title: Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5alpha-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d).
  
  
  RESULTS
  Prostate-specific antigen response rate (> or =50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse.
  
  
  CONCLUSIONS
  The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.
authors.affiliation: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Yoo-Joung
authors.initials: YJ
authors.lastname: Ko
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Duggan
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Tu
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
authors.forename: Roger
authors.initials: R
authors.lastname: Rittmaster
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism*; D001378:Azasteroids / Q000008:administration & dosage*; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism; D000068538:Dutasteride; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage*; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000728:Androgens; D001378:Azasteroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase; D000068538:Dutasteride; D007654:Ketoconazole; D006854:Hydrocortisone