Niraparib significantly delays disease progression in patients with platinum-sensitive ovarian cancer
Results of a landmark phase III trial, presented at ESMO 2016 and simultaneously published in the New England Journal of Medicine, demonstrate that the PARP inhibitor niraparib significantly improves the outcome of platinum-sensitive recurrent ovarian cancer.1,2 With niraparib, the time to disease progression was significantly delayed in patients with recurrent ovarian cancer who previously responded to platinum-based chemotherapy. Interestingly, this progression-free survival (PFS) advantage with niraparib was seen regardless of the presence or absence of germline BRCA mutations or the homologous recombination DNA repair deficiency (HRD) status. In addition to this, niraparib also significantly improved the secondary endpoints of the study, including chemotherapy-free interval (CFI) and time to first subsequent treatment (TFST).
Despite a high initial response rate to platinum and taxane treatment in patients with advanced ovarian cancer, most patients eventually have a relapse. Platinum retreatment is used in patients in whom there is an assumed platinum sensitivity, but the efficacy of this approach diminishes over time and this strategy is also associated with a cumulative toxicity. The current options for maintenance therapy in Europe consist of bevacizumab, which can only be given once, with a PFS improvement of just a few months, and the PARP inhibitor olaparib, which is only approved in patients with a germline BRCA mutation (about 10-15% of ovarian cancer patients). The randomized, placebo-controlled, phase III ENGOT-OV16/NOVA trial evaluated the efficacy and safety of maintenance therapy with niraparib, a highly selective inhibitor of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) 1/2, in a broad population of patients with platinum-sensitive, recurrent ovarian cancer.
The trial included 553 patients with platinum-sensitive, recurrent ovarian cancer, of whom 203 had a germline BRCA mutation and 350 did not. Not later than 8 weeks after completing their last dose of platinum-based chemotherapy, patients were randomly assigned in a 2:1 ratio to receive either niraparib (300 mg) or placebo once daily in 28-day cycles (with no treatment breaks) until disease progression. In total, 60% of patients in the study received 2 lines of prior therapy, while 40% previously received more than 2 treatment lines. The majority of patients in the study had advanced disease (76% stage IIIC or IV disease). After a median follow-up of 16.9 months, the median PFS in the group of patients with germline BRCA mutations was 21.0 months with niraparib compared to 5.5 months with placebo (HR[95%CI]: 0.27[0.173- 0.410], p<0.0001). In the subgroup of patients without a BRCA mutation, the median PFS was 9.3 months with niraparib compared to 3.9 months with placebo (HR[95%CI]: 0.45[0.338-0.607], p<0.0001). In the population of patients who did not have BRCA mutations, but did have HRD, niraparib decreased the risk of disease progression or death with 62% (median PFS: 12.9 months vs. 3.8 months; HR[95%CI]: 0.38[0.243-0.586], p<0.0001). Finally, an exploratory analysis in patients who were BRCA-mutation negative and did not have HRD, the median PFS was 6.9 months with niraparib (N=92) as compared to 3.8 months with placebo (N=42) (HR[95%CI]: 0.58[0.361-0.922]; p=0.0226).
Significant improvements were also observed in all secondary endpoints. In fact, compared to placebo, niraparib significantly prolonged the second progression-free survival (median PFS2 in BRCA-mutant patients: 25.8 vs. 19.5 months; HR[95%CI]: 0.48[0.280-0.821]; p=0.0062; median PFS2 in BRCA-wildtype patients: median PFS2 18.6 vs. 15.6 months; HR[95%CI]: 0.69[0.494-0.964]; p=0.0293), time to first subsequent treatment (median TFST in BRCA-mutant patients: 21.0 vs. 8.4 months; HR[95%CI]: 0.31[0.205-0.481]; p< 0.0001; median TFST in BRCA-wildtype patients: 11.8 vs. 7.2 months; HR[95%CI]: 0.55[0.412-0.721]; p<0.0001), and chemotherapy-free interval (median CFI in BRCA-mutant patients: 22.8 vs. 9.4 months; HR[95%CI]: 0.26[0.169-0.414]; p<0.0001; median CFI in BRCA-wildtype patients: 12.7 vs. 8.6 months; HR[95%CI]: 0.50[0.370-0.666]; p<0.0001).
More than 10% of patients had grade 3/4 adverse events following treatment with niraparib, of whom 28% had thrombocytopaenia, 25% had anaemia, and 11% had neutropaenia. These were generally easy to resolve with dose adjustments, after which the vast majority of patients was able to continue their treatment. Patient-reported outcomes were similar with niraparib and placebo. Patients on niraparib maintained symptom control and had a quality of life comparable to those on placebo.
In summary, the PFS in patients with platinum-sensitive, recurrent ovarian cancer was significantly longer in the niraparib group than in the placebo group, regardless of the BRCA mutation and HRD status. Niraparib was shown to improve all endpoints across a broad patient population, representing 70% of all ovarian cancer patients. As such, these landmark results have the potential to change the way this disease is treated.
- Mirza M, Monk B, Oza A et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at ESMO 2016; Abstract LBA3_PR.
- Mirza M, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer. N Engl J Med. Epub ahead of print.