DataSheet1_Efficacy and safety of PARP inhibitors combined with antiangiogenic agents in the maintenance treatment of ovarian cancer: a systematic review and meta-analysis with trial sequential analysis of randomized controlled trials.DOCX

Background: Poly (ADP-ribose) polymerase (PARP) inhibitor and antiangiogenic agent monotherapy have shown to be effective as maintenance treatment in patients with ovarian cancer (OC). However, there is currently a lack of evidence-based study to directly compare the effects of combination therapy with these two drugs. Therefore, this study aimed to compare the efficacy and safety of combination therapy with PARP inhibitors and antiangiogenic agents in women with OC using a meta-analysis.
Methods: An exhaustive search of literature was undertaken using multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library to identify pertinent randomized controlled trials (RCTs) published up until 17 December 2023. The data on progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were pooled. We computed the pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for PFS and OS, along with the relative risks (RRs) and 95% CIs for AEs. Trial sequential analysis, heterogeneity test, sensitivity analysis, and publication bias assessment were performed. Stata 12.0 and Software R 4.3.1 were utilized for all analyses.
Results: This meta-analysis included 7 RCTs with a total of 3,388 participants. The overall analysis revealed that combination therapy of PARP inhibitors and antiangiogenic agents significantly improved PFS (HR = 0.615, 95% CI = 0.517–0.731; 95% PI = 0.379–0.999), but also increased the risk of AEs, including urinary tract infection (RR = 1.500, 95% CI = 1.114–2.021; 95% PI = 0.218–10.346), fatigue (RR = 1.264, 95% CI = 1.141–1.400; 95% PI = 1.012–1.552), headache (RR = 1.868, 95% CI = 1.036–3.369; 95% PI = 0.154–22.642), anorexia (RR = 1.718, 95% CI = 1.320–2.235; 95% PI = 0.050–65.480), and hypertension (RR = 5.009, 95% CI = 1.103–22.744; 95% PI = 0.016–1580.021) compared with PARP inhibitor or antiangiogenic agent monotherapy. Our study has not yet confirmed the benefit of combination therapy on OS in OC patients (HR = 0.885, 95% CI = 0.737–1.063). Additionally, subgroup analyses further showed that combination therapy resulted in an increased risk of AEs, encompassing thrombocytopenia, vomiting, abdominal pain, proteinuria, fatigue, headache, anorexia, and hypertension (all p < 0.05).
Conclusion: Our study demonstrated the PFS benefit of combination therapy with PARP inhibitors and antiangiogenic agents in patients with OC. The OS result need to be updated after the original trial data is mature. Clinicians should be vigilant of AEs when administering the combination therapy in clinical practice.
Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023494482.

背景：聚ADP核糖聚合酶（Poly (ADP-ribose) polymerase，PARP）抑制剂与抗血管生成药物单药治疗，均已被证实可作为卵巢癌（OC）患者的维持治疗方案。然而目前尚缺乏循证医学研究直接比较二者联合治疗的疗效。因此本研究旨在通过Meta分析（meta-analysis），对比PARP抑制剂联合抗血管生成药物治疗卵巢癌女性患者的有效性与安全性。
方法：本研究通过PubMed、Web of Science、Embase及Cochrane图书馆等多个数据库进行全面文献检索，筛选截至2023年12月17日发表的相关随机对照试验（randomized controlled trials，RCT）。合并无进展生存期（progression-free survival，PFS）、总生存期（overall survival，OS）及不良事件（adverse events，AEs）相关数据，计算PFS与OS的合并风险比（hazard ratios，HR）及其95%置信区间（confidence intervals，CI），同时计算不良事件的合并相对危险度（relative risks，RR）及其95%置信区间（CI）。本研究开展了试验序贯分析（trial sequential analysis）、异质性检验（heterogeneity test）、敏感性分析（sensitivity analysis）及发表偏倚评估（publication bias assessment），所有统计分析均采用Stata 12.0及R 4.3.1软件完成。
结果：本Meta分析共纳入7项随机对照试验，涉及3388名受试者。整体分析结果显示，相较于PARP抑制剂或抗血管生成药物单药治疗，PARP抑制剂联合抗血管生成的联合治疗可显著改善患者无进展生存期（HR=0.615，95%CI=0.517~0.731；95%预测区间（prediction interval，PI）=0.379~0.999），但同时会升高不良事件发生风险，包括尿路感染（urinary tract infection，RR=1.500，95%CI=1.114~2.021；95%预测区间=0.218~10.346）、疲乏（fatigue，RR=1.264，95%CI=1.141~1.400；95%预测区间=1.012~1.552）、头痛（headache，RR=1.868，95%CI=1.036~3.369；95%预测区间=0.154~22.642）、食欲减退（anorexia，RR=1.718，95%CI=1.320~2.235；95%预测区间=0.050~65.480）及高血压（hypertension，RR=5.009，95%CI=1.103~22.744；95%预测区间=0.016~1580.021）。本研究尚未证实联合治疗对卵巢癌患者总生存期的获益（HR=0.885，95%CI=0.737~1.063）。此外，亚组分析（subgroup analyses）进一步显示，联合治疗会升高血小板减少症（thrombocytopenia）、呕吐（vomiting）、腹痛（abdominal pain）、蛋白尿（proteinuria）、疲乏、头痛、食欲减退及高血压等不良事件的发生风险（所有P<0.05）。
结论：本研究证实，PARP抑制剂联合抗血管生成药物治疗可改善卵巢癌患者的无进展生存期。总生存期的相关结果需待原始试验数据成熟后进一步更新。临床医师在临床实践中采用该联合治疗方案时，需警惕不良事件的发生。
系统评价注册：https://www.crd.york.ac.uk/PROSPERO/，注册编号CRD42023494482。