Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer [1–5]. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) abundance and activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.