Characterization and impact of canonical Wnt Signaling Pathway (WSP) alterations on outcomes of metastatic prostate cancer.

5053 Background: Recurrent alterations in the WSP have been identified in patients with advanced prostate cancer. Aberrant Wnt signaling has been implicated in disease progression and hormonal resistance in prostate cancer. We utilized a multi-institutional real-world dataset to characterize molecular alterations in the canonical WSP in men with prostate cancer, and correlate that with overall survival (OS). Methods: Prostate cancer patients who underwent tissue-based DNA and RNA sequencing utilizing a commercially available CLIA-certified assay (Caris Life Sciences) were investigated. Next generation sequencing (NGS)/ whole exome (WES) and transcriptome sequencing (WTS) was performed on prostate cancer tissue derived from prostatic and/or metastatic sites. Patients with somatic activating mutations in CTNNB, pathogenic fusions in RSPO2, or inactivating mutations in APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-MT). A subset analysis was conducted in metastatic prostate cancer (mPCa) samples with microsatellite stable (MSS) tumors excluding RNF43 (G569fs*) mutations. Comparative analyses were done using Fisher-Exact or X2 tests, and significance was determined by adjusted p value using Benjamini-Hochberg correction (q < 0.05). OS was obtained from insurance claims data and calculated using Kaplan-Meier estimates. Enriched mRNA transcripts were identified as those with an adjusted p value < 0.001, logFC > 1.5, and (-)log10 FDR > 20. Results: Overall, 21.8% (n = 715/3283) of samples were classified as WSP-MT, of which 297 (41.5%) were from primary tumor samples and 418 (58.5%) were from metastatic sites. WSP-MT were highest in metastases to CNS (54.5%, n = 12/22), liver (43.8%, n = 91/208) and lung (42.3%, n = 91/208). Compared to WSP wild-type, WSP-MT tumors had a greater frequency of dMMR/MSI-H status (18% vs. 2%, q < 0.001). In the subset of mPCa, MSS tumors (WSP-MT excluding RNF43 (G569fs*) mutations, n = 318; WSP wild-type n = 951), WSP-MT were enriched for mutations in SPOP (14.3% vs. 6.9%, q = 0.004). In these tumors, WSP-MT samples were most enriched for mRNA expression of CST1, NKD1, AXIN2, and ZNRF3 (all known canonical WSP activators). OS was inferior in mPCa WSP-MT patients compared to WSP wild-type (HR 0.49, 95% CI 0.37-0.64, p < 0.0001). Relative to WSP wild-type cases, OS was shorter from time of enzalutamide/abiraterone/apalutamide start (HR 0.25, 95% CI 0.15-0.43, p = 0.0001), and from first-line taxane chemotherapy (HR 0.47, 95% CI 0.21-1.02, p = 0.052) in pts with WSP-MT. Conclusions: Canonical WSP alterations are enriched in metastatic tumors, with highest prevalence in visceral (CNS, liver, lung) metastases. Clinical outcomes in WSP-mutant cancers are inferior with both hormonal and chemotherapies, heralding an urgent need to develop novel therapeutic strategies for such patients.