New England Journal of Medicine Publishes Results From Phase 3 PREVAIL Trial Of Enzalutamide In Men With Chemotherapy-Naïve Metastatic Prostate Cancer
Astellas Pharma Inc. (TSE: 4503) and Medivation Inc. (NASDAQ: MDVN) today announced the online publication in the New England Journal of Medicine of the results from the Phase 3 PREVAIL trial. The PREVAIL trial is an international, randomised, double-blind, placebo-controlled clinical study of enzalutamide (XTANDITM) in men with metastatic castration-resistant prostate cancer (mCRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and in whom chemotherapy is not yet clinically indicated. Enzalutamide is currently approved in Europe for the treatment of adult men with mCRPC whose disease has progressed on or after docetaxel chemotherapy.i The paper, "Benefit of Enzalutamide in Men with Chemotherapy-Naïve Metastatic Prostate Cancer," appears in the June 1 online issue.
“The PREVAIL study provides important clinical information about enzalutamide and its use in prostate cancer therapy for men whose cancer has progressed, despite treatment with androgen deprivation therapy”, said Professor Bertrand Tombal, MD, PhD, Chairman of the Division of the Urology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain (UCL) and European Principal Investigator for PREVAIL. "The results from the PREVAIL trial are encouraging as they demonstrate enzalutamide’s efficacy in the pre-chemotherapy setting, and I believe this represents a significant step forward in the way we will treat men with chemotherapy-naïve metastatic castration-resistant prostate cancer.”
A variation to amend the European Marketing Authorisation Application for enzalutamide for the treatment of adult men with mCRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and in whom chemotherapy is not yet clinically indicated was submitted for review by the European Medicines Agency on May 6, 2014. Astellas and Medivation received a priority review from the U.S. Food and Drug Administration (FDA) of their supplemental New Drug Application (sNDA) to extend the indication for enzalutamide to include treatment of men with mCRPC who have not received chemotherapy based on PREVAIL.
In the PREVAIL trial, men treated with enzalutamide demonstrated a statistically significant reduction both in the risk of death and a delay in cancer progression as compared to those treated with placebo.ii Enzalutamide reduced the risk of death by 29% (HR=0.71; p < 0.001), compared with placebo.ii In addition, treatment with enzalutamide significantly reduced the risk of radiographic progression or death by 81% compared with placebo treatment (HR=0.19; p < 0.001).ii Men taking enzalutamide experienced a 17-month delay in the time to initiation of chemotherapy compared with men taking placebo (28.0 months versus 10.8 months; HR=0.35; p< 0.0001).ii
The most common clinically relevant adverse events among the enzalutamide population as compared with placebo-treated patients in the PREVAIL trial included fatigue, hot flush and hypertension.ii Hypertension was observed in 13.4% of enzalutamide versus 4.1% of placebo-treated patients.ii Grade 3 or higher cardiac adverse events were reported in 2.8% of enzalutamide versus 2.1% of placebo-treated patients.ii Investigators reported zero seizures in the enzalutamide-treated group and one in the placebo group prior to the data cut-off date.ii One seizure was reported in the enzalutamide group after the data cut-off date.ii
About the PREVAIL Trial
The Phase 3 PREVAIL trial is a randomised, double-blind, placebo-controlled, multi-national trial that enrolled more than 1,700 patients at sites in the United States, Canada, Europe, Australia, Russia, Israel and Asia including Japan. The trial enrolled patients with chemotherapy-naïve metastatic prostate cancer whose disease progressed on a luteinizing hormone-releasing hormone analogue or after bilateral orchiectomy. The co-primary endpoints of the trial were overall survival and radiographic progression-free survival. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus placebo.
About XTANDI™
XTANDI is a novel, oral, once-daily androgen receptor signalling inhibitor. XTANDI directly targets the androgen receptors (AR) and exerts its effects on all three steps of AR signalling pathway:
- Blocks androgen bindingiii
Androgen binding induces a conformational change that triggers activation of the receptoriv
- Prevents nuclear translocationiii
Transit of the AR to the nucleus is an essential step in AR-mediated gene regulationiv - Impairs DNA bindingiii
Binding of the AR to the DNA is essential for modulation of gene expressioniv
XTANDI is currently licensed in Europe for the treatment of adult men with mCRPC whose disease has progressed on or after docetaxel therapy.i Marketing authorisation was granted by the European Commission on June 21, 2013.
XTANDI was approved by the FDA on August 31, 2012 and is indicated for the treatment of adult men with mCRPC who have previously received docetaxel.v
In March 2014, Astellas and Medivation submitted a supplemental new drug application for XTANDI for chemotherapy-naïve advanced prostate cancer to the US Food and Drug Administration.
Important Safety Information for XTANDI™
For important Safety Information for XTANDI please see the full Summary of Product Characteristics at:http://www.medicines.org.uk/emc/medicine/27912/SPC/Xtandi+40mg+soft+capsules/.
About Astellas Pharma Inc.
Astellas Pharma Inc. is a pharmaceutical company dedicated to improving the health of people around the world through provision of innovative and reliable pharmaceuticals. The organisation is committed to being a global category leader in Oncology and Urology, and has several oncology compounds in development in addition to enzalutamide. For more information on Astellas Pharma Inc., please visit our website at www.astellas.com/en.
About Medivation
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 families. For more information, please visit us at www.medivation.com.
About the Astellas/Medivation Collaboration
In October 2009, Medivation and Astellas entered into a global agreement to jointly develop and commercialise enzalutamide. The companies are collaborating on a comprehensive development program that includes studies to develop enzalutamide across the full spectrum of advanced prostate cancer as well as advanced breast cancer. The companies jointly commercialise XTANDI in the United States and Astellas will have responsibility for manufacturing and all additional regulatory filings globally, as well as commercialising XTANDI outside the United States.
i European Medicines Agency, XTANDI, (enzalutamide) Summary of Product Characteristics, 2013
ii Beer T, et al. Enzalutamide Decreases Risk of Death and Delays Progression in Phase 3 Trial of Men with Metastatic Prostate Cancer. Presentation ASCO GU February 2014
iiiTran C, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324:787-790
ivHu R, Denmeade SR and Luo J. Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer. Expert Rev Endocrinol Metab 2010; 5 (5): 753–764
vU.S. Food and Drug Administration. Enzalutamide (XTANDI Capsules). Available from: http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm317997.htm. Last accessed May 2014