This study investigates the efficacy of olaparib, a PARP inhibitor, in patients with metastatic, castration-resistant prostate cancer (mCRPC) who have DNA-repair defects. The primary endpoint was the response rate, defined as an objective response or a reduction in prostate-specific antigen (PSA) levels by 50% or a confirmed reduction in circulating tumor cells. Fifty patients were enrolled, and 16 (33%) had a response to olaparib. Next-generation sequencing identified homozygous deletions or deleterious mutations in DNA-repair genes in 16 of 49 patients (33%). Of these, 14 (88%) had a response to olaparib, including all 7 patients with *BRCA2* loss and 4 of 5 with *ATM* aberrations. The specificity of the biomarker suite was 94%. Common adverse events were anemia and fatigue. The study concludes that PARP inhibition with olaparib shows high antitumor activity in mCRPC with DNA-repair defects, suggesting a potential molecularly targeted treatment option.This study investigates the efficacy of olaparib, a PARP inhibitor, in patients with metastatic, castration-resistant prostate cancer (mCRPC) who have DNA-repair defects. The primary endpoint was the response rate, defined as an objective response or a reduction in prostate-specific antigen (PSA) levels by 50% or a confirmed reduction in circulating tumor cells. Fifty patients were enrolled, and 16 (33%) had a response to olaparib. Next-generation sequencing identified homozygous deletions or deleterious mutations in DNA-repair genes in 16 of 49 patients (33%). Of these, 14 (88%) had a response to olaparib, including all 7 patients with *BRCA2* loss and 4 of 5 with *ATM* aberrations. The specificity of the biomarker suite was 94%. Common adverse events were anemia and fatigue. The study concludes that PARP inhibition with olaparib shows high antitumor activity in mCRPC with DNA-repair defects, suggesting a potential molecularly targeted treatment option.