title: Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.
abstract: OBJECTIVE
  Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued.
  
  
  METHODS
  Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.
  
  
  RESULTS
  Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension, hypokalemia, and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen >or= 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to >or= 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented.
  
  
  CONCLUSIONS
  CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
authors.affiliation: Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
authors.forename: Alison H M
authors.initials: AH
authors.lastname: Reid
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Sarah
authors.initials: S
authors.lastname: Settatree
authors.forename: Mary
authors.initials: M
authors.lastname: Barrett
authors.forename: Christopher
authors.initials: C
authors.lastname: Parker
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Folkerd
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.forename: David
authors.initials: D
authors.lastname: Dearnaley
authors.forename: Gloria
authors.initials: G
authors.lastname: Lee
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002369:Castration; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000736:Androstenes; D000737:Androstenols; C089740:abiraterone