SAN FRANCISCO, CA USA (UroToday.com) - Complete Title: GU Cancers Symposium 2014 - Results from a phase 3, randomized, double-blind, multicenter, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy (ELM-PC 5 trial) - Abstract
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Background: Orteronel is an investigational, non-steroidal selective inhibitor of 17,20-lyase; a key enzyme in the production of steroidal hormones.
Methods: Eligible men with metastatic castration-resistant prostate cancer (mCRPC) had progressive disease (PD; radiographic or prostate-specific antigen), castrate levels of testosterone, and had received more than or equal to 360 mg/m2docetaxel within the prior 6 months. Prior orteronel, abiraterone, or ketoconazole was not permitted. Patients were randomized 2:1 to continuous 28-day cycles of oral orteronel 400 mg BID + prednisone 5 mg BID, or placebo + prednisone without regard to food. Primary endpoint: overall survival (OS); other key endpoints: radiographical progression-free survival (rPFS), 50% or more PSA decrease at 12 weeks, pain response at 12 weeks and safety (NCT01193257).
Results: One thousand ninety nine patients were randomized. The study was terminated for failing to meet its primary endpoint: median overall survival (OS) was 17.0 months (95% CI 15.2, 19.9) in patients receiving orteronel versus 15.2 months (95% CI 13.5, 16.9) in those receiving placebo (HR: 0.886 [95% CI: 0.739, 1.062]; P=0.1898). Substantial regional differences were seen in OS benefit: median OS (orteronel vs. placebo) was 20.9 vs. 16.9 mo (HR: 0.889) in North America (n=112), 18.3 vs. 17.8 mo (HR: 1.048) in Europe (n=590), and 15.3 vs 10.1 mo (HR: 0.709) in the rest of the world (n=397). In the overall population, rPFS was significantly improved in the orteronel arm, with a median of 8.3 months vs. 5.7 months in the placebo arm (HR: 0.76 [95% CI: 0.653, 0.885]; P=0.00038). Drug-related adverse events (AEs; any grade) included (orteronel/placebo) nausea (30/16%), vomiting (23/8%), fatigue (17/11%), and diarrhea (16/9%); grade 3 or higher drug-related AEs included increased lipase (12/less than 1%), increased amylase (8/less than 1%), and fatigue (3/3%). Additional sub-analyses looking at potential factors that affected OS will also be reported.
Conclusions: While orteronel + prednisone did not show a statistically significant overall OS improvement versus placebo + prednisone, rPFS findings and striking regional OS differences suggest that orteronel has clinically meaningful activity.
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Disclosures: Robert Dreicer, MD, consultant or advisory role with Janssen, Endo Pharmaceuticals, Dendreon, AbbVie, and Millennium, research funding from Progenics, Endo Pharmaceuticals, Millennium, position as an advisory board member and/or consultant of the trial sponsor; Robert Jones, MBChB, PhD, honoraria from Sanofi, Janssen, and Astellas Pharma, research funding from Millennium, Janssen, Astellas Pharma, AstraZeneca, Sanofi, Bristol-Myers Squibb, and Medivation; Stephane Oudard, MD, PhD, consultant or advisory role with Sanofi, Janssen, Takeda, Astellas Pharma, and Keocyt, honoraria from Janssen, Sanofi, and Takeda; Eleni Efstathiou, MD, PhD, consultant or advisory role with Janssen, Sanofi, Millennium, Bayer, Medivation, honoraria from Milennium, Takeda, Janssen, and Sanofi, research funding from Millennium, Takeda, Janssen, and Sanofi; Fred Saad, MD, FRCS, consultant or advisory role with Millennium, Astellas Pharma, Janssen, and Sanofi, research funding from Millennium, Astellas Pharma, Janssen, and Sanofi; Ronald De Wit, MD, PhD, consultant or advisory role with Millennium, honoraria with Millennium, research funding from Millennium; Yuanjun Shi, PhD, employment/leadership position at Takeda; Bindu Tejura, MD, employment/leadership position at Takeda, stock ownership with Millennium; David B. Agus, MD, consultant or advisory role with Millennium; Niels Geert Borgstein, MD, employment/leadership position at Takeda, stock ownership with Takeda; Joaquim Bellmunt, MD, PhD, consultant or advisory role with Millennium; Karim Fizazi, MD, PhD, consultant or advisory role with Millennium, Amgen, Astellas Pharma, Bayer, Bristol-Myers Squibb, Dendreon, Ipsen, Janssen, Novartis, and Sanofi.
Authored by Robert Dreicer, Robert Jones, Stephane Oudard, Eleni Efstathiou, Fred Saad, Ronald De Wit, Johann Sebastian De Bono, Yuanjun Shi, Bindu Tejura, David B. Agus, Niels Geert Borgstein, Joaquim Bellmunt, and Karim Fizazi for presentation at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Cleveland Clinic, Cleveland, OH; Institute of Cancer Sciences, Glasgow, United Kingdom; HEGP, Oncologie Médicale, Paris, France; University of Athens Medical School, Athens, TX; University of Montreal Hospital Center, Montreal, QC; Erasmus MC Cancer Institute, Rotterdam, Netherlands; The Institue of Cancer Research, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Takeda Pharmaceuticals International Company, Cambridge, MA; Keck School of Medicine of University of Southern California, Beverly Hills, CA; Dana-Farber Cancer Institute, Boston, MA; Institut Gustave Roussy, University of Paris Sud, Villejuif, France