title: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.
abstract: BACKGROUND
  MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease.
  
  
  METHODS
  This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718.
  
  
  RESULTS
  We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction.
  
  
  CONCLUSIONS
  We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease.
  
  
  BACKGROUND
  Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. scherh@mskcc.org
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Aseem
authors.initials: A
authors.lastname: Anand
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Dana
authors.initials: D
authors.lastname: Rathkopf
authors.forename: Julia
authors.initials: J
authors.lastname: Shelkey
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
authors.forename: Joshi
authors.initials: J
authors.lastname: Alumkal
authors.forename: David
authors.initials: D
authors.lastname: Hung
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hirmand
authors.forename: Lynn
authors.initials: L
authors.lastname: Seely
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Danila
authors.forename: John
authors.initials: J
authors.lastname: Humm
authors.forename: Steve
authors.initials: S
authors.lastname: Larson
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000556:secondary / Q000601:surgery; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide
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