Abstract 1136: Tumor genomic and transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus do not achieve an optimal PSA response to androgen deprivation therapy intensification (ADTi)

Abstract Background: Pts with mCSPC receiving ADTi and achieving PSA nadir ≤0.2 ng/mL (PSA-L) have better overall survival (OS) compared to those with a PSA nadir > 0.2 ng/mL (PSA-H). We investigate differences in genomic and transcriptomic profiling between PSA-L and PSA-H. Methods: In this IRB-approved retrospective study, eligibility criteria included confirmed mCSPC receiving ADTi and having comprehensive genomic profiling (CGP) performed by a CLIA-certified lab (Foundation Medicine and Tempus). Transcriptomic profile was evaluated from Tempus cohort. 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: 248 pts were eligible for genomic analysis (PSA-L=166, PSA-H=82). The top 5 most commonly altered genes were TMPRSS2, TP53, PTEN, APC, and SPOP. Genomic analysis did not reveal significant differences between PSA-L and PSA-H. 78 pts were eligible for transcriptomic analysis (PSA-L=55, PSA-H=23). Table shows differences in the expression of pathways between PSA-L and PSA-H. Conclusion: While there were no significant differences in genomic aberrations between PSA-L and PSA-H, gene expression profiling showed significant variations in crucial pathways, particularly the AR pathway, which might explain the better outcomes in PSA-L. After external validation, these findings may help personalize medicine prior to initiation of therapy. Differential gene set expression scores in PSA-L vs. PSA-H Pathway Normalized Enrichment Score (NES)* p-value q-value TNF-α signaling via NFKB 2.5 <0.01 <0.01 Androgen Response 1.7 <0.01 <0.01 Estrogen Response 1.7 <0.01 <0.01 Interferon-α 1.5 <0.01 <0.01 Bile Acid Metabolism -1.5 <0.01 <0.01 Coagulation -1.7 <0.01 <0.01 Epithelial Mesenchymal Transition -1.9 <0.01 <0.01 Citation Format: Vinay Mathew Thomas, Beverly Chigarira, Georges Gebrael, Chadi Chehade, Arshit Narang, Nicolas Sayegh, Nishita Tripathi, Yeonjung Jo, Clara Tandar, Ayana Srivastava, Richard Ji, Emre Dal, Gliceida Galarza Fortuna, Haoran Li, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal. Tumor genomic and transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus do not achieve an optimal PSA response to androgen deprivation therapy intensification (ADTi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1136.