Bastos Diogo A, Antonarakis Emmanuel S
Department of Oncology, Hospital Sirio-Libanes, Sao Paulo, Brazil.
Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Drug Des Devel Ther. 2016 Jul 15;10:2289-97. doi: 10.2147/DDDT.S93941. eCollection 2016.
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease.
最近，转移性去势抵抗性前列腺癌的治疗取得了重大进展，使用包括新一代雄激素受体（AR）靶向药物阿比特龙和恩杂鲁胺在内的几种新药，患者的生活质量和生存率得到了显著改善。然而，几乎所有患者最终都会对这些疗法产生耐药，大多数患者最终会死于难治性转移性疾病。最近，已经发现了几种对AR靶向疗法的耐药机制，包括AR剪接变体7（AR-V7），它是一种不依赖配体的组成型活性AR形式，与阿比特龙和恩杂鲁胺的不良预后相关。加列酮是一种具有三种作用模式（CYP17裂解酶抑制、AR拮抗和AR降解）的强效抗雄激素药物，是一种正在临床开发的新型药物，可能同时靶向全长AR和异常AR，包括AR-V7。在本手稿中，我们将首先讨论加列酮的生物学作用机制，然后回顾加列酮在转移性去势抵抗性前列腺癌患者中的I期和II期临床研究的安全性和有效性数据。加列酮（与恩杂鲁胺相比）在AR-V7阳性患者中的III期研究目前正在进行，这是该疾病中首个使用生物标志物选择设计的关键试验。
