Development of abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase inhibitor as a secondary hormonal therapy in prostate cancer

Although androgen deprivation therapy is widely accepted as the standard approach to patients with advanced prostate cancer, most patients eventually develop progressive disease despite castrate levels of testosterone. Despite its name, castration resistant prostate cancer (CRPC) is nonetheless dependent on continued activation of the androgen receptor via various signaling pathways. New secondary hormonal therapies seek to prolong suppression of the AR and thus delay the development of truly hormone “refractory” prostate cancer. Adrenal androgen synthesis represents one potential mechanism of continued AR-mediated growth in CRPC, and thus a potential target for therapy. Abiraterone acetate is an orally available small molecule that specifically inhibits the 17-alpha hydroxylase and C17,20-lyase enzymes within the adrenal steroid synthetic pathway. Preliminary data from phase I dose escalation trials suggest that PSA declines occur in a large proportion of patients and that the toxicity profile is acceptable. If ultimately proven to be efficacious in phase II/III trials, abiraterone acetate would represent the first agent mechanistically developed for the purpose of adrenal androgen suppression in prostate cancer.