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

Abstract

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.

• Authors: 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
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 31 Issue 3 Pg. 369-376 (03 2020) ISSN: 1569-8041 [Electronic] England
• PMID: 32057540 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Glucocorticoids
• Receptors, Androgen

Topics

• Chromatography, Liquid
• Glucocorticoids
• Humans
• Kidney
• Male
• Prostatic Neoplasms
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Receptors, Androgen (genetics)
• Tandem Mass Spectrometry