Background: Standard of care first line chemotherapy for epithelial ovarian cancer (EOC) is carboplatin and paclitaxel administered once every three weeks. The JGOG3016 trial reported significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel and three-weekly carboplatin. However, this benefit was not observed in the progression free survival results of ICON8, previously reported. Here, we present the final co-primary OS and updated PFS outcomes. Methods: Women aged 18 or above with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV EOC were recruited. Patients were randomly assigned to one of three groups; group 1: 3-weekly carboplatin area under the curve (AUC) 5/6 and 3-weekly paclitaxel 175mg/m2, group 2: 3-weekly carboplatin AUC5/6 and weekly paclitaxel 80mg/m2, group 3: weekly carboplatin AUC2 and weekly paclitaxel 80mg/m2, all administered by intravenous infusion. Patients entered the trial after immediate primary surgery (IPS) or received delayed primary surgery (DPS) during chemotherapy. Randomisation was performed using minimisation with stratification factors of GCIG group, disease stage and outcome and timing of surgery. Co-primary outcomes were PFS and OS, with comparisons performed between group 2 and group 1, and group 3 and group 1. Intention-to-treat analyses were powered to detect a hazard ratio of 0.75 in favour of the experimental groups. The trial is registered on clinicaltrials.gov as NCT01654146 and controlled-trials.com asISRCTN10356387. Findings: Between 6 Jun 2011 and 28 Nov 2014, 1566 women were recruited; group 1 (N=522), group 2 (N=523) and group 3 (N=521). Baseline characteristics include median age 62, 69% high grade serous carcinoma, 72% stage IIIC-IV disease, 48% IPS. By March 2020, with a median follow up of 69 months (IQR 61-75 months), 324, 309 and 313 deaths had occurred in groups 1, 2 and 3 respectively. No significant difference in OS was observed in either comparison: HR 0.87 (97.5% CI 0.73, 1.05) group 2 vs group 1, HR 0.91 (97.5% CI 0.76, 1.09) group 3 vs group 1. Most common G3/4 adverse events were reduced neutrophils (78, 183, 154 in groups 1, 2, 3) reduced white blood cell count (22, 80, 71 In groups 1, 2, 3) and anaemia (26, 66, 25 in groups 1, 2, 3). No new serious adverse events were reported. Interpretation: First-line weekly dose-dense chemotherapy does not improve OS for patients with EOC compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality ovarian cancer treatment for Caucasian women in the front-line setting. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.
