Characterizing the clinical and genomic features of androgen indifferent prostate cancer.
Authors: Jack Masur, Krzysztof Wierbilowicz, Aakrosh Ratan, Adanma Ayanambakkam, Michelle L. Churchman, 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
Journal: Journal of Clinical Oncology (2025)

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