PARP inhibitors leverage defects in DNA repair to provide improved outcomes in men with advanced prostate cancer who have mutations in DNA repair enzymes central to homologous recombination DNA repair. Defects in DNA repair occur in up to 30% of men with mCRPC, and such cancer cells depend instead on PARP-regulated DNA repair.130 Therefore, inhibition of PARP in these tumors results in cell death.131 In the randomized, open-label, phase III PROfound trial, de Bono et al. randomly assigned 387 patients with progression on enzalutamide or abiraterone acetate in a 2:1 ratio to receive olaparib (300mg twice daily) or the physician’s choice of enzalutamide or abiraterone acetate (control).43 Nineteen percent of patients randomized to antiandrogen therapy had previously received both enzalutamide and abiraterone acetate; the trial did not report the proportion of patients among the remaining 81% who received the alternative antiandrogen or report results in this subgroup. All patients had a qualifying alteration in pre-specified genes with a direct or indirect role in homologous recombination repair. Cohort A had at least 1 alteration in BRCA1, BRCA2, or ATM; and cohort B had alterations in any of the 12 other pre-specified genes (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L). The primary endpoint was imaging-based PFS in cohort A. Median PFS was 7.4 months in the olaparib group versus 3.6 months in the control group (HR for progression or death=0.34; 95% CI: 0.25 to 0.47; p<0.001). Median OS in cohort A was 18.5 months with olaparib compared to 15.1 months in the control group. Investigators noted that anemia and nausea were the main toxic effects seen in patients on olaparib. In addition to olaparib, rucaparib is also FDA approved for patients with deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy. The Triton 3 study demonstrated that rucaparib significantly improved rPFS compared to physician's choice of docetaxel or a second-generation ARPI in patients with BRCA-mutated metastatic castration-resistant prostate cancer.132 Platinum-based chemotherapy also has a mechanism of action that correlates with defects in homologous recombination DNA repair. Preliminary data have demonstrated that, similar to PARP inhibition, carboplatin may improve outcomes in men with similar DNA defects.133 However, to date there are no randomized data supporting its use. In a retrospective analysis of a single-institution cohort of men with mCRPC, pathogenic germline BRCA2 variants were noted in 8 of 141 participants. Six of eight (75%) of those men experience PSA decline >50% within 12 weeks compared to 23 of 133 (17%) of non-carriers (absolute difference=58%; 95% CI: 27% to 88%; p<0.001).133