Androgenic effects of 11-oxyandrogens in castration-resistant prostate cancer

Adrenal-derived 11-oxygenated androgens (11-oxyandrogens) emerged as potential key contributors to prostate cancer (PCa) progression by activating the androgen receptor (AR). This study investigates their clinical and mechanistic role in metastatic castration-resistant prostate cancer (mCRPC) patients initiating AR pathway inhibitors (ARPI). In a pilot study of 35 mCRPC patients initiating ARPI, serum steroids were quantified via mass spectrometry and correlated with survival. Functional assays assessed the proliferative effects of 11-oxyandrogens on CRPC cells and their inhibition by enzalutamide, supported by transcriptomic and proteomic profiling. 11-ketotestosterone (11KT) and its hydroxylated derivative, 11-hydroxytestosterone (11OHT) are the predominant potent androgens, accounting for 81% of circulating androgens. Higher baseline levels of 11KT, 11OHT, the abundant precursor 11β-hydroxyandrostenedione (11OHA4), and the downstream metabolite 11-hydroxyandrosterone (11OHAST) are linked to prolonged progression-free survival (PFS) (HR: 0.56–0.69; P < 0.05), suggesting an enhanced treatment response. 11KT and 11OHT promoted AR-driven proliferation of CRPC cells and gene expression, which was reversed by AR antagonism, suggesting they are primarily AR-mediated. Additionally, 11-oxyandrogens display distinct effects, including the activation of AR-independent pathways. 11-oxyandrogens are potent AR activators in mCRPC, with evidence suggesting they may exert distinct biological effects compared to canonical androgens. Their association with longer PFS and improved response to ARPI may reflect a more hormonally active tumor environment, potentially indicative of tumors with higher AR dependency and responsiveness to therapy. Their profiling may help predict ARPI response, warranting further investigation.