A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer

Abstract Objective This phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin (PLD) vs. PLD monotherapy. Methods Women with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.1 mg/m2 for 3 h; PLD 30 mg/m2 for 1.5 h, every 3 weeks) or PLD (50 mg/m2 for 1.5 h, every 4 weeks). Primary endpoint was OS. Secondary endpoints included investigator-assessed progression free survival (PFS) and objective response rates (ORR). At randomization, patients were stratified by time from last dose of first-line platinum therapy to disease progression, ECOG grade 0 or 1, BRCA1/2 germline mutational status, and prior PLD therapy. Exploratory endpoints included OS, PFS, and ORR in the stratified subgroups (PFI, ECOG, BRCA1/2 status, and prior PLD therapy). This trial is registered with ClinicalTrials.gov , number NCT01846611. Results 576 patients were randomized (T + PLD, n = 289; PLD, n = 287). Median OS was 23.8 months with T + PLD vs. 22.2 months with PLD (HR:0.92, 95%CI:0.73–1.18; p = 0.52). Median PFS was 7.52 vs. 7.26 months (HR:0.93, 95%CI:0.76–1.15; p = 0.52); ORR was 46% vs. 35.9% (OR:1.52, 95%CI:1.07–2.16; p = 0.01). Patients with BRCA1/2 mutations had median OS of 34.2 months with T + PLD vs. 20.9 months with PLD (HR:0.54, 95%CI:0.33–0.90; p = 0.016). Patients with BRCA1/2 mutations had median PFS of 10.1 months with T + PLD vs. 7.6 months with PLD (HR:0.72, 95%CI:0.48–1.08; p = 0.039). Patients with BRCA1/2 mutations and a 6–12 months platinum-free interval (PFI), median OS was 31.5 vs. 14.9 months, respectively (HR:0.37, 95%CI:0.17–0.82; p = 0.011). Grade 3–4 AEs were higher in T + PLD (79%) vs. PLD (54%). Conclusion Combination of T and PLD did not show favorable OS benefit nor safety; however, patients with germline BRCA1/2 mutations and/or a PFI of 6–12 months appear to have clinically relevant survival benefit with T + PLD. No new safety signals were identified.