Karim Fizazi1, Robert Jones2, Stephane Oudard2, Eleni Efstathiou2, Fred Saad2, Ronald de Wit2, Johann De Bono2, Felipe Melo Cruz2, George Fountzilas2, Albertas Ulys2, Flavio Carcano2, Neeraj Agarwal2, David Agus2, Joaquim Bellmunt2, Daniel P Petrylak2, Shih-Yuan Lee2, Iain J Webb2, Bindu Tejura2, Niels Borgstein2, Robert Dreicer2. 1. Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif; Stephane Oudard, Université Paris Descartes, Paris, France; Robert Jones, Institute of Cancer Sciences, University of Glasgow, Glasgow; Johann De Bono, The Institute of Cancer Research, London, United Kingdom; Eleni Efstathiou, University of Athens Medical School, Athens; George Fountzilas, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Fred Saad, University of Montreal Hospital Center, Montreal, Canada; Ronald de Wit, Erasmus University Medical Center, Rotterdam, the Netherlands; Felipe Melo Cruz, ABC Foundation School of Medicine, Santo André; Flavio Carcano, Hospital de Cancer de Barretos, Barretos, Brazil; Albertas Ulys, Institut of Oncology, Vilnius University, Vilnius, Lithuania; Neeraj Agarwal, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; David Agus, University of Southern California, Los Angeles, CA; Daniel P. Petrylak, Yale University Cancer Center, New Haven, CT; Shih-Yuan Lee, Bindu Tejura, Niels Borgstein, Takeda Pharmaceuticals International; Iain J. Webb, Millennium: The Takeda Oncology Company, Cambridge, MA; Robert Dreicer, Cleveland Clinic, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain. karim.fizazi@gustaveroussy.fr. 2. Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif; Stephane Oudard, Université Paris Descartes, Paris, France; Robert Jones, Institute of Cancer Sciences, University of Glasgow, Glasgow; Johann De Bono, The Institute of Cancer Research, London, United Kingdom; Eleni Efstathiou, University of Athens Medical School, Athens; George Fountzilas, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Fred Saad, University of Montreal Hospital Center, Montreal, Canada; Ronald de Wit, Erasmus University Medical Center, Rotterdam, the Netherlands; Felipe Melo Cruz, ABC Foundation School of Medicine, Santo André; Flavio Carcano, Hospital de Cancer de Barretos, Barretos, Brazil; Albertas Ulys, Institut of Oncology, Vilnius University, Vilnius, Lithuania; Neeraj Agarwal, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; David Agus, University of Southern California, Los Angeles, CA; Daniel P. Petrylak, Yale University Cancer Center, New Haven, CT; Shih-Yuan Lee, Bindu Tejura, Niels Borgstein, Takeda Pharmaceuticals International; Iain J. Webb, Millennium: The Takeda Oncology Company, Cambridge, MA; Robert Dreicer, Cleveland Clinic, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain.
Abstract
PURPOSE:Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.
RCT Entities:
PURPOSE:Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.
Authors: Karim Fizazi; Howard I Scher; Arturo Molina; Christopher J Logothetis; Kim N Chi; Robert J Jones; John N Staffurth; Scott North; Nicholas J Vogelzang; Fred Saad; Paul Mainwaring; Stephen Harland; Oscar B Goodman; Cora N Sternberg; Jin Hui Li; Thian Kheoh; Christopher M Haqq; Johann S de Bono Journal: Lancet Oncol Date: 2012-09-18 Impact factor: 41.316
Authors: Howard I Scher; Karim Fizazi; Fred Saad; Mary-Ellen Taplin; Cora N Sternberg; Kurt Miller; Ronald de Wit; Peter Mulders; Kim N Chi; Neal D Shore; Andrew J Armstrong; Thomas W Flaig; Aude Fléchon; Paul Mainwaring; Mark Fleming; John D Hainsworth; Mohammad Hirmand; Bryan Selby; Lynn Seely; Johann S de Bono Journal: N Engl J Med Date: 2012-08-15 Impact factor: 91.245
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Authors: Tracy Proverbs-Singh; Jarett L Feldman; Michael J Morris; Karen A Autio; Tiffany A Traina Journal: Endocr Relat Cancer Date: 2015-02-26 Impact factor: 5.678
Authors: Howard I Scher; Michael J Morris; Walter M Stadler; Celestia Higano; Ethan Basch; Karim Fizazi; Emmanuel S Antonarakis; Tomasz M Beer; Michael A Carducci; Kim N Chi; Paul G Corn; Johann S de Bono; Robert Dreicer; Daniel J George; Elisabeth I Heath; Maha Hussain; Wm Kevin Kelly; Glenn Liu; Christopher Logothetis; David Nanus; Mark N Stein; Dana E Rathkopf; Susan F Slovin; Charles J Ryan; Oliver Sartor; Eric J Small; Matthew Raymond Smith; Cora N Sternberg; Mary-Ellen Taplin; George Wilding; Peter S Nelson; Lawrence H Schwartz; Susan Halabi; Philip W Kantoff; Andrew J Armstrong Journal: J Clin Oncol Date: 2016-02-22 Impact factor: 44.544
Authors: Susan Halabi; William Kevin Kelly; Hua Ma; Haojin Zhou; Nicole C Solomon; Karim Fizazi; Catherine M Tangen; Mark Rosenthal; Daniel P Petrylak; Maha Hussain; Nicholas J Vogelzang; Ian M Thompson; Kim N Chi; Johann de Bono; Andrew J Armstrong; Mario A Eisenberger; Abderrahim Fandi; Shaoyi Li; John C Araujo; Christopher J Logothetis; David I Quinn; Michael J Morris; Celestia S Higano; Ian F Tannock; Eric J Small Journal: J Clin Oncol Date: 2016-03-07 Impact factor: 44.544