Background: Patients with a high-risk biochemical recurrence (BCR) of prostate cancer after local therapy, defined by a rapid PSA doubling time (≤6 mo), are likely to experience metastases and subsequently death from their disease. Early use of androgen deprivation therapy (ADT) in these patients is controversial and is associated with side effects. Non-hormonal therapies that alter the natural history of BCR disease are needed. Olaparib is a PARP inhibitor that produces responses in some men with advanced prostate cancer, particularly those with dysregulation of DNA repair genes (i.e. synthetic lethality). Preclinical data support the activity of olaparib in prostate cancer beyond the DNA repair-deficient subset, yet the optimal biomarker for treatment selection is unknown. We hypothesized that olaparib monotherapy would show activity in men with high risk BCR and sought to further define the optimal patient population for olaparib in this setting. Methods: In this investigator-initiated multi-center open-label study, eligible patients will have non-metastatic BCR after prostatectomy, with a PSA doubling time of ≤6 mo. Prior limited ADT is allowed, but testosterone must have recovered (≥150 ng/dL). Patients will receive 300mg olaparib twice daily, with disease evaluation by PSA monthly and radiographic studies every 6 mo. Patients continue olaparib until evidence of metastasis or until PSA doubles from baseline, with a minimum exposure of 3 months. The primary endpoint is the rate of decline in PSA to ≥50% from baseline (PSA50 response). Secondary endpoints include safety, progression-free survival, and the rate of durable responses. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers, done on prostatectomy specimens. The study will initially enroll an all-comer (unselected) population and will then proceed via a staged-adaptive design; if futility is observed in the all-comer population at interim analyses, enrichment with biomarker-selected patients will occur. Clinical trial information: NCT03047135