Medivation, Inc. and Astellas Pharma Inc. announced positive, new, long-term follow-up data from the phase 1-2 trial of MDV3100 in patients with advanced prostate cancer. MDV3100 is a novel, triple-acting, oral androgen receptor antagonist. These new results showed that MDV3100 continues to show durable anti-tumour activity as evaluated by median times to prostate-specific antigen (PSA) progression and radiographic progression. These findings confirm the initial phase 1-2 results published in The Lancet, in which MDV3100 consistently demonstrated anti-tumour activity in both chemotherapy-naïve and post-chemotherapy patients across endpoints, as evaluated by PSA levels, radiographic findings and circulating tumour cell (CTC) counts.

"We are very encouraged by these promising new, long-term efficacy findings, which continue to demonstrate the anti-tumour activity of MDV3100 and give us confidence that MDV3100 has the potential to benefit patients with advanced prostate cancer," said Lynn Seely, M.D., chief medical officer of Medivation.

A total of 140 men with progressive disease were enrolled in the phase 1-2 trial between July 2007 and December 2008. Of those, 18 remained on active treatment (16 chemotherapy-naive and 2 post-chemotherapy) at the time of this analysis.

PSA progression data were calculated using three distinct reporting criteria: the criteria specified in the phase 1-2 trial protocol; the most recent published PSA reporting consensus criteria (the Prostate Cancer Clinical Trials Working Group 2, or PCWG2, criteria); and an older commonly used reporting method (the Prostate-Specific Antigen Working Group 1, or PSAWG1, criteria).

The protocol-specified criteria define PSA progression as a 25% increase in PSA from starting baseline, provided that the increase is at least 5 ng/mL. This is the most liberal approach, and will produce the longest times to progression. The PCWG2 criteria define PSA progression as a 25% increase in PSA from nadir (i.e., from the lowest level of PSA attained by the patient on study), provided that the increase is at least 2 ng/mL. Under the PSAWG1 criteria, PSA progression requires: a 50% increase in PSA above nadir for patients who experienced a PSA decline of 50% on treatment; a 25% increase in PSA above nadir for patients who experienced a PSA decline < 50% on treatment; and a 25% increase in PSA above starting baseline for patients who did not experience any PSA decline on treatment; provided in each case that the PSA increase was at least 5 ng/mL. This is an intermediate approach to defining PSA progression, producing times to progression between those produced using the other two approaches.

Circulating tumour cell counts were available for 128 of 140 patients. Of those, 70 of 77 (91%) who had favourable pre-treatment counts ( < 5 cells/7.5 mL blood) remained favourable post-treatment, and 25 of 51 patients (49%) converted from unfavourable pre-treatment counts to favourable post-treatment counts.

"These positive long-term findings in both chemotherapy-naïve and post-chemotherapy advanced prostate cancer patients provide further support for our expanded development programme into earlier-stage prostate cancer patients," said Steven Ryder, M.D., president, Astellas Pharma Global Development. "In addition to the ongoing phase 3 PREVAIL trial, which is currently enrolling men with advanced prostate cancer who are chemotherapy-naïve, we and our partner Medivation plan to initiate two phase 2 trials in earlier-stage prostate cancer in the first half of this year."

All patients in the open-label, dose-escalation, phase 1-2 clinical trial had progressive disease upon enrolment and were heavily pretreated, with 77 per cent having failed at least two lines of prior hormonal therapy and 54 per cent having failed one or more chemotherapy regimens. A total of 140 men were enrolled in the trial, which evaluated MDV3100 doses between 30 and 600 mg/day. Patients could remain on treatment for as long as they continued to tolerate the drug and their disease did not progress. Efficacy endpoints included CTC counts, serum PSA levels, and soft tissue and bony metastases.

MDV3100 is currently being evaluated in two global phase 3 studies in patients with advanced prostate cancer.

The randomized, double-blind, placebo-controlled phase 3 AFFIRM trial completed enrolment in November 2010. This trial of 1,199 patients with advanced prostate cancer who were previously treated with chemotherapy is evaluating 160 mg/day of MDV3100 versus placebo. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, safety and tolerability.

A second phase 3 clinical trial of MDV3100 in advanced prostate cancer, the PREVAIL trial, is currently enrolling patients. This randomized, double-blind, placebo-controlled, multi-national trial of approximately 1,700 patients with advanced prostate cancer is evaluating MDV3100 at a dose of 160 mg taken orally once daily plus standard of care versus placebo plus standard of care. The co-primary endpoints of the trial are overall survival and progression-free survival; secondary endpoints include time to first skeletal-related event and time to initiation of cytotoxic chemotherapy.

In October 2009, Medivation and Astellas entered into a global agreement to jointly develop and commercialize MDV3100. The companies are collaborating on a comprehensive development program that includes studies to develop MDV3100 for both early-stage and advanced prostate cancer. Subject to receipt of regulatory approval, the companies will jointly commercialize MDV3100 in the US and Astellas will have responsibility for commercializing MDV3100 outside the US. Medivation received a $110 million up-front payment upon entering into the collaboration agreement, and is eligible to receive up to $335 million in development milestone payments, up to $320 million in commercial milestone payments, 50% of profits on sales in the US, and tiered, double-digit royalties on sales outside the US.

MDV3100 is an investigational therapy in clinical development for advanced prostate cancer. In preclinical experiments published in Science in April 2009, the novel, triple-acting, oral androgen receptor antagonist provided more complete suppression of the androgen receptor pathway than bicalutamide, the most commonly used anti-androgen. MDV3100 slows growth and induces cell death in bicalutamide-resistant cancers via three complementary actions - MDV3100 blocks testosterone binding to the androgen receptor, impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation) and inhibits binding to DNA. In the preclinical experiments published in Science, MDV3100 was superior to bicalutamide in each of these three actions.

Medivation, Inc. is a biopharmaceutical company focused on the rapid development of novel small molecule drugs to treat serious diseases for which there are limited treatment options. Medivation aims to transform the treatment of these diseases and offer hope to critically ill patients and their caregivers.

Astellas Pharma Inc., located in Tokyo, Japan, is a pharmaceutical company dedicated to improving the health of people around the world through provision of innovative and reliable pharmaceuticals. Astellas has approximately 16,000 employees worldwide. The organization is committed to becoming a global category leader in Urology, Immunology & Infectious Diseases, Neuroscience, DM complications & Metabolic Diseases and Oncology.