HE-3235

17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.

Prostate cancer is a common cancer in men; for metastatic disease, it has a 5-year survival rate of 30%. No FDA-approved therapy for castrate-resistant prostate cancer (CRPC) known to improve survival was available until 2004, when based on a significant survival benefit over mitoxantrone, docetaxel in combination with prednisone was approved. In combination with prednisone, cabazitaxel, which was approved in the United States in 2010, is indicated for patients with metastatic CRPC previously treated with a docetaxel-containing regimen. This case report describes the treatment of a man 58 years of age who was diagnosed with advanced prostate cancer in 2006. He was initially managed with radical prostatectomy followed by androgen deprivation therapy, but a rising prostate-specific antigen (PSA) level led to enrollment in a clinical trial of HE3235 for 6 months. Subsequently, with progression of disease, he was treated with docetaxel for 4 months and then palliative radiation therapy. Cabazitaxel was initiated in October 2010; his condition stabilized within weeks, and he experienced a progressive decline in his PSA level from a peak of 5,424 ng/ml. Continued treatment with cabazitaxel resulted in his being weaned off pain medications and resuming his normal activities. After 16 cycles of cabazitaxel, his PSA declined to 994 ng/ml as of January 2012. He tolerated the cabazitaxel well and occasionally received myeloid growth factors for treatment of neutropenia; otherwise, he experienced only mild diarrhea. This response to cabazitaxel is notable, particularly in light of prior failure of multiple therapies.