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-naıve men with metastatic prostate cancer that was resistant to multiple hormone therapies. Once-daily oral abiraterone acetate was given at doses of 250 mg, 500 mg, 750mg, 1000mg, and 2000mg 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.

Expert’s comments: This drug is first in class and is also the first new hormonally active agent to be developed for prostate cancer since the steroidal antiandrogens [1]. It was developed in the 1990 s at the Royal Marsden Hospital but was not pursued clinically until the rights to it were purchased recently by Cougar Pharmaceuticals. It is fitting that this study was conducted at the Royal Marsden Hospital and showed dramatic endocrinologic and anticancer effects in substantial numbers of patients [2]. Dexamethasone was given to all patients after resistance to abiraterone occurred [3]. In some patients, further regression of disease was observed, suggesting that nonandrogenic steroids were activating the androgen receptor pathway. All doses tested suppressed testosterone to virtually undetectable levels within 8 d. The 2000 mg/d dose was tested, but two of three patients had hypertension and hypokalemia. The 1000 mg/d dose was thus selected as the recommended phase 2 dose. Aside from PSA responses in 57% of patients, the drug also caused bone pain resolution in 8 of 11 patients, declines in LDH levels, and radiographic regression of lymphadenopathy and soft-tissue metastases.