A phase 2 trial evaluated olaparib in 50 patients with metastatic, castration-resistant prostate cancer (mCRPC) who had prior treatment failures. The study aimed to determine if olaparib, a PARP inhibitor, would be effective in patients with DNA repair gene defects. Patients received olaparib at 400 mg twice daily. The primary endpoint was response rate, defined by RECIST criteria, PSA reduction, or reduction in circulating tumor cells. Next-generation sequencing identified DNA repair gene defects in 33% of patients, with 14 of 16 patients with such defects responding to olaparib. The response rate was 33% (95% CI, 20-48), with 12 patients receiving treatment for more than 6 months. Patients with BRCA2 loss or ATM aberrations had higher response rates. Anemia and fatigue were the most common grade 3 or 4 adverse events. The study found that DNA repair defects were associated with higher response rates and longer progression-free survival. Olaparib showed antitumor activity in patients with DNA repair defects, suggesting it could be a targeted therapy for mCRPC. The results indicate that PARP inhibition may be effective in patients with specific genetic defects, highlighting the importance of molecular profiling in prostate cancer treatment. The study was well-conducted, with rigorous biomarker analysis and safety monitoring. The findings support the use of olaparib in patients with mCRPC and DNA repair defects, offering a potential new treatment option for this difficult-to-treat cancer.A phase 2 trial evaluated olaparib in 50 patients with metastatic, castration-resistant prostate cancer (mCRPC) who had prior treatment failures. The study aimed to determine if olaparib, a PARP inhibitor, would be effective in patients with DNA repair gene defects. Patients received olaparib at 400 mg twice daily. The primary endpoint was response rate, defined by RECIST criteria, PSA reduction, or reduction in circulating tumor cells. Next-generation sequencing identified DNA repair gene defects in 33% of patients, with 14 of 16 patients with such defects responding to olaparib. The response rate was 33% (95% CI, 20-48), with 12 patients receiving treatment for more than 6 months. Patients with BRCA2 loss or ATM aberrations had higher response rates. Anemia and fatigue were the most common grade 3 or 4 adverse events. The study found that DNA repair defects were associated with higher response rates and longer progression-free survival. Olaparib showed antitumor activity in patients with DNA repair defects, suggesting it could be a targeted therapy for mCRPC. The results indicate that PARP inhibition may be effective in patients with specific genetic defects, highlighting the importance of molecular profiling in prostate cancer treatment. The study was well-conducted, with rigorous biomarker analysis and safety monitoring. The findings support the use of olaparib in patients with mCRPC and DNA repair defects, offering a potential new treatment option for this difficult-to-treat cancer.