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 11b-hydroxysteroid dehydrogenase-2 (11b-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 11b-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide AE PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide AE PROSTVAC for nonmetastatic 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 AE PROSTVAC for those with glucocorticoid changes above and below the median. Results: Concurrent AR and 11b-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 AE PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide þ PROSTVAC arm, the opposite trend was observed. Conclusion: Enzalutamide and apalutamide treatment toggles renal 11b-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Clinical Characteristics of Metastatic Prostate Cancer Patients Infected with COVID-19 in South Italy

“…Patient 2 had metastatic CRPC, and so he was treated with an LHRH agonist and enzalutamide. Enzalutamide is an androgen receptor antagonist that suppresses 11β-hydroxysteroid dehydrogenase-2 and increases cortisol levels [12]. This leads to an immunosuppressive effect and a negative outcome in the presence of infection.…”

Genome-wide crosstalk between steroid receptors in breast and prostate cancers

“…4D ), which together with the increased amount of GR, leads to a systemic activation of glucocorticoid signaling and antiandrogen resistance. Furthermore, this is not restricted to tumor tissue, as patients treated with ENZ show a systemic rise in cortisol levels ( Alyamani et al 2020 ).…”

Clinical Actionability of the Genomic Landscape of Metastatic Castration Resistant Prostate Cancer

“…GR antagonists were found to be beneficial as adjuvant treatment to ARSI in preclinical models, as the expression of GR and AR seemed to be inversely correlated [ 47 ]. Androgens and glucocorticoids are known to affect each other’s signaling pathways, which suggests both pathways should be targeted in order to be effective [ 48 ]. In different clinical mCRPC treatment regiments (chemotherapeutics and abiraterone) glucocorticoids are coadministered to diminish side effects, possibly stimulating GR upregulated tumors to progress [ 47 ].…”