Antitumour activity of MDV3100 in a phase 1-2 study of advanced prostate cancer
Tuesday, 4 May 2010- MDV3100 is a novel oral androgen receptor (AR) antagonist. It was designed to bind the AR with greater affinity and prevent nuclear translocation of AR with greater efficiency than bicalutamide.
"Unlike bicalutamide, MDV3100 blocks DNA binding of AR, causing tumour cell apoptosis, and has no known agonist activity when AR is overexpressed. Antitumour activity of MDV3100 in a Phase 1-2 trial of castration-resistant prostate cancer (CRPC) was assessed by PSA, soft tissue and osseous disease and circulating tumour cells (CTC)," wrote lead author H. I. Scher who submitted an abstract on MDV3100 for the 25th Anniversary EAU Congress held in Barcelona.
Patients with progressive CRPC were enrolled in sequential cohorts of 3-6 patients at 30, 60, 150, 240, 360, 480, and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses of 60 mg/day and above to include approximately 24 additional patients per cohort.
A total of 140 patients were enrolled. PSA declines (>50% from baseline) occurred in 62% (40/65) of chemotherapy-naïve (naïve) and 51% (38/75) of post-chemotherapy patients. 25 naive and 34 post-chemotherapy patients had evaluable soft tissue disease at baseline. Partial responses were seen in 36% (9/25) of naïve and 12% (4/34) of post-chemotherapy patients.
Stable disease was observed in 44% (11/25) of naïve and 53% (18/34) of post-chemotherapy patients. For patients with baseline bone lesions, there was evidence of radiographic stabilization in 63% (26/41) of naïve and 51% (35/68) of post-chemotherapy patients. Median time to PSA progression was not reached in naïve pts and was 186 days for post-chemotherapy patients.
Median time to radiographic progression was not reached in naïve pts and was 201 days in post-chemotherapy patients. CTC counts on 60 of 65 naïve pts showed 91% (40/44) with favourable (<5) counts pretreatment maintained favourable post-treatment counts, while 75% (12/16) converted from unfavourable to favourable post-treatment. CTC counts on 68 of 75 post-chemotherapy patients showed favourable retention for 91% (30/33) and unfavourable to favourable conversion for 37% (13/35).
MDV3100 was generally well-tolerated. Fatigue was the most frequently reported adverse event. Only one subject discontinued treatment due to fatigue which coincided with disease progression. There were 2 witnessed seizures (1 each at 600 and 360 mg/day); both patients were taking concomitant medications that could cause seizures. Maximum tolerated dose of 240 mg/day was selected.
"MDV3100 is a promising candidate for the treatment of prostate cancer as assessed by PSA, imaging, and CTC in this Phase 1-2 study. A Phase 3 placebo-controlled survival trial in post-docetaxel CRPC patients has begun," the researchers said.
Source: H. I. Scher, et al., "Antitumour activity of MDV3100 in a phase 1-2 study of advanced prostate cancer," Abstract 905, Poster session; 25th Anniversary EAU Congress, Barcelona, Spain, April 16 to 20, 2010.
