A real-world clinicogenomic study of androgen receptor mutations and co-mutations in prostate cancer: Clinical implications.
Authors: Emma G. Sturgill, Daniel J. Luckett, Tarun Agrawal, Jordan T. Best, Rikki N. Williams, Manojkumar Bupathi, Mark T. Fleming, Ian D. Schnadig, Vivek Subbiah, David R. Spigel, Howard A. Burris, Andrew Jacob McKenzie, Benjamin Garmezy
Journal: Journal of Clinical Oncology (2025)

73 Background: While most prostate cancer (PCa) patients (pts) initially respond to androgen deprivation therapy, resistance commonly develops, resulting in castration-resistant PCa. In certain patients, androgen receptor ( AR ) mutations permit tumor cells to proliferate despite the absence of circulating androgens. This study leverages real-world clinicogenomic data to investigate the prevalence and clinical implications of AR mutations and co-mutations. Methods: We analyzed 3,753 pt records with PCa who underwent next-generation sequencing (NGS) from January 1, 2014 to October 1, 2024. NGS was ordered by &gt;400 physicians from &gt;180 community-based oncology clinics across the Sarah Cannon Research Institute network, and results were collated with pt medical records in the software platform, Genospace. Pts were stratified into AR -mutated ( AR m; 306 pts), AR -amplified ( AR amp; 231 pts), and AR wild-type ( AR WT; 3,216 pts) cohorts. Pts with multiple primary cancers were excluded. Results: AR mutations were detected in 306 pts (8%), with a higher detection rate in plasma- versus tissue-based NGS (15% vs 2%; p&lt;0.01). AR mutations were more common in older pts, with 68% of AR m pts &gt;70 years old compared to 53% of AR WT pts (p&lt;0.01). The most common AR mutations included L702H (51%, 156 pts), T878A (38%, 115 pts), H875Y (23%, 70 pts) and W742C (8%, 25 pts), and over half of AR m pts reported multiple AR mutations (51%, 156 pts). Several genes were more frequently mutated in AR m versus AR WT pts, including TP53 (43% vs 32%), PTEN (10% vs 6%), BRCA2 (9% vs 4%), RB1 (5% vs 2%), and BRCA1 (4% vs 1%; p&lt;0.01 for all). AR m pts reported a higher frequency of microsatellite instability (MSI) compared to AR WT pts (11% vs 2%; p&lt;0.01). Within the AR m cohort, MSI was more frequently detected by tissue- versus plasma-based NGS (26% vs 7%; p&lt;0.01). Specific AR mutations were enriched in MSI versus microsatellite stable (MSS) pts, including H875Y (50% vs 20%) and V716M (31% vs 2%; p&lt;0.01 for both). Additionally, BRCA1/2 mutations were more common in AR m/MSI pts versus AR m/MSS pts ( BRCA1 : 15% vs 3%; BRCA2 : 35% vs 6%; p&lt;0.01 for both). Pts in both the AR m (3.3 yrs) and AR amp (2.1 yrs) cohorts exhibited shorter overall survival from metastatic staging compared to the AR WT cohort (9.0 yrs; p&lt;0.01 for both). Neither specific AR mutations nor MSI status correlated with survival outcomes. Conclusions: AR mutations are frequently detected by plasma-based NGS in the real-world setting, possibly due to test selection at disease progression and/or sampling of tumor heterogeneity. However, plasma-based NGS may miss other critical alterations, such as MSI status. The high co-occurrence of MSI in AR -mutated PCa suggests potential for combination therapies involving immunotherapy and novel AR degraders. These findings emphasize the need for tissue- and plasma-based genomic profiling to guide therapeutic decisions and optimize treatment strategies for advanced PCa.