Maintenance niraparib significantly improves the progression-free survival of patients with newly diagnosed ovarian cancer
Results of the phase III PRIMA study demonstrated that frontline maintenance therapy with the PARP inhibitor niraparib significantly improves the median progression-free survival (PFS) by 5.6 months compared to placebo in patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy. In fact, compared to placebo, maintenance therapy with niraparib resulted in a 38% reduction in the risk of disease progression or death. In the subgroup of patients with homologous repair deficiency (HRD) the benefit of niraparib was even more pronounced, where the median PFS was increased from 10.4 with placebo to 21.9 months with niraparib, representing a 57% reduction in the risk of progression. Interestingly, in contrast to what was reported in the PAOLA-1 trial (see newsletter 1), HRD proficient patients also experienced a significant PFS benefit when they received niraparib maintenance (32% reduction in progression risk).
Advanced ovarian cancer is a leading cause of cancer death in women with up to 85% recurrence after completion of standard first-line platinum-based chemotherapy. Currently, there are three options for patients following first-line chemotherapy: active surveillance or maintenance therapy with either olaparib or bevacizumab. However, the use of olaparib is restricted to patients with BRCA mutations (20%) and the use of bevacizumab is limited by safety concerns and limited data in the growing number of patients receiving neoadjuvant chemotherapy. More recently, results of the NOVA study formed the basis for the approval of the PARP inhibitor niraparib as a maintenance option for all patients with recurrent ovarian cancer (both BRCA mutant and wild type). The phase III PRIMA/ENGOT-OV26/GOG-3012 study was designed to test the efficacy and safety of niraparib therapy after a response to platinum-based chemotherapy in patients with newly-diagnosed advanced ovarian cancer, including those at high-risk of relapse.
In this study, 733 patients were randomized in a 2:1 ratio to receive niraparib (n=487) or placebo (n=246). Patients were randomized within 12 weeks of finishing the last cycle of chemotherapy. At the initiation of the study, niraparib was given at a fixed dose of 300 mg, which was adjusted to include a lower dose of 200 mg for those weighing less than 77 kg and for those with platelet counts below 150K/μL. Overall, the median relative dose intensity in the study was 63%.
Patient characteristics were similar across groups. The median age of patients in the trial was 62 years, 35% had stage IV disease, 99.6% of patients with stage III disease had residual disease post debulking surgery and 67% of patients received neoadjuvant chemotherapy (no bevacizumab). The best response to platinum-based chemotherapy was a CR in 69% of the patients (31% partial response) and 51% had HRD (30% BRCA mutant 21% BRCA wild type). In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared to 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR 0.62 [95% CI: 0.50-0.76]; p<0.001). At 18 months, 42% of patients in the niraparib arm were alive and free of progression as compared to 28% in the placebo arm.
In patients with tumours that tested positive for HRD, the median PFS was 21.9 months with niraparib compared with 10.4 months for placebo (HR 0.43 [95% CI: 0.50-0.76]; p<0.001). At 18 months, this translates into a 24% higher PFS rate in the niraparib arm compared to placebo (59% versus 35%). Niraparib also outperformed placebo in patients with HRD-negative tumours. In this group, the median PFS was 8.1 months with niraparib and 5.4 months for placebo (HR 0.68 [95% CI: 0.49-0.94]). The PFS analysis in function of HRD was further broken down by BRCA status. For those with a BRCA mutation, the median PFS was 22.1 months with niraparib compared with 10.9 months for placebo (HR 0.40 [95% CI: 0.27-0.62]). Interestingly, patients with HRD-positive tumours who do not have a BRCA mutation also derived a more pronounced benefit from niraparib maintenance. In these patients, the median PFS was 19.6 versus 8.2 months, for niraparib and placebo respectively, corresponding to a 50% reduction in the risk of disease progression or death (HR 0.50 [95% CI: 0.31-0.83]).
At the interim analysis, the median overall survival (OS) was not yet reached, at just 10.8% data maturity. At this early time point, however, the 24-month OS rate in the full population was 84% in the niraparib group and 77% in the placebo arm (HR 0.70 [95% CI: 0.44-1.11]). In the HRD-positive cohort, the 24-month OS rate was 91% with niraparib and 85% for placebo (HR 0.61 [95% CI: 0.27-1.39]). Interim OS data for HRD-negative patients showed an 81% 24-month OS rate for niraparib compared with 59% for placebo (HR 0.51 [95% CI: 0.27-0.97]).
More patients experienced treatment-related adverse event (AE) of any grade in the niraparib arm compared with placebo (96.3% versus 68.9%). Grade ≥3 treatment-related AEs were experienced by 70.5% of patients in the niraparib arm compared with 18.9% of those in the placebo group. The most common AEs of grade ≥3 severity in the niraparib and placebo groups, respectively, were anaemia (31.0% versus 1.6%), thrombocytopenia (28.7% versus 0.4%), platelet count decrease (13.0% versus 0%), and neutropenia (12.8% versus 1.2%). Overall, 70.9% of patients required a dose reduction in the niraparib arm, and 12% of patients discontinued therapy due to AEs. The main AEs relating to discontinuation were myelosuppressive in nature (thrombocytopenia in 4.3%).
Niraparib therapy in patients with advanced ovarian cancer provided a clinically relevant and statistically significant improvement in PFS after response to first-line platinum-based chemotherapy in the overall patient population, with an HR of 0.62. This PFS benefit was most pronounced in HRD patients (HR: 0.43), but HRD proficient patients also experienced a PFS benefit from niraparib maintenance (HR: 0.68). As such, niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarkers subgroups after platinum-based chemotherapy in first line, consistent with prior clinical studies evaluating niraparib in recurrent ovarian cancer (NOVA and QUADRA). No new safety signals were observed and quality of life was maintained on niraparib. As such, niraparib monotherapy after first-line platinum-based chemotherapy should be considered a new standard of care in this setting.
Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Presented at ESMO 2019, Abstract LBA1.