The Efficacy and Adverse Effects of Niraparib in Ovarian Cancer: a Prospective Real-world Product Registration Study.

1. Research status at domestic and foreign

Ovarian cancer is the second fatal gynecological cancer. More than 70% of ovarian cancer patients are diagnosed as advanced. Standard treatments include optimal reduction surgery and platinum/taxane chemotherapy. Epithelial ovarian cancer (EOC) is the most common histological type of ovarian cancer, up to 20% of high-grade serous ovarian cancer shows germline and/or somatic mutations in the BRCA1/BRCA2 gene. BRCA1 and BRCA2 are tumor suppressor genes that play a central role in repairing DNA double-strand breaks (DSB) through homologous recombination (HR). Due to their increased sensitivity to DNA damage reagents, they extend the survival period of BRCA1 and BRCA2 mutant EOCs, among which BRCA2 vectors have the best survival rate. Poly-ADP-ribose polymerase (PARP) 1 is a key ribozyme involved in single-strand break repair through the base excision repair pathway. In the absence of PARP activity, these lesions are considered to have transformed into DSB. Cells lacking HR, such as BRCA mutant cells, are extremely sensitive to PARP inhibition. This phenomenon called "synthetic lethality" has led people to study PAPP inhibitors used as therapeutic agents in BRCA1/BRCA2 carriers.

Niraparib was approved by the National Medical Products Administration on December 27, 2019. It can be used as a maintenance treatment for adult patients with platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer after platinum-containing chemotherapy has achieved complete or partial remission. On September 10, 2020, niraparib became a PARP inhibitor approved in China and globally, which can be used as a single agent for the maintenance treatment of first-line and recurrent ovarian cancer regardless of the patient's biomarker status. On December 28, 2020, niraparib has been included in the new version of the medical insurance catalog. The results of the international phase III clinical trial (NOVA) of niraparib showed that niraparib can prolong the median progression-free survival of ovarian cancer patients regardless of whether the patients have germline BRCA mutations. Among patients with gBRCA mutations, the risk of disease progression was reduced by 73% and progression-free survival was 4-fold longer than in the placebo group (21 months vs. 5.5 months). In patients without the gBRCA mutation, the risk of disease progression was reduced by 55% and progression-free survival was more than 2-fold longer (9.3 months vs 3.9 months). The PRIMA clinical study showed that niraparib, as single-agent maintenance therapy, can significantly prolong the progression-free survival of first-line platinum-responsive ovarian cancer patients. The risk of disease progression and death was reduced by 38% across all treated patient populations. In BRCA-mutated, HRD-positive, and HRD-negative patients, niraparib reduced the risk of disease progression or death by 60%, 57%, and 32%, respectively. This study proves that niraparib becomes the first PARP inhibitor that can significantly improve the progression-free survival of patients regardless of biomarker status, which is expected to change the treatment of ovarian cancer in China. Recently, the first all-round, multicenter phase III clinical study in a Chinese population (NORA) showed that in patients with gBRCA mutations, median progression-free survival (PFS) was significantly longer with niraparib as second-line maintenance therapy, compared with placebo (not reached vs. 5.5 months, HR: 0.22) and those without gBRCA mutation at ESMO 2020(11.1 vs. 3.9 months, HR: 0.40). The QUADRA study shows that niraparib has a substantial survival benefit in women treated for ovarian cancer, especially in HRD-positive platinum-sensitive patients, including not only BRCA-mutated patients but also the BRCA wild-type population.

The above-mentioned studies based on niraparib are mostly randomized controlled trials (RCTs). Because RCTs often have strict inclusion and exclusion criteria, they are carried out in a highly standardized environment, so that the research subjects have good homogeneity. The validity is high, but the research results may not be able to be extrapolated to practice. Therefore, it is necessary to evaluate the role of treatments for advanced diseases in the real environment. To provide better guidance for patients, real-world evidence is needed to make up for the lack of randomized controlled trials. At present, in real-world research, there are only retrospective studies on the use of niraparib in ovarian cancer at home and abroad, and the results are consistent with their corresponding RCTs. There is a lack of prospective real-world evidence with higher levels of evidence. 2. Study drugs

The drug name is niraparib Tosylate capsules. This product is a 100mg capsule. 3. Research programs