BACKGROUND Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. PATIENTS AND METHODS Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. RESULTS Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. CONCLUSION Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

中文翻译：

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前列腺癌中的深部雄激素受体抑制利用全身性糖皮质激素暴露的性双态肾表达。

背景技术恩杂鲁胺和阿帕鲁酰胺是用于转移性和非转移性前列腺癌的有效的下一代雄激素受体（AR）拮抗剂。深度抑制AR的代谢，激素和免疫学作用尚不清楚。我们假设enzalutamide和apalutamide抑制11β-羟类固醇脱氢酶2（11β-HSD2），该酶通常将皮质醇转化为可的松，导致皮质醇浓度升高，活性与非活性糖皮质激素比率增加，并且可能对免疫疗法的反应欠佳。治疗中糖皮质激素的变化可能是主动暴露糖皮质激素和由此产生的不良后果的指标。患者和方法对人肾组织的AR和11β-HSD2表达进行染色。三项试验中的患者[新辅助药物阿帕鲁胺加亮丙瑞林，使用液相色谱-质谱联用分析了针对转移性去势抵抗性前列腺癌（CRPC）的enzalutamide±PROSTVAC（重组痘病毒前列腺特异性抗原疫苗）和针对非转移性去势敏感性前列腺癌的enzalutamide±PROSTVAC []。 LC-MS / MS）。enzalutamide±PROSTVAC的转移性CRPC研究确定了糖皮质激素变化高于中位数或低于中位数的患者的无进展生存期。结果并发的AR和11β-HSD2表达仅在男性肾脏中发生。在所有三个试验中，使用AR拮抗剂治疗时，皮质醇浓度，皮质醇/可的松比率和四氢皮质醇/四氢可的松比率在统计学上均显着上升。在恩杂鲁胺±PROSTVAC用于转移性CRPC的试验中，恩杂鲁胺组的皮质醇/可的松比例高与无进展生存期显着改善有关。然而，在enzalutamide + PROSTVAC组中，观察到相反的趋势。结论Enzalutamide和apalutamide治疗可触发肾脏11β-HSD2并显着增加生物活性糖皮质激素的指标并使其暴露，这与临床结果有关。