5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = < 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10^-5). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.