Background: We hypothesized that sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with clinically advanced CRPC and CRNEPC. Methods: CGP was performed on FFPE samples of 2,424 CRPC and 143 CRNEPC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined by principal components analysis of optimal homopolymer loci. Results: All (100%) CRPC and CRNEPC were advanced and therapy resistant. TMPRSS2+ CRPC features significantly more TP53 and PTEN GA, whereas TMPRSS2- CRPC featured more MYC and ATM GA; differences in BRCA2 and RB1 GA were not significant. RB1 GA were significantly more frequent in CRNEPC than CRPC, whereas GA in AR and ATM were more frequent in CRPC. TP53 GA frequencies were higher in TMPRSS2+ CRNEPC than in TMPRSS+ CRPC, whereas GA in PTEN and MYC were similar in comparative groups. Median TMB was higher in CRNEPC than CRPC, and higher in TMPRSS2- compared with TMPRSS+ tumors; TMB was more often ≥10 or ≥20 mut/Mb in TMPRSS2- tumors. MSI-High status was more frequently identified in the TMPRSS2- CRPC and CRNEPC groups. Conclusions: The 31% frequency of TMPRSS2+ CRPC in this study, lower than the 46% reported in early stage disease (TCGA data) suggests that this biomarker may be linked to a favorable prognosis. For CRNEPC, the higher frequency of TMPRSS2- tumors is not as striking. CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMPRSS+ and TMPRSS2- prostate tumors.