title: Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.
  
  
  METHODS
  We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.
  
  
  RESULTS
  The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.
  
  
  CONCLUSIONS
  High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
authors: Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, Maryland 21231-1000, USA. eantona1@jhmi.edu
authors: Emmanuel S
authors: ES
authors: Antonarakis
authors: Elisabeth I
authors: EI
authors: Heath
authors: David C
authors: DC
authors: Smith
authors: Dana
authors: D
authors: Rathkopf
authors: Amanda L
authors: AL
authors: Blackford
authors: Daniel C
authors: DC
authors: Danila
authors: Serina
authors: S
authors: King
authors: Anja
authors: A
authors: Frost
authors: A Seun
authors: AS
authors: Ajiboye
authors: Ming
authors: M
authors: Zhao
authors: Janet
authors: J
authors: Mendonca
authors: Sushant K
authors: SK
authors: Kachhap
authors: Michelle A
authors: MA
authors: Rudek
authors: Michael A
authors: MA
authors: Carducci
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017964:Itraconazole