Abiraterone acetate for castration resistant prostate cancer

Androgen deprivation therapy has been the standard of care in advanced prostate cancer for > 50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.