Background: Although multiple new agents have been approved for mCRPC over the last decade, median survival remains unsatisfactory at ~12-35 months. Immunotherapy targeted solely at programmed death-1 (PD-1)/PD-1 ligand-1 (PD-L1) interactions has shown limited evidence of antitumor activity in patients (pts) with prostate cancer, likely due to the immunologically “cold” nature of the tumor and low PD-L1 expression on tumor cells. However, if existing prostate cancer treatments can trigger an adaptive immune response, attracting infiltrating immune cells and increasing tumor PD-L1 expression, there is a rationale for combination with anti-PD-1/PD-L1 inhibitors to improve outcomes. The current phase 2 study will evaluate combinations of the PD-1 inhibitor nivolumab with either rucaparib (PARP inhibitor), docetaxel, or enzalutamide (androgen receptor inhibitor) in men aged ≥18 years with mCRPC (NCT03338790). Methods: Key inclusion criteria: Histologic confirmation of adenocarcinoma of the prostate, evidence of metastatic disease, ongoing androgen deprivation therapy, and evaluable tumor biopsy. Key exclusion criteria: Active brain metastases, active malignancy in prior 3 years (except apparently cured locally-curable cancers), and major surgery ≤14 days before treatment assignment. Pts will be assigned to nivolumab + rucaparib, nivolumab + docetaxel, or nivolumab + enzalutamide based on prior systemic treatment history and the presence/absence of measurable disease and homologous recombination deficiency (HRD). Nivolumab, rucaparib, and enzalutamide treatment will continue until disease progression/unacceptable toxicity (nivolumab treatment ≤2 years); docetaxel will be given for ≤10 cycles. Co-primary endpoints: Objective response per Prostate Cancer Clinical Trials Working Group 3 criteria and prostate-specific antigen response in HRD+ pts and all treated pts; secondary endpoints: Overall survival, progression-free survival, and response kinetics in HRD+ pts and all treated pts, and safety/tolerability in all treated pts. Enrollment began December 2017 with a target of ~300 pts. Clinical trial information: NCT03338790