5080 Background: Pts with DN-mCSPC have been reported to experience worse prognosis and outcomes compared to those with PLT-mCSPC. We hypothesized that gene expression profiling of pre-treatment primary prostate tumors from PLT-mCSPC pts would be distinct from those with DN-mCSPC. Methods: Eligibility criteria: histologically confirmed mCSPC and available RNAseq profiling performed by a CLIA certified lab using primary prostate biopsies collected prior to start of treatment. Pts were categorized into two cohorts: PLT-mCSPC versus DN-mCSPC. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Ninety-seven (97) patients met eligibility (52 PLT, 45 de novo). Characteristics of the overall eligible pts: median age = 65, median baseline PSA = 12.6, Gleason score ≥8 = 71%, and high volume of disease = ̃30%. Differential expression and pathway enrichment between cohorts: upregulation of cell-cycle signaling pathways (G2-M checkpoint, E2F) in pts with DN-mCSPC, and upregulation of androgen signaling and immune pathways (inflammatory response, NFKB-mediated TNF-alfa signaling) in pts with PLT-mCSPC (Table). Conclusions: These hypothesis-generating data, upon external validation, may provide the rationale for personalized therapy in men with mCSPC, such as the use of CDK4/6 inhibitors in addition to standard of care intensified ADT in men with DN-mCSPC. [Table: see text]