Background: Male BRCA mutation carriers have a 2-8-fold increased risk of prostate cancer when compared to the general population, and up to 3% of patients (pts) with prostate cancer carry an inherited mutation in BRCA1 or 2. The therapeutic implications of germline BRCA mutations in prostate cancer are largely unknown. BRCA mutation enhances sensitivity to inhibition of the PARP1 and PARP2 enzymes, due to a synthetic lethal effect on DNA repair. We therefore conducted a phase 1 study of the PARP 1, 2 inhibitor, veliparib (V), in 2 cohorts of pts- BRCA germline mutated (BRCA+) and BRCA-wild type (BRCA-wt; consisting of serous ovarian cancer and triple-negative breast cancer). Methods: A 3+3 dose escalation phase I trial was performed to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28-day cycle. Results: A total of98 (70 BRCA+ and 28 BRCA-wt) pts were enrolled. The maximum administered dose (MAD) was 500 mg BID and the MTD/RP2D was 400 mg BID. In BRCA+ cohort at doses ≥ 400 mg BID, overall response rate (ORR) defined as complete response (CR)+ partial response (PR) was 37%, and clinical benefit rate (CBR) defined as CR+PR+stable disease (SD) > 6 cycles was 40%. Three pts with BRCA2+ metastatic castration-resistant prostate cancer (mCRPC) were enrolled on the RP2D and were evaluable for response. In these pts, the ORR was 2/3 (66%) and CBR 3/3 (100%) (summarized in table). One pt with rapidly progressive mCRPC involving liver and bone achieved PR and undetectable serum PSA, and remains on therapy at 19+ cycles. The most common adverse effects in these pts were grade 1/2 nausea/vomiting, fatigue, and leukopenia consistent with the overall study population. Conclusions: Single-agent V demonstrates evidence of activity in BRCA2+ mCRPC. These data support the role of genotype-directed therapy in prostate cancer. Clinical trial information: NCT00892736