Background: In general, older pts are likely to have an advanced stage PCa, hence poor overall survival (PMID: 18660852). Owing to increased awareness and better diagnostics, the incidence of PCa has steadily increased amongst older adolescents and young adult pts (PMID: 31553489). Recent reports suggest that younger pts often are staged less adequately, present with more advanced stages, and could have worse outcomes than older pts (PMID: 33575208). Hence, elucidating the underlying molecular biology of PCa by age may unravel specific biologic features and distinct genomic expressions specific to young-age PCa, and help investigate new therapeutic targets. Methods: In this IRB-approved retrospective study, eligibility criteria included pts diagnosed with advanced PCa with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on the cohort's age cut-off points (< 65 vs. ≥65 years). DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. The statistical significance level was predetermined at 0.05. Results: 80 pts were eligible: < 65 (n=44) vs ≥65 years (n=36). No differences in Gleason score (<8/≥8), baseline PSA levels, and disease volume (high/low) between the cohorts (Table). As compared to pts ≥65 years; in young pts, (1) the three most upregulated significant pathways were oxidative phosphorylation (OXPHOS), bile acid, and fatty acid metabolism pathways, and (2) the three most downregulated significant pathways were tumor necrosis factor-alpha (TNFα) via NF-Κb, transforming growth factor-β (TGF β), and inflammatory response pathways. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show distinct genomic pathways to be upregulated in younger pts vs. older pts with advanced PCa and may guide further drug development, e.g., OXPHOS inhibitors in younger pts vs. drugs targeting inflammatory response in older pts. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with PCa.