More recently, PARP-inhibitors in combination with abiraterone or enzalutamide were FDA approved in patients with mCPRC with specific DDR mutations on the basis of three randomized trials. PROpel134, 135 randomized mCRPC patients who were unselected for DDR status to receive olaparib plus abiraterone/prednisone versus placebo plus abiraterone/prednisone. The trial met its primary endpoint with a median rPFS of 24.8 versus 16.6 months (HR=0.66; 95% CI: 0.54 to 0.81; p<0.001). However, the trial failed to demonstrate OS benefit. The FDA approved the combination only for BRCA-mutated mCRPC, determining that the modest benefit in non-BRCA patients did not justify the added toxicity. Magnitude was a biomarker-selected phase III trial enrolling patients into DDR positive and DDR negative cohorts comparing niraparib + abiraterone/prednisone versus placebo plus abiraterone/prednisone.136-138 Futility analysis led to the closure of the DDR-negative cohort.  There was a statistical improvement in median rPFS in the DDR + cohort, however the FDA determined this benefit was driven by the BRCA subgroup with FDA approval of niraparib/abiraterone in BRCA mutated mCPRC only patients. TALAPRO 2139-142 enrolled mCRPC patients into an DDR unselected cohort and a DDR-deficient cohort comparing talazoparib + enzalutamide versus placebo plus enzalutamide. In the unselected cohort median rPFS was 33.1 versus 19.5 months (HR 0.67; p<0.0001), and at final analysis (median follow-up 52.5 months), OS was statistically significant at 45.8 versus 37.0 months (HR=0.80; 95% CI: 0.66 to 0.96; p=0.016). In the DDR defecient cohort the OS benefit was 45.1 versus 31.1 months (HR=0.62; 95% CI: 0.48 to 0.81; p=0.0005). The FDA approved talazoparib/enzalutamide for DDR gene mutated mCRPC. It is important to note that the vast majority of patients enrolled in PROpel, MAGNITUDE and TALAPRO 2 had not received prior APRI therapy prior to study enrollment and thus the efficacy of combination approaches in patients with mCRPC progression on an ARPI is unknown. Additionally, there is more therapy related toxicity and cost associated with combination therapy. Treatment decision making in the mCRPC setting is increasingly complex and requires careful consideration of patient’s treatment history, genetic test results, comorbid status, and patient preference.