Neeraj Agarwal1, Catherine M Tangen2, Maha H A Hussain3, Shilpa Gupta4, Melissa Plets2, Primo N Lara5, Andrea L Harzstark6, Przemyslaw W Twardowski7, Channing J Paller8, Dylan Zylla9, Matthew R Zibelman10, Ellis Levine11, Bruce J Roth12, Amir Goldkorn13, Daniel A Vaena14,15, Manish Kohli1,16, Tony Crispino17, Nicholas J Vogelzang18, Ian M Thompson19, David I Quinn13. 1. University of Utah Huntsman Cancer Institute, Salt Lake City, UT. 2. SWOG Statistics and Data Management Center, Seattle, WA. 3. Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL. 4. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. 5. UC Davis Comprehensive Cancer Center, Sacramento, CA. 6. Kaiser Permanente-Oakland, Oakland, CA. 7. John Wayne Cancer Institute, Santa Monica, CA. 8. Johns Hopkins University School of Medicine, Baltimore, MD. 9. Metro Minnesota CCRC/Park Nicollet Clinic, St Louis Park, MN. 10. Fox Chase Cancer Center, Philadelphia, PA. 11. Roswell Park Comprehensive Cancer Center, Buffalo, NY. 12. Washington University School of Medicine, St Louis, MO. 13. USC, Norris Comprehensive Cancer Center, Los Angeles, CA. 14. University of Iowa, Iowa City, IA. 15. West Cancer Center, Germantown, TN. 16. Mayo Clinic at Rochester, Rochester, MN. 17. UsTOO Prostate Cancer Support and Education Las Vegas Chapter, Las Vegas, NV. 18. Comprehensive Cancer Centers of Nevada, Las Vegas, NV. 19. CHRISTUS Santa Rosa Health System, San Antonio, TX.
Abstract
PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months (P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.
PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months (P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.
Authors: Karim Fizazi; Robert Jones; Stephane Oudard; Eleni Efstathiou; Fred Saad; Ronald de Wit; Johann De Bono; Felipe Melo Cruz; George Fountzilas; Albertas Ulys; Flavio Carcano; Neeraj Agarwal; David Agus; Joaquim Bellmunt; Daniel P Petrylak; Shih-Yuan Lee; Iain J Webb; Bindu Tejura; Niels Borgstein; Robert Dreicer Journal: J Clin Oncol Date: 2015-01-26 Impact factor: 44.544
Authors: Johann Sebastian de Bono; Stephane Oudard; Mustafa Ozguroglu; Steinbjørn Hansen; Jean-Pascal Machiels; Ivo Kocak; Gwenaëlle Gravis; Istvan Bodrogi; Mary J Mackenzie; Liji Shen; Martin Roessner; Sunil Gupta; A Oliver Sartor Journal: Lancet Date: 2010-10-02 Impact factor: 79.321
Authors: Nicholas D James; Johann S de Bono; Melissa R Spears; Noel W Clarke; Malcolm D Mason; David P Dearnaley; Alastair W S Ritchie; Claire L Amos; Clare Gilson; Rob J Jones; David Matheson; Robin Millman; Gerhardt Attard; Simon Chowdhury; William R Cross; Silke Gillessen; Christopher C Parker; J Martin Russell; Dominik R Berthold; Chris Brawley; Fawzi Adab; San Aung; Alison J Birtle; Jo Bowen; Susannah Brock; Prabir Chakraborti; Catherine Ferguson; Joanna Gale; Emma Gray; Mohan Hingorani; Peter J Hoskin; Jason F Lester; Zafar I Malik; Fiona McKinna; Neil McPhail; Julian Money-Kyrle; Joe O'Sullivan; Omi Parikh; Andrew Protheroe; Angus Robinson; Narayanan N Srihari; Carys Thomas; John Wagstaff; James Wylie; Anjali Zarkar; Mahesh K B Parmar; Matthew R Sydes Journal: N Engl J Med Date: 2017-06-03 Impact factor: 91.245
Authors: Charles J Ryan; Matthew R Smith; Johann S de Bono; Arturo Molina; Christopher J Logothetis; Paul de Souza; Karim Fizazi; Paul Mainwaring; Josep M Piulats; Siobhan Ng; Joan Carles; Peter F A Mulders; Ethan Basch; Eric J Small; Fred Saad; Dirk Schrijvers; Hendrik Van Poppel; Som D Mukherjee; Henrik Suttmann; Winald R Gerritsen; Thomas W Flaig; Daniel J George; Evan Y Yu; Eleni Efstathiou; Allan Pantuck; Eric Winquist; Celestia S Higano; Mary-Ellen Taplin; Youn Park; Thian Kheoh; Thomas Griffin; Howard I Scher; Dana E Rathkopf Journal: N Engl J Med Date: 2012-12-10 Impact factor: 91.245
Authors: C Parker; S Nilsson; D Heinrich; S I Helle; J M O'Sullivan; S D Fosså; A Chodacki; P Wiechno; J Logue; M Seke; A Widmark; D C Johannessen; P Hoskin; D Bottomley; N D James; A Solberg; I Syndikus; J Kliment; S Wedel; S Boehmer; M Dall'Oglio; L Franzén; R Coleman; N J Vogelzang; C G O'Bryan-Tear; K Staudacher; J Garcia-Vargas; M Shan; Ø S Bruland; O Sartor Journal: N Engl J Med Date: 2013-07-18 Impact factor: 91.245
Authors: M A Eisenberger; B A Blumenstein; E D Crawford; G Miller; D G McLeod; P J Loehrer; G Wilding; K Sears; D J Culkin; I M Thompson; A J Bueschen; B A Lowe Journal: N Engl J Med Date: 1998-10-08 Impact factor: 91.245
Authors: Nicholas D James; Matthew R Sydes; Noel W Clarke; Malcolm D Mason; David P Dearnaley; Melissa R Spears; Alastair W S Ritchie; Christopher C Parker; J Martin Russell; Gerhardt Attard; Johann de Bono; William Cross; Rob J Jones; George Thalmann; Claire Amos; David Matheson; Robin Millman; Mymoona Alzouebi; Sharon Beesley; Alison J Birtle; Susannah Brock; Richard Cathomas; Prabir Chakraborti; Simon Chowdhury; Audrey Cook; Tony Elliott; Joanna Gale; Stephanie Gibbs; John D Graham; John Hetherington; Robert Hughes; Robert Laing; Fiona McKinna; Duncan B McLaren; Joe M O'Sullivan; Omi Parikh; Clive Peedell; Andrew Protheroe; Angus J Robinson; Narayanan Srihari; Rajaguru Srinivasan; John Staffurth; Santhanam Sundar; Shaun Tolan; David Tsang; John Wagstaff; Mahesh K B Parmar Journal: Lancet Date: 2015-12-21 Impact factor: 79.321
Authors: N W Clarke; A Ali; F C Ingleby; A Hoyle; C L Amos; G Attard; C D Brawley; J Calvert; S Chowdhury; A Cook; W Cross; D P Dearnaley; H Douis; D Gilbert; S Gillessen; R J Jones; R E Langley; A MacNair; Z Malik; M D Mason; D Matheson; R Millman; C C Parker; A W S Ritchie; H Rush; J M Russell; J Brown; S Beesley; A Birtle; L Capaldi; J Gale; S Gibbs; A Lydon; A Nikapota; A Omlin; J M O'Sullivan; O Parikh; A Protheroe; S Rudman; N N Srihari; M Simms; J S Tanguay; S Tolan; J Wagstaff; J Wallace; J Wylie; A Zarkar; M R Sydes; M K B Parmar; N D James Journal: Ann Oncol Date: 2019-12-01 Impact factor: 32.976