OCTOVA: A randomised phase II trial of olaparib, chemotherapy, or olaparib and cediranib in patients with BRCA-mutated platinum-resistant ovarian cancer

Abstract

Background Women with platinum resistant ovarian cancer (OC) have limited responses to standard therapy, and clinical trials with novel agents are therefore highly justified. Olaparib is a potent PARP inhibitor that has shown enhanced activity in women with relapsed BRCA-mutated OC in both platinum sensitive and resistant settings. Angiogenesis inhibitors, such as the oral tyrosine kinase inhibitor cediranib, are active in OC, and have shown additive effects when combined with PARP inhibitors preclinically, as hypoxia-induced downregulation of homologous recombination repair genes, BRCA1, 2 and RAD51 enhances PARP inhibitor sensitivity. Recent phase 2 trials in relapsed platinum-sensitive OC have also shown benefit from the combination of olaparib and cediranib compared to olaparib alone. The OCTOVA trial investigates the benefit of single agent olaparib compared to olaparib and cediranib or weekly paclitaxel in women with BRCA-mutated platinum-resistant OC. Trial design Eligible patients for OCTOVA are females aged ≥16 years with a germline or somatic BRCA1 or 2 mutation who have progressed within 6 months of previous platinum-based therapy. Patients may have received prior PARP inhibitor and antiangiogenic therapy, with at least a 6-month interval since treatment. 132 patients will be randomised, with stratification for prior PARP inhibitor exposure and prior anti-angiogenic therapy, to one of three treatment arms: paclitaxel (80mg/m2 weekly), olaparib (300mg twice daily), or cediranib (20mg once daily) and olaparib (300mg twice daily), until disease progression or unacceptable toxicity develops, and will be followed up for 18 months. Patients who progress on weekly paclitaxel will be permitted to crossover and receive single agent olaparib therapy. The primary analysis will compare the efficacy (as measured by progression-free survival) of olaparib compared to combination of olaparib and cediranib, and independently olaparib compared to paclitaxel. Secondary endpoints include safety and tolerability of the combination of olaparib and cediranib, overall survival, objective response rate, and quality of life outcomes. Clinical trial identificat