Bipolar androgen therapy in castration-resistant prostate cancer: Biological rationale, clinical evidence, and future directions

Androgen deprivation therapy remains the cornerstone of systemic treatment for advanced prostate cancer. However, progression to castration-resistant prostate cancer (CRPC) is almost inevitable. Supraphysiological androgen exposure can suppress tumor growth in selected biological contexts, a phenomenon termed the "testosterone paradox." Bipolar androgen therapy (BAT), which rapidly cycles between supraphysiological and near-castrate testosterone levels, has emerged as a novel strategy. This narrative review summarizes contemporary biological insights, clinical evidence, and evolving investigational treatment strategies for BAT in CRPC. A structured narrative literature search of Ovid MEDLINE and Embase (January 2009 to August 2025) was conducted. Chronic androgen suppression promotes adaptive androgen receptor (AR) upregulation, creating a potential vulnerability to supraphysiological androgen exposure through multiple mechanisms reviewed in this study. Clinically, BAT has been evaluated in multiple phase I-II studies involving more than 250 men with CRPC. In selected asymptomatic patients enrolled in early-phase studies, BAT demonstrated feasibility and manageable toxicity, with prostate-specific antigen and radiographic responses observed in approximately 25% to 30% of patients. To date, the most consistent clinical signal has been the restoration of sensitivity to subsequent AR pathway inhibition, along with improvements in selected health-related quality-of-life domains. Combination strategies involving AR inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, immunotherapy, and other targeted agents are under active investigation, supported by emerging biomarker-driven hypotheses. International guidelines currently classify BAT as investigational, because of the absence of phase III survival data. Bipolar androgen therapy challenges the conventional androgen suppression paradigms in CRPC and remains an investigational therapeutic strategy for CRPC.