Paschalis A, et al. - Membranous prostate-specific membrane antigen (mPSMA, a type II transmembrane protein with enzymatic function as a folate hydrolase-carboxypeptidase) expression was scored immunohistochemically from metastatic castration-resistant prostate cancer (PC) (mCRPC) and matching, same-patient, diagnostic biopsies, and associated with next-generation sequencing (NGS) and clinical outcome data by the researchers in order to illustrate PC PSMA expression and correlate this with defective DNA damage repair (DDR). The expression of mPSMA at diagnosis was correlated with higher Gleason grade and worse overall survival. Overall, at mCRPC, mPSMA expression levels rose. No detectable mPSMA were observed in 42% (n=16) of castration-sensitive prostate cancer (CSPC) and 27% (n=16) of mCRPC tissues sampled. In all mPSMA expressing CSPC and 37 mCRPC biopsies, marked intratumor heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was noted. With the least expression in liver metastases, heterogeneous intrapatient mPSMA expression between metastases was also seen. In subjects with deleterious aberrations in BRCA2 and ATM, higher mPSMA expression were noted in contrast to those in molecularly unselected mCRPC biopsies. Tumors with DDR had greater mPSMA expression. Validation studies using mCRPC transcriptomes verified these findings, also symbolizing that SOX2 high tumors have low PSMA expression. Hence, with mPSMA expression exhibiting marked inter- and intrapatient heterogeneity, membranous PSMA expression was upregulated in some but not all PCs. Moreover, in larger, prospective cohorts, DDR aberrations were correlated with higher mPSMA expression and merit further assessment as predictive biomarkers of response for PSMA-targeted therapies.