The evolving paradigm of second-line hormonal therapy options for castration-resistant prostate cancer.
OBJECTIVE
The review examines recent advances in second-line hormonal therapy for the treatment of castrate-resistant prostate cancer (CRPC).


RESULTS
Recent data highlight the continued importance of androgen signaling in CRPC. These findings have spurred the development of novel inhibitors of adrenal and intra-tumoral androgen synthesis and novel androgen signaling inhibitors with activity in CRPC. In the past year abiraterone acetate, a CYP17 (17α-hydroxylase/17, 20 lyase) inhibitor, received US FDA approval for use in the treatment of metastatic CRPC in patients previously treated with docetaxel. Additionally, the novel androgen signaling inhibitor MDV3100 has been reported to confer a survival advantage compared to placebo in the same patient population. Here we review the scientific rationale for targeting androgen signaling in CRPC and the recent pivotal trials that support the use of novel second-line hormonal therapies. Additionally, we summarize ongoing preclinical and clinical efforts to ascertain and overcome mechanisms of resistance.


CONCLUSIONS
Novel inhibitors of extra-gonadal androgen synthesis and androgen receptor function demonstrate the continued importance of androgen signaling in CRPC. These agents have improved clinical outcomes for patients with metastatic CRPC.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Kevin D
KD
Courtney
Mary-Ellen
ME
Taplin
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000728:Androgens / Q000096:biosynthesis / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides; D001562:Benzimidazoles / Q000494:pharmacology; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013867:Thiohydantoins / Q000494:pharmacology
D000726:Androgen Antagonists; D000728:Androgens; D000730:Androstadienes; D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D001549:Benzamides; D001562:Benzimidazoles; D009570:Nitriles; D011944:Receptors, Androgen; D013867:Thiohydantoins; C572045:apalutamide; D010669:Phenylthiohydantoin; C540278:enzalutamide; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene