The Efficacy and Adverse Effects of Olaparib 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 (HGSOC) 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 (DSBS) 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-adenosine diphosphate-ribose polymerase 1 is a key ribozyme involved in single-strand break (SSB) repair through the base excision repair pathway. In the absence of poly adenosine diphosphate-ribose polymerase(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 poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) used as therapeutic agents in BRCA1/BRCA2 carriers.

Olaparib is the first oral PARPi approved in the United States in December 2014 for the fourth-line treatment of advanced ovarian cancer with BRCA mutations. In the early development of PARPi olaparib, studies have found that platinum sensitivity seems to be related to a higher objective response rate between BRCA carriers and non-carriers. Gelmon et al. designed a phase II randomized trial Study 19, which evaluated the efficacy of olaparib and placebo as maintenance therapy in patients with platinum-sensitive serous ovarian cancer recurrence. Compared with the placebo group, the median progression-free survival (PFS) of the olaparib group was significantly longer (8.4 months for the olaparib group and 4.8 months for the placebo group (HR=0.35; [95) % credibility interval (CI) =0.25-0.49]; p<0.001). Post-hoc analysis showed that among BRCA germline mutations (gBRCA) carriers, the improvement of PFS in the olaparib group was greater (HR≤0.18; [95%CI=0.10-0.31]; p <0.0001). The SOLO2 study is a randomized, controlled phase III randomized controlled trial, which further confirmed the findings of patients with gBRCA mutations in Study 19. At present, based on the latest National Comprehensive Cancer Network (NCCN) guidelines and guidelines for the clinical application of PAPPi for ovarian cancer, the first-line recommends PARPi+bevacizumab (Bev) maintenance therapy, and PARPi maintenance therapy is the standard treatment for platinum-sensitive recurrent epithelial ovarian cancer.

The above-mentioned studies based on olaparib 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 world. 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 researches, there are only retrospective studies on the use of olaparib in ovarian cancer at home and abroad, and the results are consistent with its corresponding RCTs. There is a lack of prospective real-world evidence with higher levels of evidence. 2. Study drugs

The drug name is olaparib tablets. This product is a film-coated tablet. 1)150mg: green to green/gray, oval, biconvex tablets, with "OP150" engraved on one side and blank on the other side. 2)100mg: yellow to dark yellow, oval, biconvex tablets, with "OP100" engraved on one side and blank on the other side. 3. Research programs