Androgen receptor activity in biopsy specimens at initial diagnosis of prostate cancer and correlation with outcomes and treatment response.
Authors: Nicole Handa, Mohammed Alshalalfa, Yangyang Hao, Hyunnam Monica Ryu, James A. Proudfoot, Elai Davicioni, Matthew R. Cooperberg, Alejandro Berlin, Paul L. Nguyen, Daniel Eidelberg Spratt, Ridwan Alam, Ashley Ross, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2025)

409 Background: Androgen receptor activity (AR-A) has been described after radical prostatectomy (RP) and metastatic castration-sensitive prostate cancer (mCSPC). In RP specimens low AR-A is associated with basal subtypes, decreased DNA repair and increased immune activity. In mCSPC, low AR-A is associated with poor overall survival (OS) and time to progression to CRPC. However, AR-A has not been well characterized in localized disease at initial diagnosis. Here we sought to assess AR-A signatures in biopsy samples from patients across the prostate cancer risk continuum and assess correlations between AR-A and outcomes. Methods: We analyzed 150,162 biopsy samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, Inc. San Diego, CA). Transcriptome-wide expression data and clinical factors were retrieved from the Decipher GRID (NCT02609269). Patients with low and high AR-A expression as defined by Spratt et al 2019 were compared using Chi-square tests. Clinical and pathologic outcomes for specific cohorts in the overall sample population were analyzed using Cox regression. Results: Overall, 11,752 (7.8%) patients had low AR-A expression. 9.8% of patients &gt; 70 years of age had low AR-A compared to 7.6% of patients &lt;70 (p&lt;0.0001). Low AR-A was enriched in samples with poor prognostic clinical factors such as very high Decipher (p&lt;0.0001), Grade Group (GG) 5 (p&lt;0.0001) and very high NCCN risk (p&lt;0.0001). The same differences were present when looking only at patients with a PSA &lt;4 ng/mL. Like in RP samples, AR-A expression in biopsy samples positively correlated with intact DNA repair and negatively correlated with basal subtypes, PORTOS and immune infiltration scores (all p&lt;0.001). Low AR-A was prognostic of poor clinical outcomes across 4 independent retrospective cohorts. In cohort 1, intermediate risk disease (n=647), low AR-A correlated with adverse pathology at time of RP (p &lt;0.05). In cohort 2, intermediate risk disease treated with radiation therapy (RT) (n=121), low AR-A correlated with biochemical failure (p&lt;0.05). In cohort 3, high risk disease (n=405), low AR-A correlated with decreased OS (p&lt;0.05) in all patients and metastasis (p&lt;0.05) after RT and androgen deprivation therapy (ADT). Finally, in cohort 4, high risk disease treated with RT+ADT (n=100), low AR-A correlated with metastasis (p&lt;0.01). Conclusions: Overall, in a large cohort of biopsy specimens, low AR-A was associated with increased age, very high Decipher score, very high NCCN risk, and GG5 disease. Subpopulation analyses suggest that low AR-A portends a poor prognosis. Given that patients with low AR-A had decreased DNA repair activity and increased PORTOS scores, clinicians should consider post-operative RT and novel clinical trials with PARP inhibitors for these patients.