Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Ann Oncol. 2020 Mar;31(3):369-376. doi: 10.1016/j.annonc.2019.12.002. Epub 2020 Feb 11.
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.
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.
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.
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.
恩扎卢胺和阿帕鲁胺是用于转移性和非转移性前列腺癌的强效下一代雄激素受体（AR）拮抗剂。深度 AR 抑制的代谢、激素和免疫效应尚不清楚。我们假设恩扎卢胺和阿帕鲁胺抑制 11β-羟类固醇脱氢酶-2（11β-HSD2），后者通常将皮质醇转化为皮质酮，导致皮质醇浓度升高、活性与非活性糖皮质激素的比例增加，并且可能对免疫治疗的反应不理想。治疗期间糖皮质激素的变化可能作为活性糖皮质激素暴露和由此产生的不良后果的指标。
用人肾组织染色检测 AR 和 11β-HSD2 表达。对三项试验[新辅助阿帕鲁胺加亮丙瑞林、恩扎卢胺±PROSTVAC（重组痘病毒前列腺特异性抗原疫苗）治疗转移性去势抵抗性前列腺癌（CRPC）和恩扎卢胺±PROSTVAC 治疗非转移性去势敏感性前列腺癌]的患者进行皮质醇及其代谢物的液相色谱-质谱（LC-MS/MS）分析。对恩扎卢胺±PROSTVAC 治疗转移性 CRPC 研究中皮质醇变化高于和低于中位数的患者进行无进展生存期的测定。
只有在男性的肾脏中才会同时出现 AR 和 11β-HSD2 表达。在所有三项试验中，AR 拮抗剂治疗均会导致皮质醇浓度、皮质醇/皮质酮比值和四氢皮质醇/四氢皮质酮比值的统计学显著升高。在恩扎卢胺±PROSTVAC 治疗转移性 CRPC 的试验中，恩扎卢胺组中高皮质醇/皮质酮比值与显著改善的无进展生存期相关。然而，在恩扎卢胺+PROSTVAC 组中观察到相反的趋势。
恩扎卢胺和阿帕鲁胺治疗会切换肾脏 11β-HSD2，并显著增加生物活性糖皮质激素的指标和暴露量，这与临床结局相关。
