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

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

doi:10.1016/j.annonc.2019.12.002

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

Ann Oncol. 2020 Mar;31(3):369-376. doi: 10.1016/j.annonc.2019.12.002. Epub 2020 Feb 11.

Authors

M Alyamani¹, J Li², M Patel¹, S Taylor¹, F Nakamura¹, M Berk¹, C Przybycin³, E M Posadas⁴, R A Madan⁵, J L Gulley⁵, B Rini⁶, J A Garcia⁶, E A Klein⁷, N Sharifi⁸

Affiliations

¹ Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
² Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
³ Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, USA.
⁴ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
⁵ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA.
⁶ Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA.
⁷ Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA.
⁸ 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: sharifn@ccf.org.

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.

Keywords: androgens; apalutamide; enzalutamide; glucocorticoids; hormonal therapy; prostate cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Glucocorticoids
Receptors, Androgen

Abstract

Publication types

MeSH terms

Substances

Grants and funding