Houston Methodist West Hospital, Houston, TX, USA.
Houston Methodist Hospital, Houston, TX, USA.
Am J Health Syst Pharm. 2022 Jul 22;79(15):1224-1235. doi: 10.1093/ajhp/zxac105.
This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC).
PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects.
Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.
本文总结了目前已获得监管部门批准用于治疗晚期前列腺腺癌（以下简称前列腺癌，PC）的雄激素受体（AR）靶向治疗方法。
PC 是一种雄激素依赖性恶性肿瘤，其配体包括睾酮和二氢睾酮与 AR 结合，启动雄激素-AR 复合物转位到细胞核，随后 AR 介导靶基因的转录。雄激素剥夺疗法（ADT），包括促性腺激素释放激素（GnRH）激动剂联合或不联合 AR 拮抗剂（抗雄激素）、GnRH 拮抗剂或双侧睾丸切除术，构成了转移性去势敏感 PC 和/或去势抵抗性 PC（CRPC）患者治疗的基础。ADT 也是前列腺切除术和/或放疗后高危、早期 PC 的一种选择。尽管抑制性腺和/或肾上腺雄激素通常对初始治疗非常有效，但最终仍会产生耐药性，导致 CRPC，其特征为 AR 信号通路的重新激活、AR 基因过表达以及 AR 配体结合域的突变等机制，导致疾病进展，增加症状负担并最终导致死亡。然而，CRPC 患者的疾病仍然依赖于雄激素信号，这些患者继续接受 ADT 以维持去势水平的血清睾酮。在这种情况下，通常会在 ADT 中添加针对 AR 的新型激素治疗药物，例如直接靶向 AR 的药物（如 AR 拮抗剂）。靶向 AR 信号通路导致第二代 AR 拮抗剂的开发，其中包括恩杂鲁胺、阿帕鲁胺和达罗他胺。与第一代药物相比，这些药物没有部分激动作用，对 AR 的亲和力更高，据推测可改善 CRPC 患者的生存结局。最后，ADT（包括第二代 AR 拮抗剂）的出现，为治疗相关不良反应的支持性护理带来了新的机遇。
在晚期 PC 患者中靶向 AR 信号通路方面取得了重大进展。需要进一步的研究来确定最佳治疗方案，以最大限度地提高治疗效果。减轻治疗相关不良反应为推进临床药学实践提供了新的机会。
