Pts with mCSPC undergoing ADT-I and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) any time after start of therapy was associated with improved overall survival (OS) versus those with a PSA nadir >0.2 ng/mL (PSA-H) (HR: 0.17, P<0.0001) (Chi AUA 2021, abstract 1281). We hypothesized that tumor gene expression profiling in PSA-H would be distinct from PSA-L. Eligibility: confirmed mCSPC on ADT-I with Androgen Receptor Axis Targeted Therapy (ARAT) and availability of RNAseq profiling performed by a CLIA-certified lab using primary prostate biopsies collected before treatment. DEseq2 package was used to identify differentially expressed genes in PSA-H versus PSA-L cohorts. Gene Set Enrichment Analysis (GSEA) was used to identify pathways enriched in each cohort. All analyses were done using R v4.2. Eligible pts= 33 (11 PSA-H, 22 PSA-L) had a median age 65 years, median baseline PSA of 23.3 ng/ml, Gleason ≥8 ∼79%, de novo 55% and high-volume disease per CHAARTED criteria ∼52%. Pts with PSA-H had downregulation of the androgen response, estrogen response, and TNF-α signaling pathway, and upregulation of the interferon-alpha and coagulation pathway (Table).Table: 1413PGSE Scores contrast PSA-H versus PSA-LPathwayNormalized enrichment score (NES)P-valueQ-valuesTNFA_Signaling via_NFKB-2.04632<<<0.001<<<0.001Androgen response-1.67726<0.0010.005Estrogen response late-1.64446<<0.0010.001Coagulation1.5609930.0010.005Interferon-alpha response1.890529<<0.0010.001Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts Open table in a new tab Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts mCSPC pts not achieving an optimal response to ADT-I have downregulated pre-treatment tumor AR signaling and TNF-α signaling and upregulation of inflammatory molecular pathways characterized by increased angiogenesis, adhesiveness, and invasiveness (PMIDs: 34696780, 12429291). After external validation, these data may provide upfront identification of patients who may not respond to intensified ADT, and aid with counselling, prognostication, and trial enrollment.