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.

Findings: 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.

Interpretation: 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.

Funding: 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.

Figure 1

Pharmacokinetics and pharmacodynamics of MDV3100. A, Steady-state serum concentrations by dose level. B. Sagittal and coronal views of PET scans at baseline and 4 weeks post-treatment. The sagittal and coronal images 1 hour after FDHT administration at baseline and 4 weeks after beginning MV3100 therapy show a reduction in FDHT accumulation in tumor within the vertebrae, in comparison to the cardiac and aortic blood pool, where FDHT metabolites circulate bound to serum proteins. C. Percentage change in FDHT SUV_max average from baseline to 4 weeks by dosage. At baseline, all 22 patients had at least 1 FDHT-avid lesion that could serve as an index lesion, with the number of index lesions per patient as follows: 5 index lesions, 17 patients; 3 index lesions, 3 patients; 1 index lesion, 2 patients. At baseline the median FDHT SUV_max average was 7.81. Quantitatively, all 22 patients showed a clear-cut reduction of SUV, with a greater reduction at higher doses. This is evidence that MDV3100 is binding its target, ie the androgen receptor, and that changes are persistent with therapy.

Figure 2

Waterfall plot of percent change in PSA from baseline. A, maximal decline from baseline; B, decline at 12 weeks from baseline (red lines show patients who discontinued treatment before 12 weeks for an adverse event or disease progression); C, 12-week declines by dose level.

Figure 3

Time to progression. A, PSA progression using the protocol definition of a 25% or greater rise from baseline; B, PSA progression using the PCWG criterion of a 25% or greater rise from nadir; C, Imaging.