Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer.
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.
Rutgers Cancer Institute of New Jersey; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Mark N
MN
Stein
Neal
N
Patel
Alexander
A
Bershadskiy
Alisa
A
Sokoloff
Eric A
EA
Singer
D000726:Androgen Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000730:Androstadienes / Q000627:therapeutic use; D000736:Androstenes; D000737:Androstenols / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001823:Body Composition / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002319:Cardiovascular System / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism; D009281:Naphthalenes / Q000627:therapeutic use; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000627:therapeutic use; D014020:Tissue Extracts / Q000627:therapeutic use
C410798:AR protein, human; D000726:Androgen Antagonists; D000730:Androstadienes; D000736:Androstenes; D000737:Androstenols; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008901:Mineralocorticoids; D009281:Naphthalenes; D011944:Receptors, Androgen; D043823:Taxoids; D014020:Tissue Extracts; C511774:sipuleucel-T; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; C571806:orteronel; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene