Molecular and clinical correlates of high PSMA/FOLH1 mRNA expression in primary and metastatic prostate cancer (PC)

Background: The FOLH1 gene encodes prostate-specific membrane antigen (PSMA), a trans-membrane glycoprotein that is expressed in PC cells. PSMA is a target for diagnostic imaging and treatment in PC. We utilized a database of molecularly profiled PC tumors to evaluate correlates of high FOLH1 mRNA expression. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on PC specimens (n=7,558) through Caris Life Sciences. FOLH1-High/Low expression was defined as above/below median RNA transcripts per million (TPM). Androgen receptor (AR), neuroendocrine (NEPC), MAPK, and T-cell inflamed RNA signature scores were calculated. Tumor cell PD-L1+ expression ($2+, $5%; SP142) was assessed by IHC. Overall survival (OS) and time on treatment (TOT) were calculated from time of diagnosis or therapy start. Results: Specimens were derived from the prostate gland (n=4495, 59.5%), lymph nodes (n=858, 11.4%), bone (n=568, 7.5%), liver (n=359, 4.7%), urinary tract (n=340, 4.5%), lung (n=116, 1.5%), and other metastatic sites (n=822, 10.9%). Relative to the prostate (390.9 TPM), FOLH1 mRNA expression varied by metastatic site, with highest expression in lymph nodes (518.2 TPM, p,0.001) and lowest expression in lung (209.7 TPM, p,0.001) and liver metastases (143.1 TPM, p,0.001). Higher FOLH1 expression significantly correlated with presence of AR-V7 variants (18% vs 15%) and ASXL1 (6% vs 3.9%) alterations, and fewer alterations in FOX1A (7.9% vs 10.6%), APC (4% vs 10.3%), PIK3CA(3.1% vs 6.4%), CTNNB1 (3.1% vs 4.8%), and PIK3R1 (0.7% vs 2%). High FOLH1 expression positively associated with AR signaling score, MAPK activation, and T-cell inflammation, and negatively correlated with NEPC signaling (all p,0.001). Tumors with high FOLH1 expression were more frequently PD-L1+ (3.9% vs 2.2%, p,0.01). Among primary tumors, OS was similar between FOLH1 high and low groups; however, among metastatic tumors, OS was improved in patients (pts) with high FOLH1 expression compared to low expression (96.3 vs 87.9 months, HR 0.82 95% CI 0.73–0.92). There was no difference in TOT among pts receiving ARSIs, taxanes, or PARPi. Among 149 pts that received 177Lu-PSMA-617, there was a trend towards improved TOT in FOLH1-high (n=78) versus -low (n=71) tumors (HR 0.76, 95%CI 0.55–1.05). Conclusions: This is the largest combined genomic, transcriptomic and survival outcomes analysis of PSMA (FOLH1) expression in PC. In PC, greater FOLH1 mRNA expression was associated with higher AR signaling scores and AR-V7 expression, and fewer mutations in the Wnt and PI3K pathways. FOLH1-high pts showed greater T cell inflammation and PD-L1 expression, and lower NEPC signaling. High FOLH1 expression was associated with greater OS among patients with metastatic tumors, with a trend towards improved outcomes to 177Lu-PSMA-617. Such pts may benefit from distinct therapeutic strategies. Research Sponsor: None.