Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq: patient biopsies]

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. 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) 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 high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation The COMbination of BAT and Nivolumab (COMBAT-CRPC; NCT03554317) clinical trial was a single-arm, multicenter, open-label phase II study of BAT in combination with the anti-PD1 agent nivolumab for patients with CRPC that had progressed on at least 1 novel AR-target therapy. Patients were required to have soft tissue metastases amenable to biopsy to participate. Patients were treated with 3 cycles of BAT — testosterone cypionate 400 mg intramuscular every 28 days — followed by concurrent BAT and 480 mg nivolumab intravenously every 28 days until progression. Paired core needle tumor biopsies were performed prior to treatment and after 3 cycles of BAT monotherapy. Response was assessed with PSA at each cycle, and chest, abdomen, and pelvis CT scans and technetium-99 bone scan every 3 cycles. 15 paired biopsies were analyzed via Bulk RNAseq (30 samples total). >>> Submitter declares that the raw data will be deposited in dbGaP due to patient privacy concerns <<<