Background: PSMA targeted therapy has recently emerged as a promising approach for patients with advanced prostate cancer. However, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses. Methods: Baseline, treatment and outcomes data along with tumor whole-exome sequencing (WES) data were retrospectively evaluated in anti-PSMA-treated patients (pts). Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with overall/progression-free/survival (OS/PFS) and PSA response. Results: We analyzed 25 pts treated with PSMA targeted radionuclide therapies refractory to standard therapy. 15 received 177Lu-J591, 8 received 177Lu-PSMA-617, 1 received both, and 1 225Ac-J591. WES data (n=28) showed an incidence of AR, BRCA1, BRCA2, ATM alterations (copy number variations and point somatic mutations) in 71.4% (n=20), 11.1% (n=3), 29.6% (n=8), and 14.3% (n=4), respectively. Variables found with backward selection with AIC criterion for PFS and OS suggest significant clinical and molecular predictors of PFS/OS (Table). Conclusions: Knowledge of prognostic factors such as baseline narcotic use and ALP, and BRCA1/BRCA2 and TP53 alterations may have potential clinical utility in patients being considered for anti-PSMA targeted radionuclide therapies. Validation of these findings in larger prospective trials is warranted.