Phase III NORA Trial: Niraparib Maintenance Shows Overall Survival Trend in Platinum-Sensitive Recurrent Ovarian Cancer
Maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor may do more than just delay disease progression for patients with platinum-sensitive, relapsed ovarian cancer; it might also improve overall survival, according to data presented during the December 2022 European Society for Medical Oncology (ESMO) Virtual Plenary.1
Ad hoc interim overall survival results of niraparib maintenance treatment using an individualized starting dose demonstrated a favorable overall survival trend compared with placebo. Based on the adjusted overall survival analysis, median overall survival increased from 34 months to 46 months (hazard ratio [HR] = 0.69). Niraparib was also well tolerated, with no new safety signals identified based on longer-term follow-up, authors of the study reported.
“Despite the fact that 43% of patients in the placebo arm crossed over to receive the PARP inhibitor after relapse, adjusted overall survival analysis showed improved median overall survival in the intention-to-treat population, including both germline BRCA–mutated and nongermline BRCA–mutated subgroups of patients,” said lead study author Mansoor Raza Mirza, MD, Chief Oncologist at Rigshospitalet, Copenhagen University Hospital, and Medical Director of the Nordic Society of Gynecologic Oncology–Clinical Trial Unit, Denmark.
Mansoor Raza Mirza, MD
As Dr. Mirza explained, NORA is the first double-blind, randomized, placebo-controlled, phase II trial evaluating the efficacy and safety of niraparib as maintenance treatment with an individualized starting dose in a Chinese population with platinum-sensitive recurrent ovarian cancer.
Patients who had high-grade serous or dominantly high-grade serous ovarian cancer and had received at least two previous lines of platinum-containing chemotherapy and were in partial or complete remission to their last platinum-based regimen were randomly assigned to receive niraparib once daily or placebo once daily until disease progression or unacceptable toxicity. Patients were stratified according to germline BRCA mutation status, response to last chemotherapy, and time to disease progression after penultimate platinum-based regimen (6–12 months vs > 12 months).
The previously reported primary analysis showed significantly improved progression-free survival with niraparib maintenance compared with placebo in patients with platinum-sensitive relapsed ovarian cancer, regardless of germline BRCA mutation status. In the intention-to-treat population, median progression-free survival increased from 5.4 months to 18.3 months (HR = 0.32). Progression-free survival also increased in both germline BRCA–mutated (HR = 0.22) and nongermline BRCA–mutated (HR = 0.40) subgroups, respectively.
The aim of this ad hoc interim analysis was to investigate the effect of niraparib on overall survival in this population. Both unadjusted and adjusted overall survival analyses were performed. The first data cutoff was for primary analysis in February 2020. The overall survival data cutoff was September 2022.
Ad Hoc Interim Analysis
As Dr. Mirza reported, overall survival maturity at the time of data cutoff was 44%. In the intention-to-treat population, median overall survival was numerically longer with niraparib vs placebo, increasing from 43 months to 46 months.
According to Dr. Mirza, however, it is important to note that 43% of patients in the placebo arm crossed over to receive a PARP inhibitor after disease progression, including 54% in the germline BRCA–mutated subgroup and 26% in the nongermline BRCA–mutated subgroup.
“In the overall survival analysis adjusted to subsequent PARP inhibitor therapy in the intention-to-treat population, we saw an increase in median overall survival from 24 months to 46 months, with a hazard ratio of 0.692,” said Dr. Mirza. He noted that a consistent overall survival trend was observed by censoring patients receiving a PARP inhibitor in the placebo arm, regardless of germline BRCA status.
Unadjusted subgroup analysis for patients with germline BRCA–mutated disease favored overall survival for niraparib maintenance despite crossover to a PARP inhibitor in the control arm in 54% of patients (HR = 0.764). The adjusted analysis still showed improved overall survival with niraparib maintenance (HR = 0.882).
- Niraparib maintenance therapy using an individualized starting dose demonstrated a favorable overall survival trend compared with placebo in the intention-to-treat population in both patients with germline BRCA–mutated and nongermline BRCA–mutated, platinum-sensitive, relapsed ovarian cancer.
- According to the study investigators, all subgroups, including those stratified by age, time to disease progression, best response to last platinum-based chemotherapy, and germline BRCA mutation status, benefited from niraparib with respect to overall survival.
Similarly, in the nongermline BRCA–mutated population, unadjusted analysis showed an increase in median overall survival from 38 months to 43 months despite crossover to a PARP inhibitor in the control arm in 36% of patients (HR = 0.855). Adjusted overall survival with the subsequent PARP inhibitor treatment showed an increase in median overall survival from 32 months to 43 months (HR = 0.624).
“Regardless of the subgroup, our analysis found no detrimental effects with PARP inhibitor maintenance,” said Dr. Mirza. “All subgroups, including those stratified by age, time to disease progression, best response to last platinum-based chemotherapy, and germline BRCA mutation status, benefited from niraparib with respect to overall survival.”
Of note, no new safety signals were observed as of the most recent data cutoff. Two patients (1.1%) with germline BRCA mutation in the niraparib arm developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). No patients developed MDS or AML in the placebo arm, said Dr. Mirza.
DISCLOSURE: Dr. Mirza has reported financial relationships with AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zai Lab, Ultimovacs, Apexigen, and Deciphera.
1. Mirza MR, Wu X, Zhu J, et al: 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. ESMO Virtual Plenary. Abstract VP7-2022. Presented December 15, 2022.
Abstract discussant of the NORA trial, Antonio González-Martín, MD, PhD, Director of the Department of Medical Oncology at Clinica Universidad de Navarra, Madrid, said that despite the results of this ad hoc interim analysis, “the jury is still out” regarding the overall survival benefit of PARP...