Background: Two previous Phase II trials studying pembrolizumab (Pembro) in 38 patients suggest it may be efficacious for prostate cancer (PC). Methods: Fifty-four consecutive men with recurrent or advanced prostate cancer were treated with 1 to 9 cycles of Pembro 200 mg every 3 weeks with or without SBRT at a private medical oncology clinic specializing in PC. Charts were retrospectively reviewed for response and toxicity. Definitions: Response (R) = >50% PSA decline; Progressive Disease (PD) = >50 % PSA increase. Stable Disease (SD)= neither response or progression. Results: 43 men completed 3 cycles of Pembro and were evaluable for toxicity. Toxicity was comparable to reports with other cancers besides PC, with 30.2% (13/43) having Grade 2 or higher toxicity. 31 men completed 4 cycles of Pembro and were evaluable for response. For the 31, the median Gleason score was 4+4=8. Treatment prior to Pembro was enzalutamide (26), abiraterone (18), and sipuleucel-t (23) and docetaxel (20). All but 4 men were castrate resistant (CRPC). Ten men got SBRT to a metastasis shortly before or during Pembro. Number of mutations were determined by the Guardant 360 assay. 17/31 (55%) were responders (19%) or had stable disease (35%). Characteristics of the two subgroups, R (6/31) + SD (11/31) versus PD (14/31), are presented in the table. Conclusions: Disease stabilization or response occurred in slightly more than half of the men treated with 4 or more cycles of Pembro. These positive responses were more common in men with lower PSA, fewer bone mets, fewer mutations, less previous chemotherapy, and there was a trend toward greater benefit in castrate sensitive disease and older men. In a separate abstract related to this patient cohort, the predictive ability of inherited mutations disrupting microRNA signaling were assessed for their capacity to predict toxicity (n=40). The table shows medians of the subgroups in the left 5 columns and the total number of patients in the right 3 columns for the 31 patients evaluable for response.