title: A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases.
abstract: OBJECTIVE
  Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed.
  
  
  RESULTS
  At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm.
  
  
  CONCLUSIONS
  There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.
authors.affiliation: Center for Cancer Research, National Cancer Institute, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. wdfigg@helix.nih.gov
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Yinong
authors.initials: Y
authors.lastname: Liu
authors.forename: Philip
authors.initials: P
authors.lastname: Arlen
authors.forename: James
authors.initials: J
authors.lastname: Gulley
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Michael C
authors.initials: MC
authors.lastname: Cox
authors.forename: Suoping
authors.initials: S
authors.lastname: Zhai
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.forename: Allyson
authors.initials: A
authors.lastname: Parr
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yang
authors.forename: Clara C
authors.initials: CC
authors.lastname: Chen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jones
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
mesh_terms: D000368:Aged; D019386:Alendronate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D004359:Drug Therapy, Combination; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D007654:Ketoconazole; D019386:Alendronate