Background: Men with mPC with visceral metastasis, as compared to non-visceral disease have inferior outcomes regardless of therapy (PMID: 25403629). Herein, we hypothesize that visceral versus non-visceral metastasis sites differ with regards to underlying genomic alterations (GA). These GA possibly drive metastasis to visceral sites and mediate a more aggressive disease. Identifying these GA may guide future trial designs by better stratifying patients and predicting therapy responses. Methods: In this retrospective analysis, inclusion criteria were: diagnosis of mPC and comprehensive genomic profiling of metastatic tissue by CLIA certified lab. Liver and lung were defined as visceral while bone and lymph nodes were defined as non-visceral metastasis. Evaluated GA were p53, RB1, PTEN, AR, TMB, CDK12, SPOP, MYC, MET, BRCA genes, BRAF, ARID1A. Fisher’s Exact Test was used to compare GA in visceral and non-visceral tumor tissue. Results: Overall 54 men with mPC with visceral (n=8) and non-visceral (n=46) metastatic tissue biopsies were evaluated. Visceral biopsies included liver (3) and lung (5). Non-visceral biopsy sites included lymph nodes (33) and bone (13). Men with or without visceral metastasis had similar baseline characteristics (Fisher’s Exact Test and Wilcoxon Rank Test; Table). Visceral tumor tissue had a significantly greater odds of having RB1 mutation [OR = 12.09; 95% CI = (1.12, 178.21); p-value 0.02] as compared to non-visceral tumor tissue. Conclusions: RB1 GA were more common in visceral as compared to non-visceral metastatic sites in mPC. RB1 loss is associated with ineffectiveness to CDK4/6 inhibitors (PMID 26633733). These hypothesis-generating data suggest that men with mPC with visceral metastasis may not optimally benefit by enrollment on CDK4/6 inhibitor trials. BLM, NA: equal contribution.