Ovarian cancer is one of the most common reproductive system tumors. The incidence of ovarian cancer in China is on the rise. Poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) is a DNA repair enzyme associated with DNA damage repair. PARPi takes PARP as a target to kill tumor cells, especially for tumors with homologous recombination (HR) dysfunction. Currently, PARPi has been widely used in clinical practice, mainly for the maintenance of advanced ovarian epithelial cancer. The intrinsic or acquired drug resistance of PARPi has gradually become an important clinical problem with the wide application of PARPi. This review summarizes the mechanisms of PARPi resistance and the current progress on PARPi-based combination strategies.

Poly ADP-ribose polymerase inhibitors (PARPi), which approved in recent years, are recommended for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer and other cancers by The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Because most of PARPi are metabolized by cytochrome P450 enzyme system, there are extensive interactions with other drugs commonly used in cancer patients. By setting up a consensus working group including pharmaceutical experts, clinical experts and methodology experts, this paper forms a consensus according to the following steps: determine clinical problems, data retrieval and evaluation, Delphi method to form recommendations, finally formation expert opinion on PARPi interaction management. This paper will provide practical reference for clinical medical staff.
聚腺苷二磷酸核糖聚合酶抑制剂(PARPi)是近年上市被美国国立综合癌症网络(NCCN)和中国临床肿瘤学会(CSCO)指南推荐用于上皮性卵巢癌、乳腺癌、胰腺癌、前列腺癌等肿瘤治疗的药物。大多数PARPi通过细胞色素P450酶代谢，因此与肿瘤患者常用的其他药物之间存在广泛的相互作用。文章通过组建包括药学专家、临床专家、方法学专家等人员的共识工作组，按照确定临床问题、资料检索评价、德尔菲法形成共识意见，最终形成PARPi相互作用管理的指导性专家意见，为临床医务人员提供实践参考。.

High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.

Poly ADP-ribose polymerase inhibitor (PARPi) has become an important maintenance therapy for ovarian cancer after surgery and cytotoxic chemotherapy, which has changed the disease management model of ovarian cancer, greatly decreased the risk of recurrence, and made the prognosis of ovarian cancer better to certain extent. The three PARPis currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ovarian cancer are Olaparib, Niraparib and Rucaparib. With the incremental results from new clinical trials, the applicable population of PARPi for ovarian cancer have expanded to population with non-BRCA mutations. Although BRCA mutated population are still the main beneficiaries of PARPi, recent clinical trials indicated PARPis\' therapeutic potential in non-BRCA mutated population, especially in homologous recombination repair deficiency (HRD) positive population. However, lack of unified HRD status detection method poses a challenge for the accurate selection of PARPi beneficiaries. The reversal of homologous recombination (HR) function during the treatment will not only cause resistance to PARPis, but also reduce the accuracy of the current method to determine HRD status. Therefore, the development of reliable HRD status detection methods to determine the beneficiary population, as well as rational combination treatment are warranted. This review mainly summarizes the latest clinical trial results and combination treatment of PARPis in ovarian cancer with non-BRCA mutations, and discusses the application prospects, including optimizing combination therapy against drug resistance, developing unified and accurate HRD status detection methods for patient selection and stratification. This review further poses an interesting topic: the efficacy and safety in patients retreated with PARPis after previous PARPi treatment---\"PARPi after PARPi\".

OBJECTIVE: The treatment landscape for ovarian cancer has shifted in recent years with the approval of poly ADP-ribose polymerase inhibitors in 2014. Most patients with ovarian cancer have advanced disease at diagnosis. Understanding how treatments for advanced disease work in real-world settings must be assessed to provide care for these patients. Therefore, the objective of this study was to locate and assess real-world studies measuring the safety and effectiveness of poly ADP-ribose polymerase inhibitors and analyze the results.Data sources: A targeted systematic literature review was conducted in April 2020 of PubMed/Medline. Inclusion criteria consisted of observational studies using real-world data of olaparib, rucaparib, or niraparib as an intervention in the treatment of ovarian cancer. In addition, studies needed to assess either clinical effectiveness or safety. Once studies were identified, we aimed to narratively describe the studies\' patient population, intervention effectiveness, and/or safety.Data summary: Our systematic review identified six studies assessing the real-world effectiveness and/or safety of poly ADP-ribose polymerase inhibitors, with five assessing olaparib, one assessing poly ADP-ribose polymerase inhibitors as a composite, and none assessing either niraparib or rucaparib. The median progression free survival in the real-world trials for olaparib ranged from 12.7 to 15.6 months. The median overall survival in the real-world trials for olaparib ranged from 30.9 to 35.4 months. Rates of treatment discontinuation due to adverse events for olaparib ranged from 4.4% to 12.5%.
CONCLUSIONS: The identified studies showed slightly higher, but comparable results for median progression free survival, median overall survival, and discontinuation due to adverse events compared to the respective randomized controlled trials.