ArticleAnnals of oncology : official journal of the European Society for Medical Oncology2020
Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.
Article in Annals of oncology : official journal of the European Society for Medical Oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 25 citations in OpenAlex.
- Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.The oncologist · 2023Trial
- 3beta-HSD1-mediated steroid back-conversion maintains androgen signaling in prostate cancer.Molecular cancer research : MCR · 2026Article
- HSD3B1 links ileal steroid metabolism to bile acid regulation in patients with prostate cancer.The Journal of clinical investigation · 2026Article
- Metabolomic Insights Into Saliva as a Non-Invasive Surrogate for Serum to Enable Community-Based Biomarker Investigation.The Prostate · 2026Article
- Article
- Untargeted metabolomics revealed urinary metabolic pattern for discriminating prostate cancer from benign prostatic hyperplasia in Chinese participants.Frontiers in oncology · 2025Article
- Personalized nanovaccines for treating solid cancer metastases.Journal of hematology & oncology · 2024Review
- Article
- The role of 11-oxygenated androgens in prostate cancer.Endocrine oncology (Bristol, England) · 2023Review
- Glucocorticoid regulation of cancer development and progression.Frontiers in endocrinology · 2023Review
- 5-Hydroxyeicosatetraenoic Acid Controls Androgen Reduction in Diverse Types of Human Epithelial Cells.Endocrinology · 2022Article
- Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer.Journal of the National Cancer Institute · 2022Article
- Article
- Targeting Glucocorticoid Metabolism in Prostate Cancer.Endocrinology · 2021Review
- Genome-wide crosstalk between steroid receptors in breast and prostate cancers.Endocrine-related cancer · 2021Review
- Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes.Scientific reports · 2021Article
- Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation.Science translational medicine · 2021Article
- Hormonal Therapy for Prostate Cancer.Endocrine reviews · 2021Review
- Clinical Actionability of the Genomic Landscape of Metastatic Castration Resistant Prostate Cancer.Cells · 2020Review
- Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2.bioRxiv : the preprint server for biology · 2020Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundEnzalutamide 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
methodsHuman 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.
resultsConcurrent 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.
conclusionEnzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.
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