title: Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations.
abstract: Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Daan Joost
authors.initials: DJ
authors.lastname: De Maeseneer
authors.affiliation: Department of Urology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Charles
authors.initials: C
authors.lastname: Van Praet
authors.affiliation: Department of Urology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Lumen
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium. Electronic address: Sylvie.Rottey@UGent.be.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rottey
mesh_terms: D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000736:Androstenes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D059002:Androgen Receptor Antagonists; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone
keywords: Abiraterone; Antiandrogens; Castration resistant; Drug resistance; Enzalutamide; Prostatic neoplasms