Background: Androgen deprivation therapy (ADT) is the backbone of treatment for patients (pts) with metastatic prostate cancer (PCa), but many pts find this difficult to tolerate. Treatment with non-castrating regimens may avoid or delay the toxicities of hormonal therapy. The activity of PARP inhibitors (PARPi) in pts with homologous recombination DNA-repair (HRD) mutations (muts) and metastatic castration-resistant PCa has been established. We hypothesized here that the benefit of ARPi can be maintained in the absence of ADT in a biomarker-selected (HRD mutated) population with PCa. We designed a Phase 2 study in men with hormone-naïve, metastatic PCa who harbored a germline HRD mut treated with rucaparib monotherapy (without ADT). Methods: This was a multi-center, single arm Phase 2 study (NCT03413995) in men with asymptomatic hormone-sensitive metastatic PCa who received rucaparib 600mg by mouth daily. During consenting, pts were informed and had to opt out of ADT-based therapy. Pts must have had a germline mutation in an HRD gene on clinical-grade testing. The primary endpoint was confirmed PSA₅₀ response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 25% absolute increase in PSA₅₀ response from a null of 50%. Results: 12 pts were enrolled, 7 with BRCA1/2 and 5 with CHEK2 muts. The confirmed PSA₅₀ response rate to rucaparib was 41.7% (N=5/12, 95% CI: 19.3-68.1%), which did not meet the pre-specified efficacy boundary to enroll additional patients to 2^nd stage. In pts with measurable disease, the ORR was 60% (N=3/5, all with BRCA2). Median rPFS on rucaparib was 10.3 months (95% CI: 4.0 mo - NR). At the time of the interim analysis, 3 pts remained on study. The majority of adverse events (AE) were Grade ≤2 and expected. Translational studies are ongoing. Conclusions: Rucaparib can induce clinical responses in a biomarker-selected PCa population without concurrent ADT. However, the pre-specified threshold of PSA₅₀ response was not met. Although durable responses were observed in a subset of pts, PARPi without ADT in metastatic hormone sensitive PCa will not be pursued. Clinical trial information: NCT03413995.