Characterizing the clinical and genomic features of androgen indifferent prostate cancer.

• DOI: 10.1200/jco.2025.43.5_suppl.222
• Publication Date: 2025-02-18T14:42:46Z
• Authors: Jack Masur; Krzysztof Wierbil...; Aakrosh Ratan; Adanma Ayanambakkam; Michelle L. Churc...; Saum Ghodoussipour; Laura Graham; George Daniel Grass; Sumati Gupta; Sean Kern; Jennifer King; Zin Myint; Seyi Oderinde; Robert J. Rounbehler; Bodour Salhia; Eric A. Singer; Yousef Zakharia; Bryce Paschal; Paul Vincent Viscuse

222 Background: Androgen indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse AIPC remains a poorly understood malignancy. This study aims to characterize the clinical genomic features of AIPC. Our work ultimately seeks identify biomarkers with diagnostic therapeutic potential. Methods: Utilizing Oncology Research Information Exchange Network (ORIEN) database, we queried all (PC) patients, identified metastatic castrate resistant (MCRPC) samples, aimed enrich for using previously described characteristics. cohort included three subgroups: aggressive variant (AVPC) defined as having alterations in at least two TP53, RB1, PTEN; neuroendocrine PC (NEPC) small cell histology or NEPC signature score ≥ 0.25 (1); double-negative (DNPC), non-NEPC patients low AR expression/AR signaling score. We compared characteristics analysis vs non-AIPC samples who developed MCRPC. Clinical was done Wilcoxon rank sum test Fisher's exact test. Gene expression performed DESeq2 GSEA. Results: Of 1,496 total available analysis, 323 (22%) those, 39 (12%) met criteria (17 AVPC, 13 NEPC, 9 DNPC) 284 (88%) were non-AIPC. Median age diagnosis 62 years 85% white, 87% Fifty-seven percent had ECOG ≥1 16% Forty-three de novo disease 15% (p=0.003). TMPRSS2-ERG gene fusions found significantly higher proportion (38.5% 16%, p=0.014). Homologous recombination deficiency (HRD) tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) (p=0.019). Using Set Enrichment Analysis (GSEA), that genes defining response androgens involved oxidative phosphorylation most downregulated, whereas epithelial mesenchymal transition (EMT), interferon response, angiogenesis upregulated samples. Conclusions: There rate metastasis cohort. The downregulated androgen EMT pathways suggest enrichment indifference our methodology. Upregulated immune well MSI opportunities investigation. Future directions include more focused vitro vivo actionable targets. 1. Beltran H, et al. Nat Med . 2016;22(3):298-305. doi:10.1038/nm.4045.