Joyce F Liu1, Mark F Brady2, Ursula A Matulonis1, Austin Miller2, Elise C Kohn3, Elizabeth M Swisher4, David Cella5, William P Tew6, Noelle G Cloven7, Carolyn Y Muller8, David P Bender9, Richard G Moore10, David P Michelin11, Steven E Waggoner12, Melissa A Geller13, Keiichi Fujiwara14, Stacy D D'Andre15, Michael Carney16, Angeles Alvarez Secord17, Katherine M Moxley18, Michael A Bookman19. 1. Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA. 2. NRG Oncology; Clinical Trial Development Division; Biostatistics & Bioinformatics; Roswell Park Comprehensive Cancer Center, Buffalo, NY. 3. Gynecologic Cancer Therapeutics, National Cancer Institute, Rockville, MD. 4. Gynecologic Oncology, University of Washington, Seattle, WA. 5. Department of Medical Social Sciences, Northwestern University Health System, Chicago, IL. 6. Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. 7. Texas Oncology, Fort Worth Cancer Center, Fort Worth, TX. 8. Gynecologic Oncology, University of New Mexico, Albuquerque, NM. 9. Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA. 10. Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY. 11. Gynecologic Oncology, Cancer Research Consortium of West Michigan, Munson Medical Center, Traverse City, MI. 12. Gynecologic Oncology, Cleveland Clinic Health System, Cleveland, OH. 13. Ob/Gyn & Women's Health, University of Minnesota, Minneapolis, MN. 14. Gynecologic Oncology, Saitama Medical University International Medical Center; Hidaka-Shi, Japan. 15. Executive Chair, Sutter Cancer Research Consortium, Sutter Health Research Enterprise, Sacramento, CA. 16. Kapialoni Medical Center for Women & Children, University of Hawaii, Honolulu, HI. 17. Gynecologic Oncology, Duke University Medical Center, Durham, NC. 18. Stephenson Cancer Center Gynecologic Cancers Clinic, University of Oklahoma Health Sciences Center, Oklahoma City, OK. 19. Director, Gynecologic Oncology Therapeutics, Kaiser Permanente Northern California, San Francisco, CA.
Abstract
PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.
PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.
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