EU CHMP Recommends Approval of Zejula (Niraparib) for First-Line Maintenance Treatment of Advanced Ovarian Cancer Regardless of Biomarker Status; Already Marketed in China

September 22, 2020 /BioValleyBIOON/ ---GlaxoSmithKline(GSK) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending the approval of the targeted anticancer drug Zejula (Chinese brand name: Zele; generic name: niraparib) as a first-line maintenance therapy for patients with advanced ovarian cancer who have responded to platinum-based chemotherapy, regardless of theirBiomarkersHow is the status?

The CHMP opinion is the final step in the marketing authorization procedure prior to approval by the European Commission (EC). The CHMP opinion will now be submitted to the EC for review; the EC typically endorses the CHMP’s opinion and issues a final decision within two months. If approved,Zejula will become the first single-agent PARP inhibitor in the EU for first-line maintenance treatment of patients with advanced ovarian cancer who have responded to platinum-based chemotherapy.

In late April this year, Zejula received U.S.FDAApproved as monotherapy maintenance treatment for female patients with advanced ovarian cancer (including epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer) who have achieved complete or partial response to first-line platinum-based chemotherapy, regardless ofBiomarkersStatus Update. This approval marks a significant advancement in the treatment of ovarian cancer. Previously, only 20% of patients with ovarian cancer—specifically those harboring BRCA mutations (BRCAm)—were eligible for PARP inhibitor monotherapy as first-line maintenance treatment.

Clinical data show that, in the overall study population (regardless ofBiomarkersstatus), the BRCA-mutated population, the homologous recombination deficiency (HRD-positive) BRCA-wild-type population, and the homologous recombination proficient (HRD-negative) population, Zejula as first-line maintenance therapy reduced the risk of disease progression or death by 38%, 60%, 50%, and 32%, respectively, compared with placebo.

The application for Zejula as first-line monotherapy maintenance treatment for advanced ovarian cancer is based on the results of the Phase III PRIMA study (ENGOT-OV26/GOG-3012). In this study, patients with advanced-stage (Stage III or IV) disease who achieved a response after first-line platinum-based chemotherapy were randomized in a 2:1 ratio to receive either Zejula or placebo as maintenance therapy. The primary endpoint was progression-free survival (PFS). The study incorporated an individualized starting dose regimen for Zejula: patients with a baseline body weight <77 kg and/or a platelet count <150K/μL received a starting dose of 200 mg once daily; all other patients received a starting dose of 300 mg once daily.

The results showed that the study met its primary endpoint: in the entire study patient population (regardless ofBiomarkerstatus), when used as first-line maintenance therapy, Zejula significantly reduced the risk of disease progression or death by 38% compared with placebo (HR=0.62, 95% CI: 0.50–0.75, p<0.001). Importantly, clinically meaningful and statistically significant benefits were observed in both the homologous recombination deficiency (HRD-positive) and homologous recombination proficient (HRD-negative) subgroups. These results were driven by a clinically meaningful reduction in the risk of disease progression: BRCA-mutated tumors (60% risk reduction, HR=0.40, 95% CI: 0.27–0.62, p<0.001), homologous recombination deficient (HRD-positive) BRCA wild-type tumors (50% risk reduction, HR=0.50 [95% CI: 0.30–0.83], p=0.006), homologous recombination proficient (HRD-negative)Tumor(Risk reduced by 32%, HR=0.68 [95% CI=0.49–0.94], p=0.020).

In the interim analysis of overall survival (OS), Zejula also demonstrated an encouraging trend toward OS improvement compared with placebo. The prespecified interim OS analysis showed a benefit favoring Zejula in the overall study population (HR 0.70; 95% CI: 0.44–1.11). In the homologous recombination deficiency (HRD) subgroup, 91% of patients treated with Zejula were alive at 24 months of treatment, compared with 85% of those receiving placebo (HR=0.61; 95% CI: 0.27–1.40). These data are immature, and their significance is not yet fully clear. The interim OS analysis also showed that in the homologous recombination proficiency (HRP) subgroup, 81% of patients treated with Zejula were alive at 24 months of treatment, compared with 59% of those receiving placebo (HR=0.51; 95% CI: 0.27–0.97).

The safety profile observed in this study was consistent with the known safety profile of Zejula. The most common grade 3 or higherAdverse ReactionsIncludingAnemia(31%), thrombocytopenia (29%), and neutropenia (13%). Implementation of individualized dosing regimens based on body weight and/or platelet count can reduce the incidence of treatment-emergent adverse events (TEAEs) associated with hematologic therapy. No new safety signals were identified. Validated patient-reported outcomes indicated similar quality of life in the Zejula treatment group and the placebo group.

Globally, ovarian cancer is the eighth most common cause of cancer-related death among women. In the United States and Europe, approximately 22,000 and 65,000 women are diagnosed with ovarian cancer each year, respectively. Although first-line platinum-based chemotherapy achieves high response rates, approximately 85% of patients will experience disease recurrence. Once recurrent, the disease is difficult to cure, and the interval between recurrences shortens with each subsequent relapse.

The PRIMA study enrolled patients who responded to first-line platinum-based chemotherapy, including those at high risk of disease progression—a population with significant unmet medical needs that has been underrepresented in previous first-line ovarian cancer studies. This landmark study demonstrated the importance of Zejula as first-line maintenance therapy and its clinical benefits for women with ovarian cancer. First-line maintenance monotherapy with Zejula following surgery and first-line platinum-based chemotherapy provides patients with an important new treatment option, potentially fundamentally transforming the treatment paradigm for ovarian cancer.

The active pharmaceutical ingredient of Zejula is niraparib, an oral small-molecule poly(ADP-ribose) polymerase (PARP) inhibitor that leverages defects in DNA repair pathways to preferentially kill cancer cells. This mechanism of action endows the drug with the potential to treat a broad range of tumors characterized by DNA repair deficiencies. PARP is associated with a wide spectrum ofTumorType-related, especiallyBreast Cancerand ovarian cancer. Zejula was developed by Tesaro,GlaxoSmithKlineIn December 2018, Tesaro was acquired for $5.1 billion (approximately £4 billion). In late September 2016, Zai Lab entered into a licensing agreement with Tesaro, securing the rights to Zejula in mainland China, Hong Kong, and Macau.

Zejula was approved for marketing in March 2017. Currently, its approved indications include: (1) maintenance treatment of patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved a complete or partial response to platinum-based chemotherapy. (2) Treatment of patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously received three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either of the following two criteria: (a) deleterious or suspected deleterious BRCA mutation; (b) genomic instability score (GIS) positivity and disease progression more than 6 months after responding to the last platinum-based chemotherapy.

In Hong Kong and Macao, China, Zejula (Zele) was approved for marketing in October 2018 and June 2019, respectively. In mainland China, the National Medical Products Administration (NMPA) approved Zejula (Zele) on December 27, 2019, with the indication for maintenance treatment of adult patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved complete or partial response to platinum-based chemotherapy. (Bioon.com)

Original Source: GSK receives CHMP positive opinion recommendingapproval of Zejula (niraparib) as first-line monotherapy maintenance treatment for women with platinum-responsive advanced ovarian cancer