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| |  MDV3100 Demonstrates Antitumour Activity in Castration-Resistant Prostate Cancer: EORTC-NCI-AACR By Chris Berrie GENEVA -- October 23, 2008 -- The novel small-molecule androgen-receptor antagonist MDV3100 is generally well tolerated, and shows encouraging antitumour activity in patients with castration-resistant prostate cancer (CRPC). An early, ongoing study on MDV3100 was presented here at the 20th International Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR). Overexpression of the androgen receptor contributes to progression of CRPC, noted Mohammad Hirmand, MD, Study Medical Monitor, Medivation, San Francisco, California, speaking on behalf of the Prostate Cancer Clinical Trials Consortium. In his presentation on October 22, Dr. Hirmand commented that "[MDV3100] is different from other androgen-receptor antagonists in the fact that it not only blocks the androgen receptor, but also prevents its nuclear translocation and DNA binding." "Currently available agents in the setting of androgen-receptor overexpression actually act as agonists, rather than antagonists, so they actually make the disease worse, while this compound has no known agonist activity," Dr. Hirmand explained. This study was designed to determine the safety, pharmacokinetics, and antitumour activity of MDV3100, including measures of prostate-specific antigen (PSA) and circulating-tumour-cell (CTC) levels, as well as soft tissue and bone metastases. One hundred and twenty patients have been enrolled in the ongoing study, with the data including 73 patients (median age, 68 years) with the 3 lowest expanded dose levels (60, 150, and 240 mg/day), followed for >24 weeks. All study subjects have CRPC with serum testosterone <50 ng/dL and progressive disease according to the following: rising PSA levels; Response Evaluation Criteria in Solid Tumours (RECIST) progression criteria for soft tissue disease; or at least 2 new lesions on bone scan. Men were excluded from the study who had less than 2 prior chemotherapy regimens, brain metastases, or active epidural disease, and a history of other malignant disease within the previous 5 years. Baseline characteristics of the group included a median Gleason score of 8 and a median PSA level of 46.9 ng/mL. MDV3100 was initially administered at 30 mg/day orally, with sequential escalations and enrolment expanded to 24 patients (12 chemotherapy-naïve, 12 postchemotherapy) per dose level >=60 mg/day. According to PSA levels, 55% of the chemotherapy-naïve group (n = 42) saw at least a 50% decline in PSA level at week 12 compared to baseline. Similar results were seen in the postchemotherapy group, 42% (n = 31) of whom saw at least a 50% decline in PSA level at week 12 compared to baseline. Overall, the proportion of all patients with 90% or greater PSA decline at week 12 followed a dose-response trend: 60 mg/day, 9%; 150 mg/day, 13%; and 240 mg/day, 29%. CTC levels were available for 63 patients, with 85% of those with pretreatment favourable counts (<5) maintaining these levels. Furthermore, of those with unfavourable CTC levels before treatment (>=5), 33%, 56% and 58% converted to favourable CTC levels for the 60-, 150- and 240-mg/day treatments, respectively. Safety and tolerability were assessed according to adverse events (AEs), with soft-tissue and bone-marrow metastases assessed by computer tomography/magnetic resonance imaging. Radiographic assessment demonstrated improvements at 12 weeks, with partial responses (5 patients) and stable disease (16 patients) seen in patients with soft-tissue disease, and with stable bone disease seen in 32 patients. There were no reports of serious treatment-related AEs. The most frequent AE was fatigue, which led to 1 discontinuation. Dr Hirmand concluded, "We are going on to explore higher doses, especially given the fact that there seems to be a nice dose-response trend emerging as well." Funding for this study was provided by Medivation, USA.
[Presentation title: Phase 1/2 Study of MDV3100 in Castration-Resistant Prostate Cancer. Abstract 160]
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