Maintenance Niraparib Shows Favorable OS in Platinum-Sensitive Recurrent Ovarian Cancer

Maintenance niraparib (Zejula) demonstrated a numerical improvement in overall survival (OS) compared with placebo in patients with previously treated platinum-sensitive, recurrent ovarian cancer, according to the results of an interim OS analysis of the NORA trial (NCT03705156).

Although OS was only at 44% maturity, there was a 16% reduction in the risk of death with niraparib, with a median OS of 46.32 (95% CI, 41.03–not evaluable [NE]) with niraparib and 43.37 months (95% CI, 33.08-NE) with placebo (HR, 0.821; 95% CI, 0.558-1.207; P=.3152).

“[The] NORA study demonstrated that niraparib maintenance treatment using an individualized starting dose provides a favorable [OS] trend compared with placebo in the intention-to-treat population, germline BRCA-mutated population, and non–germline BRCA-mutated population with platinum-sensitive, recurrent ovarian cancer,” Mansoor Raza Mirza, MD, chief oncologist in the Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark, stated when presenting data from the analysis in December 2022 during a European Society for Medical Oncology Virtual Plenary session.¹

NORA is a randomized, double-blind, placebo-controlled phase 3 trial exploring the use of individualized starting doses of niraparib in Chinese patients with platinum-sensitive, recurrent ovarian cancer.

Prior results from the study showed significantly improved progression-free survival (PFS) with niraparib compared with placebo. In the intention-to-treat population, the median PFS was 18.3 months (95% CI, 10.9-NE) with niraparib vs 5.4 months (95% CI, 3.7-5.7) with placebo (HR, 0.32; 95% CI, 0.23-0.45; P<.0001). By germline BRCA mutation status, those with the mutation had a median PFS of not reached (NR; 95% CI, 11.0-NE) vs 5.5 months (95% CI, 3.7-6.9) with niraparib and placebo, respectively (HR, 0.22; 95% CI, 0.12-0.39; P<.0001), and 11.1 months (95% CI, 7.5-NE) vs 3.9 months (95% CI, 3.7-6.9) for those without a germline BRCA mutation (HR, 0.40; 95% CI, 0.26-0.61; P<.0001).²

Investigators conducted an ad hoc interim analysis to get an early indication of the OS benefit of niraparib in this patient population. They also adjusted survival by censoring patients in the placebo arm who switched to receive subsequent PARP inhibition.

Patients in the niraparib arm (n=177) were followed for OS for a median of 45.67 months (range, 6.93-58.02) and 44.45 months (range, 5.13-53.16) in the placebo arm (n=88).

Mirza clarified that OS benefit was seen despite patients in the placebo arm going on to receive subsequent PARP inhibition. In the placebo arm, 43% of patients went on to receive a PARP inhibitor, including 54% of patients with a germline BRCA mutation. When adjusting for subsequent PARP inhibition, the median OS was 46.32 months (95% CI, 41.03-NE) in the niraparib arm and 34.30 months (95% CI, 31.80-NE) in the placebo arm (HR, 0.692; 95% CI, 0.446-1.074; P=.0988).

In the germline BRCA mutation subgroup, the median OS was NR (95% CI, 35.38-NE) in the niraparib arm compared with 47.61 months (95% CI, 31.57-NE) in the placebo arm (HR, 0.764; 95% CI, 0.398-1.464). When adjusting again for subsequent PARP treatment, the median OS with placebo was 42.09 months (HR, 0.882; 95% CI, 0.387-2.011).

Among those with no germline BRCA mutations, the median OS was 43.10 months (95% CI, 38.41-NE) with niraparib and 38.41 months (95% CI, 29.54-NE) with placebo (HR, 0.855; 95% CI, 0.529-1.381). Adjustment for PARP inhibition after the study showed a median OS of 32.59 months (95% CI, 23.69-NE) with placebo (HR, 0.624; 95% CI, 0.371-1.047).

OS analyses by subgroup did not show a detrimental effect for any group, according to Mirza. Yet, patients who achieved a complete response to prior chemotherapy (HR, 0.582; 95% CI, 0.328-1.032) and those with a shorter time to progression after prior treatment (HR, 0.623; 95% CI, 0.330-1.175) showed particular benefit. Older patients showed less benefit with an HR of 1.685 (95% CI, 0.540-5.263), although this was a small subgroup (n=37).

No new safety signals were observed in the interim analysis. One patient in the niraparib arm who had a germline BRCA mutation developed myelodysplastic syndrome and another developed acute myeloid leukemia.

Study Design

NORA enrolled patients with platinum-sensitive, recurrent ovarian cancer who had a high-grade serous or predominantly serous histology or a known germline BRCA mutation. Additionally, patients were required to have completed at least 2 prior lines of platinum-containing therapy and achieved a partial or complete response to the most recent chemotherapy regimen.

Patients were randomly assigned 2:1 to either the niraparib or placebo arms and received their individualized dose until disease progression or unacceptable toxicity. All patients were stratified by germline BRCA mutation status, response to last chemotherapy, and time to progression after last regimen.

The protocol for the study was amended to individualized starting doses after the first 16 patients, who all received 300 mg. Starting doses were 200 mg daily for patients with a baseline body weight below 77 kg or platelet count below 150,000/μL, and 300 mg for those above these thresholds.

The primary end point was PFS by blinded independent central review; secondary end points included OS, chemotherapy-free interval, time to first subsequent therapy, and safety.

Participants were enrolled from September 2017 through February 2019. The OS interim analysis was conducted with a data cutoff of September 23, 2022.

Patient characteristics were balanced between the 2 arms. Overall, patients had a median age of 54 years (range, 35-78) and the majority of patients had an ECOG performance status of 1 (60.4%), high-grade serous histology (98.1%), at least 12 months to progression from the time of the last platinum-based regimen (68.3%), a complete response to prior therapy (51.7%), and no germline BRCA mutations (62.3%).

At the time of the analysis cutoff, 21.5% of patients in the niraparib arm were still receiving treatment compared with 2.3% in the placebo arm.

_REFERENCES:

_{1. Mirza MR, Wu X, Zhu J, et al. VP7-2022: An ad-hoc interim overall survival results of niraparib with individualized starting dose as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (NORA): a double-blind, randomized, placebo-controlled, phase III trial. Ann Oncol. 2022;34(1):124-125. doi:10.1016/j.annonc.2022.11.007}

_{2. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2021;32(4):512-521. doi:10.1016/j.annonc.2020.12.018}