Background: Prostate cancer (PCa) patients (pts) with DNA repair defects (aka “BRCAness”) generally have more aggressive disease and a worse overall prognosis compared to men without BRCAness (PMID: 33781305). Biochemical recurrence (BCR) develops in almost one-third of men with PCa after treatment with local therapy. We hypothesized that treatment with rucaparib monotherapy in men with systemic treatment naïve high-risk nmHSPC would result in acceptable disease control, allow a delay of androgen deprivation therapy (ADT) and the onset of metastasis. Methods: This is a single-arm, open-label, phase II trial; eligibility criteria: (1) Histologically proven prostate adenocarcinoma, presence of one of the following alterations in (by soft tissue or liquid biopsy): BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, NBN, PALB2, RAD51C, RAD51D, RAD51, RAD51B, (2) No radiographic evidence of metastatic disease by conventional scans (3) PSA doubling time of ≤10 months. The primary endpoint: PSA progression-free survival (PSA-PFS). Secondary endpoints: safety, the proportion of pts with a PSA 50% response (PSA50), and an undetectable PSA. Results: Seven pts were enrolled in the study with the following pathogenic alterations: ATM (n=3), BRCA2 (n=2), BRCA1 (n=1), BRIP1 (n=1), RAD51(n=1), and received treatment with rucaparib at 600 mg twice daily. A 4-week treatment duration comprised one cycle. The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI: 0 - 85.11 months). 2/7 patients achieved PSA50; both had nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 pt each). No dose-limiting toxicities or severe AEs were seen. The study was prematurely terminated in June 2022 after the accrual of 7 pts because next-generation scans (e.g., PSMA-PET) became the standard of care for pts with BCR. Conclusions: Rucaparib demonstrated acceptable toxicity and preliminary efficacy in pts with PCa with BCR. Gene alteration-specific efficacy will be presented in the meeting. Limitations: Small cohort, no comparison arm. Hence results should be interpreted cautiously but generally consistent with larger prospective trials of PARP inhibitors. Clinical trial information: NCT03533946.