Re: Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms that Castration- Resistant Prostrate Cancer Commonly Remains Hor-

Expert’s summary: Abiraterone acetate, a small molecule inhibitor of cytochrome P17 (CYP17), inhibits 17 alpha-hydroxylase and C17, 20 lyase, both key enzymes in androgen synthesis. It was tested in 21 chemotherapy-naı̈ve men with metastatic prostate cancer that was resistant to multiple hormone therapies. Once-daily oral abiraterone acetatewas given at doses of 250 mg, 500 mg, 750 mg, 1000 mg, and 2000 mg and resulted in dramatic declines in serum testosterone, estradiol, dehydroepiandrosterone (DHEA), and androstenedione. Such declines were paralleled by rapid declines in prostate-specific antigen (PSA) of >30%, 50%, and 90% in 14 (66%), 12 (57%), and 6 (29%) patients, respectively. Radiographic regression of disease, normalization of lactate dehydrogenase (LDH), and reduced pain from prostate cancer with reduced analgesic use were also documented. Even when PSA and radiographic progression occurred on drug, hormone levels did not rise. Abiraterone was well tolerated, although secondary mineralocorticoid excess upstream of the CYP17 blockade commonly induced hypertension, hypokalemia, and edema. Dexamethasone 0.5 mg/d suppressed the mineralocorticoid excess symptoms. The 1000 mg/d dose cohort was expanded to nine patients, and that dose was the recommended for phase 2 (combined with glucocorticoids) because there was no further increase in upstream steroids at doses >750 mg/d. The authors concluded that CYP17 blockade by abiraterone was safe and had significant antitumor activity, confirming the hypothesis that castration-resistant prostate cancer remains dependent on androgen receptor signaling.