Background: LuPSMA, a radioligand targeting the cell surface protein PSMA, is approved for men with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) following an androgen receptor (AR)-signaling inhibitor (ARSI) and docetaxel. DNA damage repair gene (DDR) mutations are common in mCRPC, and given that ionizing radiation induces DNA damage, we hypothesized that the presence of these alterations could associate with improved clinical outcomes to LuPSMA. Data also suggests that the presence of DDR mutations may correlate with PSMA expression, providing further motivation to evaluate if DDR alterations are associated with the clinical activity of LuPSMA. Methods: We abstracted retrospective data from all patients at our center who received at least one cycle of LuPSMA per the FDA label and who had panel-based sequencing performed (e.g. UW-Oncoplex, Foundation One). Patients with somatic or germline alterations in a DDR gene were assigned to the DDR deficient cohort, while patients with somatic testing negative for a DDR gene mutation were assigned to the DDR intact cohort. Mutations in any DDR gene were considered for the purpose of stratifying between genomic subgroups. Differences in baseline PSMA SUVmean and PSA₅₀ responses (i.e. ≥50% decline in PSA) were compared between cohorts. Results: Of 91 patients who received ≥1 cycle of LuPSMA, 54 had genetic testing. 35 (64%) received ≥2 lines of prior ARSI therapy, 30 (56%) received ≥2 lines of prior chemotherapy and 15 (28%) received prior PARP inhibitor. 21 patients had alterations in a DDR gene and the remaining 33 patients had somatic testing without an identifiable DDR mutation. PSMA SUVmean was similar between groups: 8.04 (95% CI: 6.95 - 9.12) (DDR intact) vs. 7.32 (95% CI: 6.23 – 8.41) (DDR deficient), p = 0.37. 7/33 (21%) patients in the DDR intact group achieved PSA₅₀ response compared to 11/21 (52%) in the DDR group (p= 0.018). Survival data is immature but will be presented at the meeting. Rapid autopsy (RA) was performed in one subject with a BRCA2 mutation (baseline PSMA SUVmean 5.6) and immunohistochemistry analysis revealed profound loss of PSMA following progression on LuPSMA. Conclusions: Mutations in DDR genes were associated with a higher PSA₅₀ response rate following LuPSMA compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that higher response rates in the DDR cohort may have been mediated primarily by increased sensitivity to ionizing radiation. Evaluation for associations between DDR mutational status and survival endpoints is needed and will require a larger sample size and longer follow up. RA post-LuPSMA revealed loss of PSMA expression, suggesting that antigen loss may be a relevant resistance mechanism.