Integrated clinical and molecular characterization of WNT pathway alterations in metastatic castration-resistant prostate cancer (mCRPC) liver metastases (mets).

5048 Background: mCRPC patients (pts) with liver mets (LM) have an aggressive clinical course and poor response to established treatments. LM frequently exhibit low PSMA expression, limiting the utility of PSMA-targeted therapies. The mechanisms driving hepatic organotropism and therapy resistance in advanced disease are poorly understood. Methods: We analyzed metastatic biopsies with matched transcriptional and genomic profiling from 4 independent mCRPC cohorts from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) West Coast Dream Team, SU2C/PCF East Coast Dream Team, University of Washington rapid autopsy program, and Weill Cornell Medicine. Tumors were classified by FOLH1 gene expression tertile and by androgen receptor (AR) and neuroendocrine (NE) gene signature expression. Individual cohorts were assessed for differential gene expression and validated between cohorts. Cohorts were pooled for genomic and survival analyses. Multivariable Cox proportional hazard models were used to assess outcomes. Results: 595 mCRPC biopsies were analyzed, comprising 88 (15%) liver, 130 (22%) non-liver visceral, 166 (28%) bone, and 211 (35%) lymph node mets. 54% of pts had prior androgen receptor pathway inhibitor (ARPI) exposure and 29% had prior taxane chemotherapy. LM had lower FOLH1 expression (log2FC = -1.5, q < 0.001) than non-LM. Amongst FOLH1 -low LM, 32% had elevated NE gene expression, with high histological concordance (80% NE prostate cancer [NEPC], 9% adenocarcinoma with NE features). WNT pathway mutations in APC or CTNNB1 were enriched in LM compared to non-LM (20% vs. 10%, p = 0.01) and FOLH1- low compared to FOLH1 -high mets (16% vs. 6%, p = 0.006). Notably, in FOLH1 -low LM, APC mutations were exclusively found in tumors with low NE gene expression (28% vs. 0%, p = 0.02). In contrast, NE LM were enriched for alterations in RB1 (71% vs. 15%, p < 0.001) and homologous recombination repair genes (41% vs. 15%, p = 0.04). Compared to NE LM, non-NE FOLH1 -low LM demonstrated persistence of AR signaling, enrichment for inferred ß-catenin transcription factor activity, and upregulation of adaptive metabolic pathways including HIF-1α mediated hypoxia signaling and unfolded protein response. ß-catenin downstream targets including CCND1, MYC, MSX2, AXIN2, and LEF1 were transcriptionally upregulated, while AR targets STEAP1 and KLK2 remained highly expressed. In the overall cohort, WNT pathway mutations were associated with shorter treatment duration on first-line ARPI (HR 2.2, 95% CI 1.04-4.8, p = 0.03) and inferior overall survival from start of first-line ARPI (HR 1.7, 95% CI 1.04-2.7, p = 0.03). Conclusions: WNT pathway alterations are enriched in a clinically aggressive PSMA-low subset of non-NE mCRPC that maintains luminal markers, suggesting distinct clonal evolution from NEPC and clinical actionability with emerging therapies.