The China National Medical Products Administration has accepted a supplemental New Drug Application for niraparib for use as a frontline maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
Samantha Du, PhD, founder and chief executive officer of Zai Lab Limited
Samantha Du, PhD
The China National Medical Products Administration (NMPA) has accepted a supplemental New Drug Application (sNDA) for niraparib (Zejula) for use as a frontline maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.1
The sNDA is based on findings from the phase III PRIMA study (ENGOT-OV26/GOG-3012), in which frontline maintenance therapy with niraparib improved median progression-free survival (PFS) by 5.6 months compared with placebo for patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy.2,3
In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared with 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 <.001). In patients with tumors that tested positive for homologous recombination deficiency (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 <.001).
"We believe Zejula is a potential best-in-class PARP inhibitor due to its compelling efficacy, once-daily dosing and superior pharmacokinetic properties including its ability to cross the blood brain barrier," said Samantha Du, PhD, founder and chief executive officer of Zai Lab Limited, which in-licensed rights to Zejula from GSK for Mainland China, Hong Kong and Macau.
“The NMPA’s acceptance of our sNDA submission for Zejula as a first-line monotherapy treatment after surgery and platinum-based chemotherapy has the potential to both fundamentally change how women with ovarian cancer are treated in China and significantly expand Zejula’s market opportunity. Zai Lab remains committed to make a meaningful impact on the way cancer is treated in China and globally, and we plan to continue to develop and bring many new and innovative treatment options to patients in need,” added Du.
The PRIMA study randomized 733 patients 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. The median relative dose intensity in the study was 63%. Gonzalez-Martin noted that future presentations would focus on the potential impact of this dose change.
Patient characteristics were similar across groups. The ECOG performance status was 1 for approximately 70% of patients, two-thirds had a FIGO stage of III, and a third had stage IV disease. The primary tumor locations were the ovary, fallopian tube, and peritoneum. The majority of patients had serous histology (~95%). Most patients had achieved a complete response to prior chemotherapy (70%). Two-thirds of patients received neoadjuvant chemotherapy, and none received bevacizumab, as the study was designed prior to approval of the VEGF inhibitor in the frontline setting.
At the interim analysis, 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).
Analysis of the HRD group 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). In those with HRD-positive tumors who were negative for a BRCA mutations, the median PFS was 19.6 versus 8.2 months, for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.31-0.83).
Niraparib outperformed placebo across several patient subgroups for PFS, including those with HRD-negative tumors. 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). 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% vs 68.9%). Grade ≥3 treatment-related AEs were experienced by 65.3% of patients in the niraparib arm compared with 6.6% of those in the placebo group. The most common AEs of grade ≥3 severity in the niraparib and placebo groups, respectively, were anemia (31.0% vs 1.6%), thrombocytopenia (28.7% vs 0.4%), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 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, with 4.3% from thrombocytopenia.
Niraparib monotherapy is approved as a maintenance therapy in the recurrent ovarian cancer setting. The PARP inhibitor is also approved for the treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with ≥3 prior chemotherapy regimens, and whose cancer is associated with homologous recombination deficiency—positive status.
In the United States, also based on the PRIMA study, the FDA accepted an sNDA for niraparib in February 2020 for use as a frontline maintenance treatment for women with advanced ovarian cancer who responded to platinum-based chemotherapy regardless of biomarker status.