Interim safety analysis of a randomized phase II trial comparing pembrolizumab with radiation versus pembrolizumab, olaparib, and radiation in localized high risk prostate cancer.

362 Background: Preclinical data suggest synergy between immune checkpoint blockade, PARP inhibition, and radiation. This randomized trial evaluates the safety of pembrolizumab (pembro) with standard-of-care (SOC) radiation and androgen deprivation therapy (ADT), with or without olaparib, in high-risk localized prostate cancer. Methods: Patients with NCCN-defined high- or very high-risk localized prostate cancer were randomized to Arm 1 (1 yr pembro + olaparib 200 mg BID + SOC RT/ADT) or Arm 2 (1 yr pembro + SOC RT/ADT). SOC included ADT (18–24 mo) and IMRT to 70 Gy/28 fractions to prostate/seminal vesicles and 47.6 Gy/28 fractions to pelvic nodes. Safety was assessed per CTCAE v5.0. The primary endpoint is PSA nadir ≤0.06 ng/mL within six months after RT; planned sample size is 64. Results: Eighteen patients were enrolled; one withdrew before treatment, leaving 17 who received ≥1 cycle of pembro. Median age was 68 (range, 53–84) and PSA 9.0 ng/mL (range, 1.5–118). Twelve (67%) had Gleason 4–5, 13 (72%) had PSMA PET–positive nodes, and 15 (83%) met very high-risk criteria. Median pembro exposure was 11 cycles (range, 2–17). Fatigue and GI upset occurred in all patients. Renal/urinary AEs were slightly more common in Arm 1 (86% vs 60%), nearly all grade 1–2. Grade ≥3 events were more frequent in Arm 1, mainly labs (71%), cardiac (29%), infections (29%), and respiratory (29%) while labs (60%), and vascular disorders (50%) in Arm 2. Immune-related AEs included rash, fatigue, nausea, anorexia, musculoskeletal pain, and dry mouth; serious events were myositis (G2), colitis (G3), optic neuropathy (G4), and pneumonitis (G5). Two withdrew and two deaths occurred (immune pneumonitis, unrelated sepsis/MI). Steroids were required in 24%, with 12% also needing additional immunosuppression. Conclusions: Pembro with RT/ADT was feasible and generally tolerable. Adding olaparib did not increase high-grade toxicity, though low-grade urinary AEs were more frequent. All serious immune-mediated AEs, including one treatment-related death, were linked to pembro. Due to slow accrual, the trial was amended to a single-arm study of pembro + olaparib + RT (NCT05568550). Clinical trial information: NCT05568550.