Interim Safety Analysis of a Randomized Phase II Trial Comparing Pembrolizumab With Radiation Versus Pembrolizumab, Olaparib, and Radiation in Localized High-Risk Prostate Cancer

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PURPOSE Preclinical data suggest synergy between immune checkpoint blockade, poly (ADP-ribose) polymerase inhibition, and radiation therapy (RT). This randomized phase II study evaluated the safety of pembrolizumab with standard-of-care (SOC) RT and androgen-deprivation therapy (ADT), with or without short-course olaparib, in high-risk or very high-risk localized prostate cancer. METHODS Patients were randomly assigned 1:1 to arm 1 (pembrolizumab + olaparib 200 mg twice a day + SOC RT/ADT) or arm 2 (pembrolizumab + SOC RT/ADT). Safety was assessed per Common Terminology Criteria for Adverse Events v5.0. The primary end point was prostate-specific antigen nadir ≤0.06 ng/mL within 6 months following RT; the planned sample size was 64. This report presents a prespecified safety analysis. RESULTS Eighteen patients were enrolled; 1 withdrew before treatment, leaving 17 who received ≥1 cycle of pembrolizumab (arm 1, N = 7; arm 2, N = 10). Median follow-up was 260 days in arm 1 and 236 days in arm 2. Median pembrolizumab exposure was nine cycles (range, 2-34), and all patients in arm 1 completed three cycles of olaparib. All patients experienced ≥1 adverse event (AE), most grade 1 to 2. Common events included fatigue, diarrhea, lymphopenia, anemia, hypertension, and hyperglycemia. Creatinine elevation was numerically more common in the olaparib arm. Grade ≥3 events occurred in both arms and were mainly laboratory abnormalities. Three serious AEs occurred, including 1 patient with immune-mediated pneumonitis that resulted in death. Median time to first immune-mediated AE was 90.5 days and 64 days for grade ≥3 events. No unexpected safety signals were observed. CONCLUSION Pembrolizumab with RT/ADT, with or without short-course olaparib, was feasible. No clear short-term safety signal attributable to olaparib was observed. One treatment-related death from immune-mediated pneumonitis occurred, notable in this curative-intent population. Ongoing follow-up will evaluate efficacy (ClinicalTrials.gov identifier: NCT05568550 ).

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