defined by PCWG3 guidelines: signs of clinical progression, increased alkaline phosphatase, PSA increase, or positive imaging assessments. Pts received pembro 200 mg Q3W with continuation of enza for up to 35 cycles or until progression/intolerable toxicity. Imaging was performed Q9W for 1 year and then Q12W thereafter. The primary end point was ORR per blinded independent central review (BICR) by RECIST v1.1 (C4). Secondary end points were disease control rate (DCR=CR+PR+SD or non-CR/non-PD ≥6 mo), PSA response rate (≥50% reduction), rPFS (PCWG3-modified RECIST v1.1), OS, and safety (C4, C5); DOR (C4). DOR, rPFS, and OS were calculated using the product-limit (Kaplan-Meier) method for censored data. Results: Of 126 pts (C4, 81; C5, 45), 107 discontinued, primarily because of progression. Median follow-up was 13.7 mo (C4, 11.8; C5, 18.6). ORR (95% CI) for pts with measurable disease was 12% (6-22) in C4; DCR for all pts was 51% (39-62) in C4 and 51% (36-66) in C5 (Table). Treatment-related AEs of any grade/grade 3-5 occurred in 75%/26% pts in C4 and 69%/24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/6%). All except 1 pt (grade 3 rash treated with IV steroids) were treated with oral/topical steroids or had no intervention.

Conclusions: Addition of pembro to enza after enza resistance showed modest antitumor activity in pts with RECIST-measurable and bone-predominant mCRPC. The combination had manageable safety and is being evaluated in a phase 3 trial. [Table presented]



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