Efficacy And Safety Of Different PARP Inhibitors In Advanced Ovarian Cancer

Objective:At present,the efficacy of poly ADP ribose polymerase（PARP）inhibitors in maintenance treatment of advanced ovarian cancer has been well established in rife clinical studies.However,there is still no head-to-head study about the efficacy and incidence of adverse events of different PARP inhibitors.Therefore,the network meta-analysis by Stata 16.0 MP based on frequentist methodology was used to make comparison with regard to the efficacy and safety of different PARP inhibitors in advanced ovarian cancer（including newly diagnosed and recurrent ovarian cancer）.So as to provide a theoretical basis for the clinical selection and utilization of PARP inhibitors.Methods:Databases including Pub Med,The Cochrane Library,Embase,Scopus,Google Scholars,CNKI,Wanfang,VIP were retrieved for articles on PARP inhibitor therapy in advanced ovarian cancer from inception to January 2022.Handicraft search was additionally performed to enroll more dissertations.Then screening procedure was discreetly carried out according to the inclusion and exclusion criteria.The quality of enrolled literature was meticulously evaluated by Review Manager 5.3 based on Cochrane risk bias assessment tool.The primary outcomes were OS and PFS.The secondary outcomes were adverse events and cost-effectiveness.STATA 16.0 MP was implemented for network meta-analysis to generate odds ratio（OR）for binary outcomes and mean for consecutive outcomes.Then the consistency and inconsistency are tested to explore the stability of the results.Finally,the funnel chart was maded to observe the effect of small sample study.Results:Eventually 21 literature reporting 5359 patients and 9 interventions were enrolled.All patients were diagnosed with advanced ovarian cancer and classified into stage III or IV according to FIGO（including recurrence and non-recurrence）.The9 regimens were olaparib+antivascular drugs（including bevacizumab,cediranib,pazopanib）,niraparib+antivascular drugs,olaparib,niraparib,lucaparib,antivascular drugs,liposomal doxorubicin,non-platinum chemotherapy,placebo.The results of the network meta-analysis show that:（1）In all patients,at 6^thmonth,compared with placebo,olaparib+antivascular agents,niraparib+antivascular agents,olaparib,and niraparib significantly increased PFS rates by 2.03 to 26.76-fold,and olaparib（OR=0.17,95%CI=0.04 to 0.68,SUCRA=54.2%）was associated with niraparib（OR=0.11,95%CI=0.02 to 0.52,SUCRA=34.2%）was significantly inferior to olaparib+antivascular（SUCRA=96.5%）,while olaparib+antivascular was not significantly different from niraparib+antivascular.At 12^thmonth,the above four drugs significantly increased PFS rates by2.81 to 22.48-fold compared with placebo,and olaparib（OR=0.24,95%CI=0.07-0.82,SUCRA=61.9%）was significantly inferior to niraparib（OR=0.16,95%CI=0.04-0.71,SUCRA=43.9%）compared with olaparib+antivascular drug（SUCRA=95.4%）,and no significant difference between olaparib+antivascular drug and niraparib+antivascular drug.At 18^thmonth,the above four drugs still significantly increased PFS rates by 2.01 to 12.62-fold compared with placebo,and niraparib（OR=0.23,95%CI=0.06 to 0.87,SUCRA=41.4%）was significantly inferior to niraparib+antivascular drug（SUCRA=88%）,while olaparib（OR=0.40,95%CI=0.08to 1.96）,and no significant difference between olaparib+antivascular drug（OR=0.92,95%CI=0.13 to 6.50）and niraparib+antivascular drug.At 24^thmonth,compared with placebo,olaparib+antivascular agents,olaparib and niraparib significantly increased PFS rates by 1.53 to 10.36-fold,and niraparib（OR=0.22,95%CI=0.06 to0.88,SUCRA=46.6%）was significantly worse than olaparib+antivascular agents（SUCRA=96.7%）,but olaparib vs.olaparib+antivascular drug and no significant difference between olaparib and niraparib.At 30^thmonth,there was still a significant2.63 to 7.93-fold increase in PFS rates between olaparib and olaparib+antivascular agents compared with placebo,and there was no significant difference between them.（2）In patients with breast cancer susceptibility gene mutation（BRCAm）,PFS was consistently significantly better than placebo and not significantly different from each other at 6,12,18,and 24 months for olaparib+antivascular agents,lucaparib,olaparib,and niraparib.（3）In patients with Homologous Recombination Deficiency（HRD）,at 6^thmonth,compared with placebo,niraparib+antivascular drugs,lucaparib,olaparib and niraparib significantly increased PFS rates by 2.84 to 16.68-fold,and olaparib（OR=0.22,95%CI=0.06 to 0.83,SUCRA=51.3%）and niraparib（OR=0.22,95%CI=0.07 to 0.72,SUCRA=48.1%）were significantly inferior to niraparib+antivascular drugs（SUCRA=98.5%）and lucaparib was not significantly different from niraparib+antivascular drugs（OR=0.27,95%CI=0.07 to 1.03）.At 12^thand 18^thmonth,niraparib+antivascular drug,lucaparib,olaparib and niraparib remained significantly better than placebo,but there was no significant difference between the four.At 24^thmonth,compared with placebo,lucaparib,olaparib,and niraparib still significantly increased PFS rates by 2.18 to 17.88-fold,and niraparib（OR=0.17,95%CI=0.04-0.68,SUCRA=45.5%）was significantly inferior to lucaparib（SUCRA=98.6%）,while there was no significant difference between olaparib and lucaparib（OR=0.29,95%CI=0.07 to 1.22）.（4）In the OS analysis,at 24^thmonth,in all patients,olaparib+antivascular agents significantly increased OS rates by 0.58 to 2.13-fold compared with placebo,and there was no significant difference between the two.In BRCAm patients,olaparib（SUCRA=74.7%）versus niraparib（SUCRA=68.8%）was significantly better than placebo（SUCRA=14.9%）,and there was no significant difference between them,while there was no significant difference between olaparib combined with an antivascular drug and placebo.In HRD-positive patients,there was no significant difference between olaparib and niraparib compared to placebo.（5）In the probability of grade 3 and 4 adverse events,compared with placebo,the incidence of AEs was significantly increased 1.63 to 17.29-fold for olaparib,niraparib,olaparib+antivascular drugs and niraparib+antivascular drugs,and niraparib（OR=3.10,95%CI=1.88 to 5.13,SUCRA=31%）,olaparib+antivascular drugs（OR=4.90,95%CI=1.90 to 12.64,SUCRA=15.2%）,and niraparib+antivasc-ular drugs（OR=6.95,95%CI=2.53 to 19.08,SUCRA=6.1%）were significantly more frequent than olaparib（SUCRA=72.6%）.In terms of hematologic toxicity,in anemia,there was a significant incidence of olaparib+antivascular agents,olaparib,niraparib,lucaparib,and niraparib+antivascular agents compared with placebo,and there were no significant differences between them.In neutropenia,there was a significant difference between olaparib,niraparib and niraparib+antivascular agents compared with placebo,but no significant difference between the three.In thrombocytopenia,the incidence of niraparib and niraparib+antivascular agents was significantly higher than placebo.In gastrointestinal reactions,nausea and vomiting were analyzed and there was a significant incidence of olaparib,lucaparib,niraparib,olaparib+antivascular drug and niraparib+antivascular drug compared to placebo,but not significantly different from each other.Conclusion:At the level of PFS analysis,PARP inhibitors combined with antivascular agents were superior to PARP inhibitors alone compared with placebo for 18 months in all types of patients,while at 18 to 30 months,olaparib was not significantly different from olaparib+antivascular agents and niraparib was inferior to olaparib+antivascular agents.In patients with BRCA mutations,all PARP inhibitors significantly increased PFS rates,but were not significantly different from each other.niraparib was significantly worse than lucaparib and olaparib was not different from lucaparib in HRD-positive patients by 24 months of PFS.At the level of overall survival analysis,there were no significant differences among PARP inhibitors.In the probability of grade 3 and 4 adverse events,olaparib was significantly lower than other types of interventions,while no significant differences were found in separate analyses of hematological toxicity and gastrointestinal reactions,respectively.Of course,the above still needs to be confirmed by clinical studies with large samples.