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.
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.
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.
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.
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.
Copyright 2010 Elsevier Ltd. All rights reserved.