The European Commission has approved niraparib for use as a frontline monotherapy maintenance option in adult patients with advanced epithelial, high-grade ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response after platinum-based chemotherapy.
The European Commission has approved niraparib (Zejula) for use as a frontline monotherapy maintenance option in adult patients with advanced epithelial, high-grade ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response (PR) after platinum-based chemotherapy.1
This regulatory decision marks niraparib as the first PARP inhibitor to receive approval for use in the European Union as a monotherapy for patients with advanced disease, irrespective of biomarker status, according to GlaxoSmithKline (GSK).
“Over 65,000 women in Europe are diagnosed with ovarian cancer each year,” Hal V. Barron, MD, chief scientific officer and president of R&D at GSK, stated in a press release. “This approval of [niraparib] means that many more women will have the option to receive this innovative medicine earlier, potentially extending the time they may spend without their devastating cancer progressing.”
Previously, in April 2020, the FDA approved niraparib for the same indication based on data from the pivotal phase 3 PRIMA trial (ENGOT-OV26/GOG-3012), which demonstrate that frontline maintenance treatment with the PARP inhibitor improved progression-free survival (PFS) by 5.6 months versus placebo in patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy.2,3
In the overall study population, the median PFS with niraparib versus placebo was 13.8 months and 8.2 months, respectively; this translated to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.50-0.76; P <.001). Patients with homologous recombination deficiency (HRD) positivity also experienced an improvement in median PFS with niraparib versus placebo, at 21.9 months versus 10.4 months, respectively (HR, 0.43; 95% CI, 0.50-0.76; P <.001).
In the double-blind, randomized, placebo-controlled phase 3 PRIMA trial, 733 patients were randomized 2:1 to receive either the PARP inhibitor (n = 487) or placebo (n = 246). Participants underwent randomization within 12 weeks of receiving the last cycle of chemotherapy.
At study start, niraparib was given at a fixed dose of 300 mg. For patients who weighed less than 77 kg or who had platelet counts that were below 150 L/μL, the dose was reduced to 200 mg. The median relative dose intensity in the trial was 63%. Treatment was administered once daily continuously over a 28-day cycle.
About 70% of patients included on the trial had an ECOG performance status of 1. One-third of patients had stage IV disease, while two-thirds had a FIGO stage of III. The primary tumor locations were ovarian, fallopian tube, and peritoneum. About 95% of participants had serous histology and two-thirds received neoadjuvant chemotherapy. No participants had received treatment with bevacizumab (Avastin) because the trial had been designed prior to the approval of the agent for use in the frontline setting.
The primary end point of the trial was PFS per blinded independent committee review, while secondary end points included overall survival (OS) and patient-reported outcomes (PROs). Stratification was based on whether patients received neoadjuvant chemotherapy, if their best response to frontline treatment led to a complete response (CR) or PR, HRD status, and the companion diagnostic used for each patient.
The median OS had not yet been reached at the time of the interim analysis, with data maturity at just 10.8%. In the overall study population, the OS rate at 24 months was 84% with niraparib versus 77% with placebo (HR, 0.70; 95% CI, 0.44-1.11). Patients with HRD positivity had a 24-month OS rate of 91% with the PARP inhibitor versus 85% with placebo (HR, 0.61; 95% CI, 0.27-1.39).
Investigators also evaluated PFS in patients with HRD positivity and BRCA mutations. The median PFS with niraparib versus placebo in patients who harbored a BRCA mutation was 22.1 months and 10.9 months, respectively (HR, 0.40; 95% CI, 0.27-0.62). In those with HRD positivity who did not harbor a mutation, the median PFS with the PARP inhibitor was 19.6 months versus 8.2 months with placebo (HR, 0.50; 95% CI, 0.31-0.83).
Patients who were not positive for HRD also experienced a PFS benefit with niraparib over placebo. The median PFS in these patients in the investigational versus placebo arms was 8.1 months versus 5.4 months, respectively (HR, 0.68; 95% CI, 0.49-0.94). In this subgroup, the 24-month OS rates with niraparib and placebo were 81% and 59%, respectively (HR, 0.51; 95% CI, 0.27-0.97).
Regarding safety, more any-grade treatment-related toxicities were observed with niraparib compared with placebo, at 96.3% versus 68.9%, respectively. The incidence of grade 3 or higher treatment-related adverse effects was also higher with the PARP inhibitor versus placebo, at 65.3% versus 6.6%, respectively. The most frequently reported effects that were grade 3 or higher in severity included anemia (31.0% with niraparib vs 1.6% with placebo), thrombocytopenia (28.7% vs 0.4%, respectively), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 1.2%).
Additionally, 70.9% of those who were given niraparib needed a dose reduction, while 12% reported toxicities that led to discontinuation of treatment. The effects that resulted in treatment discontinuation were myelosuppressive and included thrombocytopenia (4.3%).
Additionally, updated results from a subanalysis of PRIMA presented during the 2020 ESMO Virtual Congress showed that quality of life (QoL) according to PROs was not found to be reduced with niraparib versus placebo, despite toxicities associated with the treatment.4
The instruments used to evaluate PROs in PRIMA included the Functional Ovarian Symptoms Index (FOSI), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the EORTC Questionnaire Ovarian Cancer Module (EORTC QLQ-OV28), and the EurQol 5-Dimension 5-Level (EQ-5D-5L) assessment.
As part of the FOSI evaluation, participants answered questions that focused on lack of energy, nausea, vomiting, or stomach cramps. The mean FOSI health utility index (HUI) scores were found to be similar between the 2 treatment arms; this was true with regard to overall FOSI-assessed symptoms, as well.
Similar scores between the 2 arms were also reported via the EORTC QLQ-C30 questionnaire. No differences with regard to QoL, pain, or fatigue were reported between the 2 arms. The EORTC QLQ-QV28 evaluation for the subset of patients with ovarian cancer revealed no difference between the arms with regard to abdominal symptoms and chemotherapy-related effects.
Regarding the EQ-SD-SL questionnaire, the HUI-evaluated change from baseline was not determined to be statistically different in the investigational versus the control arm; this was also true for the EQ-SD-SL scores that were calculated through the use of a visual analog scale.
“Until now, only women with BRCA-mutant ovarian cancer, representing just 20% of patients with advanced ovarian cancer, were eligible to be treated with a PARP inhibitor as monotherapy in the first-line maintenance setting,” Antonio Gonzalez-Martin, MD, co-director of the Department of Medical Oncology at the Clinica Universidad de Navarra, added in the release. “Expanding the potential use of [niraparib], regardless of biomarker status, is an important step forward in treating this challenging cancer.”
In September 2020, niraparib was also approved for frontline maintenance in China for use in the same indication.