SAN FRANCISCO, CA USA (UroToday.com) - Presented by Tomasz Beer, MD, FACP at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Knight Cancer Institute, Portland, OR USA
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Background: Enzalutamide, an orally administered androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher et al, NEJM 367:13, 2012). This study examined whether enzalutamide could prolong OS and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC.
Methods: In this randomized, double-blind, placebo-controlled, multinational phase 3 study (NCT01212991), chemotherapy-naive patients with mCRPC were stratified by site and randomized 1:1 to enzalutamide 160 mg/day or placebo. OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Planned sample size was 1,680 with 765 deaths to achieve 80% power to detect a target OS hazard ratio (HR) of 0.815 with a type I error rate of 0.049 and a single interim analysis at 516 (67%) deaths. The co-primary endpoint of rPFS had sufficient power to detect a target HR of 0.57 and a type I error rate of 0.001 with a minimum of 410 events.
Results: A total of 1,717 men were randomized (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70; 95% CI: 0.59-0.83; P< 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P< 0.0001). At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months (mo) (95% CI, 31.5–upper limit not yet reached [NYR]) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit NYR) in the placebo arm. Median rPFS was NYR (95% CI: 13.8–upper limit NYR) in the enzalutamide arm vs 3.9 mo (95% CI: 3.7-5.4) in the placebo arm. Seizure events were reported in two patients. The Independent Data Monitoring Committee considered the benefit-risk ratio to favor enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide. Secondary endpoints and safety analysis will be presented.
Conclusions: Treatment with enzalutamide significantly improves OS and rPFS in men with chemotherapy-naive mCRPC. Clinical trial information: NCT01212991.
Author(s): Tomasz M. Beer, Andrew J. Armstrong, Cora N. Sternberg, Celestia S. Higano, Peter Iversen, Yohann Loriot, Dana E. Rathkopf, Suman Bhattacharya, Joan Carles, Johann S. De Bono, Christopher P. Evans, Anthony M. Joshua, Choung-Soo Kim, Go Kimura, Paul N. Mainwaring, Harry H. Mansbach, Kurt Miller, Sarah B. Noonberg, Peter M. Venner, Bertrand Tombal; Oregon Health & Science University-Knight Cancer Institute, Portland, OR; Duke Cancer Institute and the Duke Prostate Center, Division of Medical Oncology and Urology, Duke University, Durham, NC; San Camillo and Forlanini Hospital, Rome, Italy; University of Washington/Seattle Cancer Care Alliance, Seattle, WA; Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; Memorial Sloan-Kettering Cancer Center, New York, NY; Medivation, Inc., San Francisco, CA; Vall d'Hebron University Hospital, Barcelona, Spain; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, United Kingdom; UC Davis Comprehensive Cancer Center, Davis, CA; Princess Margaret Cancer Centre, Toronto, ON, Canada; Asan Medical Center, Seoul, South Korea; Nippon Medical School Hospital, Tokyo, Japan; Icon Cancer Care, South Brisbane, Australia; Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Oncology, University of Alberta, Edmonton, AB, Canada; Cliniques Universitaires Saint-Luc, Brussels, Belgium