Background: Pts with mCSPC receiving i-ADT and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) demonstrate significantly better overall survival (OS) as compared to those with a PSA nadir > 0.2 ng/mL (PSA-H) (Chi AUA 2021, Saad ASCO 2022). We hypothesized that tumor gene expression profile would differ between PSA-L and PSA-H. Methods: In this IRB-approved retrospective study, eligibility criteria included confirmed mCSPC receiving i-ADT with androgen receptor-axis-targeted therapy (ARAT) and availability of RNAseq profiling performed by a CLIA-certified lab of primary prostate biopsies collected before treatment. Pts were divided into 2 groups: PSA-L and PSA-H based on achieving a PSA nadir ≤0.2 ng/mL at any time during treatment course. 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 (q values) for each differentially expressed gene. These results were subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R studio v4.2. Results: 78 pts were eligible: 55 were PSA-L, and 23 were PSA-H. The most significantly upregulated pathways in PSA-L were the TNFA signaling, androgen response (AR), estrogen response, and interferon-alpha response pathways. The most upregulated pathways in PSA-H were epithelial-mesenchymal transition, coagulation, and bile acid metabolism pathways. Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show that mCSPC pts on i-ADT with PSA-L have distinct baseline tumor gene expression profiles, such as upregulation of AR signaling, compared to pts with PSA-H. After external validation, these findings may help personalize medicine prior to initiation of therapy in pts not expected to achieve PSA-L.

Positive NES = upregulation in PSA-L pts, and negative NES = downregulation in PSA-L pts.