The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications

The discovery of the benefits of castration for prostate cancer treatment in 1941 led to androgen deprivation therapy, which remains a mainstay of the treatment of men with advanced prostate cancer. However, as early as this original publication, the inevitable development of castration-resistant prostate cancer was recognized. Resistance first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of the androgen receptor axis. Evaluation of clinical specimens demonstrates that castration-resistant prostate cancer cells remain addicted to androgen signalling and adapt to chronic low-testosterone states. Paradoxically, results of several studies have suggested that treatment with supraphysiological levels of testosterone can retard prostate cancer growth. Insights from these studies have been used to investigate administration of supraphysiological testosterone to patients with prostate cancer for clinical benefits, a strategy that is termed bipolar androgen therapy (BAT). BAT involves rapid cycling from supraphysiological back to near-castration testosterone levels over a 4-week cycle. Understanding how BAT works at the molecular and cellular levels might help to rationalize combining BAT with other agents to achieve increased efficacy and tumour responses.