Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

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.

Annals of oncology : official journal of the European Society for Medical Oncology. 2020 Feb 07 [Epub ahead of print]

M Alyamani, J Li, M Patel, S Taylor, F Nakamura, M Berk, C Przybycin, E M Posadas, R A Madan, J L Gulley, B Rini, J A Garcia, E A Klein, N Sharifi

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA., Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, USA., Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, USA., Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA., Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA., Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA., Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA; Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA. Electronic address: .