title: Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer.
abstract: BACKGROUND
  Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer.
  
  
  OBJECTIVE
  Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis.
  
  
  METHODS
  We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily.
  
  
  RESULTS
  Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydroxyprogesterone downstream of 17α-hydroxylase remained unchanged. However, 3α5α-17-hydroxypregnanolone, which can be converted via the backdoor pathway toward 5α-dihydrotestosterone, increased significantly and correlated with levels of the major 5α-dihydrotestosterone metabolite androsterone. In contrast, urinary metabolites of 11-deoxycortisol and active glucocorticoids declined significantly. Addition of dexamethasone to abiraterone acetate significantly suppressed ACTH and endogenous steroids, including 3α5α-17-hydroxypregnanolone.
  
  
  CONCLUSIONS
  CYP17A1 inhibition with abiraterone acetate is characterized by significant suppression of androgen and cortisol synthesis. The latter is associated with a rise in ACTH that causes raised mineralocorticoids, leading to side effects and incomplete 17α-hydroxylase inhibition. Concomitant inhibition of 17,20-lyase results in diversion of 17-hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway. Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis.
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey SM2 5PT, UK. Gerhardt.attard@icr.ac.uk
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
authors.forename: Alison H M
authors.initials: AH
authors.lastname: Reid
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.forename: Amy Mulick
authors.initials: AM
authors.lastname: Cassidy
authors.forename: Emilda
authors.initials: E
authors.lastname: Thompson
authors.forename: Nikhil Babu
authors.initials: NB
authors.lastname: Oommen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Folkerd
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000736:Androstenes; D000737:Androstenols; D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D054316:Biomarkers, Pharmacological; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone