Background: The clinical activity of PARPi in patients with homologous recombination DNA-repair mutations and metastatic prostate cancer has now been established. Focusing specifically on patients with a germline mutation in a pre-specified group of DNA-repair genes, we hypothesize that targeted therapy with PARPi should be sufficient to induce a clinical response irrespective of hormonal (castration-sensitive/resistant) status. For men with metastatic hormone sensitive prostate cancer (mHSPC), this trial would also provide an alternative to ADT. Methods: This study is a multi-center, open-label, single arm Phase II trial. Eligible patients are those with mHSPC without prior ADT. All patients must have a documented germline mutation in a homologous recombination DNA-repair gene (BRCA1, BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM). Patients on trial must be ineligible for or decline standard-of-care hormonal treatment. A mandatory tumor biopsy will be performed prior to therapy. A second, optional tumor biopsy is planned after three months of therapy. Patients will be treated with Rucaparib 600mg po twice daily. Patients will be followed monthly with clinic visits and safety labs with PSA. The primary endpoint is the proportion of patients with a ≥ 50% decrease in PSA from baseline (PSA₅₀ response). A total enrollment of 30 patients is planned to detect an improved PSA₅₀ response rate from 50% to 75% with 90% power (one sided type I error of 0.1). The total number of patients allowed with a non-BRCA1, -BRCA2, or –ATM mutations will be capped at 10. For patients who do not respond to PARPi, we have incorporated safety rules into the study design to take patients off study at first signs of progression. Secondary endpoints include safety, progression-free survival, and objective response. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers. Clinical trial information: NCT03413995