Suppression of gonadal
testosterone synthesis represents the standard first line
therapy for treatment of metastatic
prostate cancer. However, in the majority of patients who develop
castration-resistant
prostate cancer (CRPC), it is possible to detect persistent activation of the
androgen receptor (AR) through
androgens produced in the adrenal gland or within the
tumor itself.
Abiraterone acetate was developed as an irreversible inhibitor of the dual functional
cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and
17,20-lyase.
CYP17 is necessary for production of nongonadal
androgens from
cholesterol. Regulatory approval of
abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with
abiraterone and
prednisone versus
prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by
abiraterone results in accumulation of upstream
mineralocorticoids due to loss of
cortisol-mediated suppression of pituitary
adrenocorticotropic hormone (
ACTH), providing a rationale for development of
CYP17 inhibitors with increased specificity for
17,20-lyase (
orteronel,
galeterone and VT-464) that can potentially be administered without exogenous
corticosteroids. In this article, we review the development of
abiraterone and other
CYP17 inhibitors; recent studies with
abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of
abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to
CYP17 inhibitors leading to clinical trials with
drug combinations designed to prolong
abiraterone benefit or restore
abiraterone activity.