Resistance to castrating therapy and androgen deprivation therapy in prostate cancer is due in part to adaptive upregulation of androgen receptor levels by castration-resistant prostate cancer cells in the setting of prolonged exposure to a low-testosterone environment. In a study reported in Science Translational Medicine, Schweizer and colleagues investigated whether such androgen receptor overexpression might be exploited in castration-resistant prostate cancer by alternating between exposure to supraphysiologic testosterone levels, to promote castration-resistant prostate cancer cell death, and near-castrate testosterone levels, an approach termed ‘bipolar’ androgen therapy.
In a pilot study, 16 asymptomatic patients with a low/moderate metastatic burden received testosterone cypionate (400 mg intramuscularly, day 1 of 28-day cycle) and etoposide (100 mg, days 1–14). Patients with declining prostate-specific antigen levels after 3 cycles continued on intermittent testosterone monotherapy, with castrating therapy being continued to suppress endogenous testosterone. Bipolar androgen therapy was well tolerated and resulted in prostate-specific antigen response in half of the patients and radiographic response in half. All patients eventually had prostate-specific antigen progression, but four remained on treatment for at least 1 year. Each of 10 evaluable patients had prostate-specific antigen reduction in response to androgen-ablative therapies after bipolar androgen therapy, suggesting that this approach may restore sensitivity to androgen-deprivation therapy.
The investigators concluded: “[Bipolar androgen therapy] shows promise as treatment for [castration-resistant prostate cancer] and should be further evaluated in larger trials.” ■
Schweizer MT, et al. Sci Transl Med 7:269ra2, 2015.