Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past eight decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new androgen receptor signaling inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the second generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances toward more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.

中文翻译：

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雄激素受体信号抑制剂：化疗后、化疗前和现在对去势敏感的前列腺癌。

基于 Huggins、Hodges 和其他人的开创性工作，在过去的八十年中，激素疗法已被确定为晚期前列腺癌 (PC) 的有效方法。然而，很快就很明显，通过手术或药物去势进行的雄激素剥夺疗法 (ADT) 无法充分抑制雄激素受体 (AR) 轴，由于雄激素的肾上腺和肿瘤内来源以及其他机制，临床耐药性不可避免地出现。早期通过添加肾上腺靶向药物（氨基鲁米特、酮康唑）或 AR 拮抗剂（氟他胺、比卡鲁胺、尼鲁米特、环丙孕酮）来增强 ADT 的努力未能实现总生存 (OS) 获益，尽管它们确实显示出一些临床活性有限的证据。最近，四种新型雄激素受体信号抑制剂 (ARSIs) 成功进入临床实践。具体来说，CYP17 抑制剂醋酸阿比特龙和第二代 AR 拮抗剂（enzalutamide、apalutamide 和 darolutamide）为 PC 患者带来了 OS 益处，证实了在去势抵抗性 PC 中重新激活 AR 信号的重要性，并验证了该领域提出的重要概念几十年前，但迄今为止仍未得到证实，包括肾上腺靶向治疗和联合雄激素阻断。在过去的十年里，AR 轴定位在更全面的方向上取得了稳步进展。现在的问题是，我们是否已经实现了可能的最大 AR 轴抑制，或者是否仍有改进的空间。这篇评论，