Purpose: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. Patients and Methods: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to 4 cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered non-prostate tumors were enrolled in cohort B and not reported. The primary endpoint was 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Results: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were 2 in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% (95% CI 1-28%) in cohort A with 2 responders; neither had microsatellite instability or a tumor mutational burden ≥10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA-PFS was 7.0 months (95% CI 3.6-11.4) in cohort A and 4.5 months (95% CI 3.4-13.8) in cohort C. Median OS was 9.0 months (95% CI 6.2-12.3) in cohort A and 13.8 months (95% CI 3.6-not reached) in cohort C. Conclusions: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

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