Safety and Efficacy of Oral Testosterone Undecanoate Followed by Enzalutamide as Therapy for Men With Metastatic Castrate Resistant Prostate Cancer

Metastatic prostate cancer is a highly significant disease that claims the lives of approximately 30,000 American men each year. Androgen Deprivation Therapy (ADT) is initially very effective but is never curative as all men eventually develop castrate resistant prostate cancer (CRPC). A major factor driving resistance is the ability of prostate cancer (PCa) cells to adapt to the chronic low androgen conditions by upregulating androgen receptor (AR) activity through overexpression, gene amplification and expression of truncated, transcriptionally active AR variants that lack the ligand-binding domain. Persistent signaling through AR makes CRPC sensitive to more potent inhibition of AR by abiraterone acetate or second generation anti-androgens such as enzalutamide. Yet these therapies have a limited duration of benefit prior to development of resistance, often through further increase in AR levels.

While this marked upregulation of AR can drive resistance, the investigators have demonstrated that it also creates a therapeutic vulnerability to exposure to high levels of androgen. However, the investigators have also found that sustained exposure of CRPC to supraphysiological levels of androgens results in downregulation of AR and acquired resistance to this therapy. Therefore the investigators have developed a therapy called Bipolar Androgen Therapy (BAT) in which testosteronecypionate 400 mg IM is administered every 28 days to result in cycling from supraphysiological (\>1500 ng/dL) to near-castrate levels. The rationale for cycling was that high serum T would kill high AR expressing CRPC while low serum T would prevent adaptation to high T and kill low AR expressing CRPC.

To date the investigators have treated approximately 250 men with BAT across four completed studies in asymptomatic men with CRPC. The key findings have been that BAT: (a) could be safely administered; (b) did not produce symptomatic disease progression; (c) produced sustained PSA and objective responses in approximately 30-40% of patients; (d) re-sensitized and prolonged response of patients to subsequent antiandrogen therapy. While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity and restoring libido and sexual function. BAT also produced favorable effects on body composition by increasing skeletal muscle mass and decreasing subcutaneous and visceral fat. Thus, incorporation of BAT into the treatment paradigm has the potential to improve the quality of life and well-being of PCa patients and minimize the morbidity from the metabolic sequelae produced by androgen ablative therapies.