Background: Recent data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. Immune checkpoint blockade is a promising avenue in mCRPC treatment. We hypothesize that increased DNA damage by O will complement anti-tumor activity of immune checkpoint inhibitor, D, in mCRPC (NCT02484404).Methods: Eligible pts have mCRPC with adequate end organ function and biopsiable disease (bone or soft tissue). Prior treatment with enzalutamide and/or abiraterone is required. D is administered at 1500 mg iv q28 days with O at 300 mg po q12 h. Primary endpoint is PFS. Secondary endpoints include PSA responses, safety and ORR. Single arm pilot study with a total accrual of 25 pts. On-study core biopsies undergo mutational analysis. Results: 6 pts have enrolled (median age 67 yr [range 60-79], median ECOG PS 1 [1-2]). Median baseline PSA: 258.1 (54.1-809.9 ng/mL). 4 pts have Gleason score (GS) > 8 and 2 pts have GS of 7. Grade 3/4 adverse events include anemia 2/6 (33%), thrombocytopenia, lymphopenia, nausea, febrile neutropenia, aspiration pneumonia [1 each, (17%)]. Conclusions: Exploiting synergy of D+O is a treatment option for heavily pre-treated pts. Preliminary data shows D+O is tolerable and active in mCRPC pts without germline BRCA mutation. Paired tumor biopsies and blood samples including ctDNA are being collected. Accrual is ongoing. Clinical trial information: NCT02484404