Ovarian cancer is the ninth most common cancer in women—approximately 185 000 women died from the disease worldwide in 2018.1 At initial diagnosis, ovarian cancer typically responds to platinum-based therapy. However, cure remains elusive and disease recurs in approximately 70% of patients.2 At progression, most patients receive further chemotherapy, which is associated with toxicity. The type of chemotherapy administered usually depends on the timing of recurrence. If disease recurs 6 months or longer after completion of platinum-containing therapy, further platinum-based therapy (with or without bevacizumab) is widely used at first or second relapse. Cumulative myelosuppression, neurotoxicity, and allergy to platinum-based therapy can be limiting factors in patients receiving multiple lines of treatment.3, 4, 5 In three randomised, phase 3 trials, maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor (niraparib, olaparib, or rucaparib) significantly improved progression-free survival versus placebo after platinum-based chemotherapy for platinum-sensitive recurrent ovarian cancer.6, 7, 8 Previous trials of bevacizumab have shown minimal toxicity during the maintenance phase of treatment, with most toxicities appearing during the concomitant chemotherapy phase.9, 10
Research in context
Evidence before this study
The AVANOVA2 trial was designed to evaluate the combination of niraparib and bevacizumab administered using the schedule identified in the part 1 dose-escalation phase of the AVANOVA trial. At the time the trial was initially designed, results from the NOVA phase 3 trial evaluating niraparib as maintenance treatment were not available. Results from a randomised, phase 2 trial showed that combining the investigational anti-angiogenic agent cediranib with the PARP inhibitor olaparib significantly improved progression-free survival versus olaparib alone, especially in patients whose tumours did not harbour a germline BRCA mutation. A search of PubMed using the search terms “angiogenic”, “PARP”, and “ovarian” with no restriction on dates did not reveal any other trials evaluating the combination of an anti-angiogenic agent and a PARP inhibitor in ovarian cancer.
Added value of this study
The AVANOVA2 trial showed a significant improvement in progression-free survival with the combination of niraparib plus bevacizumab compared with niraparib alone, which was observed irrespective of homologous recombination deficiency status or chemotherapy-free interval. Both agents in the combination regimen are approved and well established treatments for ovarian cancer and the regimen was not hampered by the high incidences of diarrhoea previously observed with the investigational agent cediranib.
Implications of all the available evidence
Chemotherapy-free regimens are attractive to patients, avoiding the substantial toxicity of platinum-based regimens, and might enable prolongation of the chemotherapy-free interval. The combination regimen identified in AVANOVA2 will be compared with chemotherapy and bevacizumab in a randomised, phase 3 trial.
For patients with BRCA-mutated ovarian cancer and multiple disease relapses, single-agent PARP inhibitors show antitumour activity11, 12 and are considered appealing to patients, providing a chemotherapy-free treatment option. When the present trial was designed, phase 1 data were available showing the activity of niraparib in the treatment (vs maintenance) setting for ovarian cancer, irrespective of BRCA status.13 The subsequent single-arm QUADRA study14 in more than 400 patients showed the activity of single-agent niraparib in pretreated disease, irrespective of BRCA mutation or homologous recombination deficiency (HRD) status. Indirect evidence further supporting the treatment strategy emerged from analyses of the phase 3 maintenance trials showing complete responses in patients with measurable disease treated with maintenance PARP inhibitors.8, 15, 16 The proven efficacy of anti-angiogenic agents17, 18, 19 and PARP inhibitors offers the opportunity to develop chemotherapy-free combination regimens that avoid the need for repeated platinum-based therapies. Moreover, combining these two approaches could improve clinical outcomes: hypoxia induced by anti-angiogenic therapies might increase DNA damage and genetic instability,20 resulting in defective homologous recombination that could enhance sensitivity to PARP inhibitors.21 In a randomised, phase 2 trial in platinum-sensitive recurrent ovarian cancer, combination therapy with a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (cediranib, an unapproved investigational agent) and a PARP inhibitor (olaparib) significantly improved progression-free survival versus olaparib alone (median progression-free survival 16·5 months with the combination vs 8·2 months with olaparib alone; hazard ratio [HR] 0·50 (95% CI 0.30–0.83; p=0.006).22, 23 The progression-free survival benefit with the combination was driven by the treatment effect in patients with wild-type or unknown BRCA status, translating into an overall survival benefit in this subgroup (median overall survival 37·8 months with the combination vs 23·0 months with olaparib alone; HR 0.44 (95% CI 0.19–1.01, nominal p=0.047). However, cediranib-associated diarrhoea was problematic in the combination group, with 10 (23%) of 44 patients having grade 3 or 4 diarrhoea; 77% of the combination group required dose reductions.22 Furthermore, cediranib is not commercially available as treatment for ovarian cancer.
In the AVANOVA trial, we combined two agents that are approved for the treatment of recurrent ovarian cancer: the PARP inhibitor niraparib, which has shown efficacy in ovarian cancer irrespective of BRCA and HRD status, and the anti-VEGF monoclonal antibody bevacizumab, which has shown efficacy and good tolerability, leading to regulatory approval across treatment settings in ovarian cancer.9, 17, 18, 24, 25 AVANOVA part 1 (dose-escalation phase in 12 patients) identified a regimen of intravenous bevacizumab 15 mg/kg once every 3 weeks with once-daily niraparib 300 mg as capsules for phase 2 evaluation in AVANOVA2.26 This chemotherapy-free regimen showed good tolerability and encouraging activity in platinum-sensitive recurrent ovarian cancer. Here, we report results from the randomised, phase 2 AVANOVA2 trial designed to determine whether the combination of niraparib with bevacizumab improved progression-free survival compared with niraparib alone.