AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

AGO and Coordinating Center for Clinical Trials Philipps University of Marburg Marburg Germany

AGO and Department of Gynecology and Gynecologic Oncology Kliniken Essen Mitte Essen Germany

AGO and Department of Gynecology and Obstetrics Oberschwabenklinik Krankenhaus St Elisabeth Ravensburg Germany

AGO and Department of Gynecology Klinikum der Stadt Ludwigshafen GmbH Ludwigshafen Germany

AGO and Department of Obstetrics and Gynecology University Hospital LMU Munich Germany

AGO and Department of Obstetrics and Gynecology University Medical Center Mainz Germany

AGO and Oncogynecologic Center Department of Obstetrics and Gynecology General Faculty Hospital Charles University of Prague Prague Czech Republic

AGO Austria and Department of Obstetrics and Gynecology Paracelsus Medical University Salzburg Austria

BGOG and CHU de Liège University of Liège Liège Belgium

Center for Cancer Biomarkers CCBIO Department of Clinical Science University of Bergen Bergen Norway

DGOG and Department of Medical Oncology Radboud University Medical Centre Nijmegen The Netherlands

GEICO and Medical Oncology Department Clínica Universidad de Navarra Madrid Spain

GINECO and Centre René Gauducheau Institut de Cancerologie de l'Ouest Saint Herblain France

GINECO and Department of Gynecologic Cancer and Medical Oncology Centre Oscar Lambret Lille France

GINECO and Medical Oncology Department Centre Léon Bérard University Claude Bernard Lyon Lyon France

MaNGO and European Institute of Oncology and University of Milan Bicocca Milan Italy

MITO and Department of Uro Gynecologic Oncology Istituto Nazionale per Io Studio e la Cura dei Tumori 'Fondazione G Pascale' IRCCS Naples Italy

MITO and Division of Gynecologic Oncology Department of Women and Children's Health and Public Health Fondazione Policlinico Gemelli IRCCS Rome Italy

NSGO and Department of Gynecology Haukeland Universitetssykehus Bergen Norway

NSGO and Department of Gynoncology and Gynecology and Obstetrics Kymenlaakso Central Hospital Kotka Finland

NSGO and Department of Oncology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

NSGO and Department of Oncology University Hospital Linköping Linköping Sweden

NSGO and National Institute of Oncology Bratislava Slovakia

Oncology Medicine Boehringer Ingelheim International GmbH Biberach Germany

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Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-403.

Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356-87.

Burger RA, Brady MF, Bookman MA, et al. Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83.

Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-96.

Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30:2039-45.

Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779-91.

Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-8.

du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 2014;32:3374-82.

Khalique S, Banerjee S. Nintedanib in ovarian cancer. Expert Opin Investig Drugs 2017;26:1073-81.

Ledermann JA, Hackshaw A, Kaye S, et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011;29:3798-804.

du Bois A, Kristensen G, Ray-Coquard I, et al. AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2016;17:78-89.

Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015;16:928-36.

Madeddu C, Gramignano G, Kotsonis P, et al. Microenvironmental M1 tumor-associated macrophage polarization influences cancer-related anemia in advanced ovarian cancer: key role of interleukin-6. Haematologica 2018;103:e388-91.

Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018;48:812-830.e14.

du Bois A, Weber B, Rochon J, et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized Gynecologic Cancer InterGroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J Clin Oncol 2006;24:1127-35.

Pfisterer J, Weber B, Reuss A, et al. AGO-OVAR; GINECO. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a Gynecologic Cancer InterGroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006;98:1036-45.

du Bois A, Herrstedt J, Hardy-Bessard AC, et al. Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol 2010;28:4162-9.

Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154-64.

Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274-84.

Coleman RL, Oza AM, Lorusso D, et al. ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-61.

Pignata S, Lorusso D, Joly F, et al. Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: the randomized phase 3 trial MITO16B-MaNGO OV2B-ENGOT OV17. J Clin Oncol 2018;36(Suppl):Abstract 5506.

Monk BJ, Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010;28:3107-14.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495-505.