Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis

Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis Xu Liu, Kan Wu, Dan Zheng, Chuanxu Luo, Yu Fan, Xiaorong Zhong, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-116023/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBC). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC. Methods On August 2020, we searched all published phase II/III clinical studies of PARP inhibitors in advanced/metastatic TNBC patients. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points included overall response rate (ORR), progression-free survival (PFS) and adverse events. Results Ten clinical trials were identified, with a total of 1495 patients included. Pooled analyses showed that the addition of PARP inhibitors could provide a significant improvement of ORR (risk ratio [RR]=2.00, 95% confidence interval [CI]: 1.14–3.50, p=0.02) and PFS (hazard ratio [HR]=0.68, 95 %Cl: 0.59-0.77, p<0.0001) compared to chemotherapy in the whole population. In subgroup analysis, BRCA mutated patients have a higher objective response to PARP inhibitor, with a RR of 2.85 (95%CI: 1.34–6.06, p=0.007) compared to BRCA wild-type patients. However, no significant differences in ORR were observed between homologous recombination deficiency (HRD) positive and non-HRD subgroup (RR=1.82, 95%CI: 0.81–4.08, p=0.14). Hematologic toxicities were common adverse events of PARP inhibitors. Conclusions PARP inhibitors are an effective option for the treatment of advanced or metastatic TNBC patients. BRCA mutated patients could derive more benefits from PARP inhibitors when compared to BRCA wild-type patients. In clinical application, hematological toxicity related to PARP inhibitors should be monitored regularly. Cancer Biology Oncology Metastatic triple-negative breast cancer PARP inhibitor BRCA mutation Homologous recombination deficiency Efficacy Safety Figures Figure 1 Figure 1 Figure 1 Figure 2 Figure 2 Figure 2 Figure 3 Figure 3 Figure 3 Figure 4 Figure 4 Figure 4 Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, accounting for 15 to 20% of all cases of breast cancer.( 1 , 2 ) Cytotoxic chemotherapy is currently the mainstay of treatment for TNBC due to lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.( 3 ) Unfortunately, TNBC is frequently resistant to chemotherapy and eventually evolves lethal metastatic disease, with a median survival of approximately 1 year.( 4 , 5 ) Notably, more than one-third of TNBC patients will have distant metastases,( 6 ) and no standard of care therapy exists for metastatic TNBC (mTNBC) patients.( 7 ) Therefore, development of new therapeutic approach for patients with mTNBC are urgently needed. With the advancement of genomics analysis, new druggable targets are being identified, which may contribute to broadening the novel therapeutic scenario for mTNBC. Among patients with TNBC, about 10–30% cases present with BRCA1 or BRCA2 gene mutations.( 8 , 9 ) On the other hand, approximately 70% of BRCA1 -mutated breast cancers are triple negative phenotype.( 10 ) BRCA1 and BRCA2 genes are involved in the homologous recombination repair (HRR) pathway and responsible to repair DNA double-strand breaks. HRR pathway also contains many other genes such as ATM, PALB2, RAD51, CDK12, CHK1/2 . Alterations on these genes can lead to homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase (PARP) is an important enzyme in the repair of DNA single-strand breaks.( 11 , 12 ) Thus, inactivation of PARP in tumors with HRD will increase genomic instability, ultimately result in cell death. Preclinical studies have shown that cancer cells with functional BRCA1 or BRCA2 mutation are sensitive to PARP inhibition,( 13 ) providing a strong rationale for treating mTNBC with PARP inhibitors. There are currently several PARP inhibitors being tested in clinical trials for mTNBC patients. Based on the promising results observed in clinical trials, olaparib has been approved by the Food and Drug Administration (FDA) for the treatment of patients with germline BRCA -mutated, HER2-negative metastatic breast cancer.( 14 , 15 ) Whereas, several clinical trials suggested that PARP inhibitors also conferred a survival benefit in metastatic TNBC patients irrespective of BRCA status.( 16 , 17 ) Thus, in this systematic review and meta-analysis, we aimed to comprehensively evaluate the efficacy and safety of PARP inhibitors in advanced or metastatic TNBC based on available clinical trial results. We also explored biomarkers to identify the subgroups of patients who could most benefit from PARP inhibitors. Methods Search strategy On August 2020, A systematic literature search was performed by two independent reviewers through PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.( 18 ) The search terms are as following: ((“Poly(ADP-ribose) Polymerase inhibitors” OR “PARP inhibitors”) OR “Olaparib” OR “rucaparib” OR “talazoparib” OR “veliparib” OR “niraparib” OR “iniparib”) AND (“breast”) AND (“randomized controlled trial” OR “clinical trial”). Inclusion and exclusion criteria Inclusion criteria: ( 1 ) Phase II and Phase III clinical trials evaluating the efficacy of PARP inhibitor as single-agent or in combination with other anticancer drugs in patients with advanced or metastatic TNBC were considered for inclusion. ( 2 ) The eligible studies mentioned objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or safety outcomes. ( 3 ) Only English-language articles were included. Exclusion criteria: ( 1 ) Phase I clinical trial, case reports, editorials, review articles, retrospective studies were excluded; ( 2 ) Single-arm studies that did not report BRCA or HRD status were not included. ( 3 ) Clinical trials focused on neoadjuvant therapy. ( 4 ) Finally, for the continuously updated and published follow-up data, the latest results were considered for analysis. The selected studies were identified based on inclusion and exclusion criteria by two independent reviewers (X. Liu and K. Wu). Data extraction Two authors (Xu. Liu and K. Wu) independently extracted data from eligible studies included in the meta-analysis. The following data was included: first author's information, year of publication, study design, trial phase, ClinicalTrial.gov Number, sample size, BRCA or HRD status, type of intervention/control, efficacy results (ORR and PFS) and numbers of adverse events (AEs) in each arm. If the PFS was only represented by Kaplan-Meier curve, the Engauge digitizer 4.1 software was used to digitize and extract the data (only in one study( 19 )). Risk of bias assessment The potential risks of bias in the selected studies was independently assessed by two reviewers (Xu. Liu and K. Wu), using the Cochrane Risk of bias tool, which included selection bias, performance bias, detection bias, attrition bias, reporting bias, and other possible sources of bias. The risk of bias was graded as high, low or unclear risk. Disagreement was resolved through consensus or a third reviewer (X.R. Zhong). Study objectives The objectives of this study were to compare the antitumor efficacy and safety between the PARP inhibitor group and the chemotherapy group. The primary outcomes of this meta-analysis were ORR and PFS, AEs were the secondary outcomes. We also performed exploratory subgroup analyses to investigate treatment activity of PARP inhibitors in the BRCA mutated vs BRCA wild-type group, and HRD group vs non-HRD group. Statistical analysis The hazard ratio (HR) with its 95% confidence interval (CI) was calculated to compare the PFS. The risk ratios (RR) and 95% CI was calculated to measure the ORR and AEs. A two-sided p value 50% and p value < 0.05), a random effects model was applied; otherwise a fixed effect model was used. Funnel plot was used to detect potential publication bias. All statistical analyses were performed using Review Manager software version 5.3. Results Study selection and characteristics After the electronic databases searches, a total of 2689 records were initially retrieved (Fig. 1 ). After removing duplicates and screening titles and abstracts, only 27 full-text articles were further assessed for their eligibility based on inclusion/exclusion criteria. After full-text review, 17 published articles were excluded for the following reasons: 5 articles did not report the related outcomes of this study population; five studies reported the results from the same population; 4 were clinical trials for neoadjuvant therapy in TNBC; two single-arm studies did not report HRD or BRCA mutation status; one single-arm study only reported BRCA mutation. Ultimately, 10 clinical trials were included for final pooled analysis, including 7 randomized controlled trials( 14 , 16 , 17 , 19 – 22 ) and 3 single-arm studies.( 23 – 25 ) For BROCADE study,( 21 ) they randomly set up two comparison groups: veliparib with carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel, and veliparib plus temozolomide versus placebo plus carboplatin/paclitaxel, we only evaluated veliparib plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel in order to avoid statistical influences on research weights. The main features of the selected studies and enrolled patients were summarized in Table 1 . All clinical trials reported the antitumor efficacy of PARP inhibitors in patients with advanced or metastatic TNBC, ranging from 21 to 519 patients per study. Globally, a total of 1495 patients were included in the meta-analysis, of whom 735 patients harbored somatic or germline BRCA1/2 mutations. Table 1 Characteristics of the selected studies. Study (Year) Study Name (NCT number) Phase Study design Treatment Total no. of TNBC patients No.of BRCA mut patients No.of BRCA wt patients No.of HRD patients Gelmon et al. (2011) NCT00679783 II Single-arm Olaparib 21 5 16 NA O’Shaughnessy et al. (2011) NCT00540358 II RCT Iniparibs + gemcitabine and carboplatin vs gemcitabine and carboplatin 123 NA NA NA O’Shaughnessy et al. (2014) NCT00938652 III RCT Iniparibs + gemcitabine and carboplatin vs gemcitabine and carboplatin 519 NA NA NA Kummar et al. (2016) NCT01306032 II RCT Veliparib + cyclophosphamide vs cyclophosphamide 45 7 4 NA Robson et al. (2017) OlympiAD NCT02000622 III RCT Olaparib vs standard therapy 150 150 0 NA Litton et al. (2018) EMBRACA NCT01945775 III RCT Talazoparib vs standard single-agent therapy 190 190 0 NA Han et al. (2018) BROCADE NCT01506609 II RCT Veliparib + carboplatin/paclitaxel vs placebo + carboplatin/paclitaxel 120 120 0 NA Vinayak et al. (2019) TOPACIO NCT02657889 II Single-arm Niraparib + pembrolizumab 55 15 27 20 Shimomura et al. (2019) EO UMIN000018721 II Single-arm Olaparib + Eribulin 29 5 24 9 Diéras et al. (2020) BROCADE3 NCT02163694 III RCT Veliparib + carboplatin-paclitaxel vs placebo + carboplatin/paclitaxel 243 243 0 NA NCT ClinicalTrials.gov identifier, TNBC Triple-negative breast cancer, BRCA mut BRCA mutation, BRCA wt BRCA wild type, HRD homologous recombination deficiency. Efficacy of PARP inhibitors in advanced/metastatic TNBC PARP inhibitors vs control To evaluate the effect of PARP inhibitors on the patients with advanced/metastatic TNBC, we first conducted a pooled analysis comparing the antitumor efficacy between the PARP inhibitor group and the chemotherapy group. Seven randomized controlled trials were pooled into the analysis of ORR or PFS,( 14 , 16 , 17 , 19 – 22 ) which included 778 advanced/metastatic TNBC patients who received PARP inhibitors (Olaparib, iniparibs, veliparib or talazoparib) and 568 participants who were administered with chemotherapies. In the whole population, the pooled RR showed that PARP inhibitor treatment significantly improved the incidence of achieving ORR compared to chemotherapy (RR = 2.00, 95% CI: 1.14–3.50, p = 0.02) (Fig. 2 a). The pooled analysis for PFS indicated that the PARP inhibitor group had a better PFS when compared with the chemotherapy group (HR = 0.68, 95% Cl: 0.59–0.77, p < 0.0001) (Fig. 3 a). With regard to the clinical benefit of PARP inhibitors in patients with BRCA mutation, four randomized controlled trials were eligible for the analysis of ORR or PFS.( 14 , 20 – 22 ) The studies above showed that compared with chemotherapy, the PARP inhibitor treatment significantly improved ORR (RR = 3.63, 95% CI: 2.18–6.05, p < 0.0001) (Fig. 2 b), and PFS (HR = 0.61, 95% CI: 0.50–0.74, p < 0.0001) in the germline/somatic BRCA mutated patients (Fig. 3 b). Three clinical trials focused on the efficacy of PARP inhibitors in advanced or metastatic TNBC irrespective of BRCA or HRD status,( 16 , 17 , 19 ) we performed a pooled analysis in this unselected population. Results showed that no significant difference in terms of the ORR was observed between the PARP inhibitor group and the chemotherapy group (RR = 1.22, 95% CI: 0.99–1.52, p = 0.07) (Fig. 2 c). However, PARP inhibitors had significant improvements in PFS (HR = 0.74, 95% CI: 0.62–0.89, p = 0.001) (Fig. 3 c). Subgroup analysis of the efficacy of PARP inhibitors BRCA mutated vs BRCA wild-type To further compare the efficacy of PARP inhibitors in the BRCA mutated and BRCA wild-type populations, we subsequently conducted an exploratory analysis directly comparing these two groups. Three studies mentioned ORR in two subgroups and were incorporated into this analysis.( 23 – 25 ) Subgroup analysis demonstrated that PARP inhibitors could provide a significant improvement in ORR to the BRCA mutated patients in comparison to the BRCA wild-type patients, with a RR of 2.85 (95% CI: 1.34–6.06, p = 0.007) (Fig. 4 a). HRD vs non-HRD It is still unclear whether, in addition to BRCA mutations, HRD status can be used as a biomarker to predict PARP inhibitors sensitivity in the advanced/metastatic TNBC setting. Therefore, we performed subgroup analyses of the HRD positive group vs. the non-HRD group to address this question. Two articles were eligible for this analysis, and only ORR data was available in two studies with less statistical power.( 24 , 25 ) Interestingly, there were not significant differences in ORR when comparing the HRD positive subgroup to the non-HRD subgroup (RR = 1.82, 95% CI: 0.81–4.08, p = 0.14) (Fig. 4 b). Adverse events of PARP inhibitor In this study, seven randomized controlled trials that reported AEs were used to risk analysis. The comparative safety profile in terms of AEs of interest was shown in Table 2 . On the whole, the results showed that the incidence of AEs in the PARP inhibitor group was similar to that in the chemotherapy group, regardless of any grade AEs (98.94% vs. 98.98%, RR = 1.00, 95% CI: 0.99–1.01, p = 0.66), and grade ≥ 3 AEs (76.32% vs. 79.68%, RR = 0.97, 95% CI: 0.88–1.07, p = 0.54). Notably, PARP inhibitor weakly increased the overall risk to suffer serious AEs compared with chemotherapy (26.88% vs. 24.57%, RR = 1.18, 95% CI: 1.00–1.38, p = 0.05). In PARP inhibitor group, for any grade events, the five most common AEs were nausea (64.00%), neutropenia (60.30%), thrombocytopenia (59.20%), anemia (59.17%) and fatigue (51.70%); and for grade ≥ 3 AEs, they were neutropenia (47.03%), thrombocytopenia (30.32%), anemia (27.56%), leukopenia (14.78%) and fatigue (5.13%). The pooled data showed that compared with the chemotherapy group, the PARP inhibitor group had an increased incidence of AEs in terms of grade ≥ 3 thrombocytopenia (p < 0.001), any grade nausea (p < 0.001) and any grade vomiting (p = 0.04). Table 2 Summary of the adverse events (AEs). Adverse events No. of studies Adverse events/total patients (%) RR 95%CI P value PARP inhibitors Control treatment Any grade adverse events 6 1311/1325 (98.94) 779/787(98.98) 1.00 0.99–1.01 0.66 Grade ≥ 3 adverse events 6 809/1060 (76.32) 541/679 (79.68) 0.97 0.88–1.07 0.54 Any grade neutropenia 6 799/1325 (60.30) 533/787 (67.73) 0.90 0.78–1.03 0.12 Grade ≥ 3 neutropenia 7 633/1346 (47.03) 430/805 (53.42) 0.85 0.69–1.05 0.13 Any grade anemia 6 784/1325 (59.17) 407/787 (51.72) 1.22 0.97–1.54 0.09 Grade ≥ 3 anemia 7 371/1346 (27.56) 158/805 (19.63) 1.52 0.86–2.67 0.15 Any grade thrombocytopenia 5 663/1120 (59.20) 359/696 (51.58) 1.19 0.99–1.43 0.06 Grade ≥ 3 thrombocytopenia 6 346/1141 (30.32) 149/714 (20.87) 1.50 1.26–1.77 < 0.001 Any grade leukopenia 6 346/1325 (26.11) 209/787 (26.56) 0.95 0.82–1.10 0.51 Grade ≥ 3 leukopenia 7 199/1346 (14.78) 121/805 (15.03) 1.00 0.81–1.22 0.98 Any grade fatigue 6 685/1325 (51.70) 415/787 (52.73) 1.05 0.97–1.14 0.22 Grade ≥ 3 fatigue 6 68/1325 (5.13) 44/787 (5.59) 1.04 0.72–1.51 0.83 Any grade nausea 6 848/1325 (64.00) 439/787 (55.78) 1.17 1.09–1.26 < 0.001 Grade ≥ 3 nausea 6 30/1325 (2.26) 21/787 (2.67) 0.87 0.49–1.55 0.64 Any grade constipation 5 406/1120 (36.25) 245/696 (35.20) 1.12 0.99–1.27 0.08 Grade ≥ 3 constipation 5 6/1120 (0.54) 3/696 (0.43) 1.19 0.35–4.06 0.78 Any grade vomiting 6 424/1325 (32.00) 224/787 (28.46) 1.16 1.01–1.33 0.04 Grade ≥ 3 vomiting 6 32/1325 (2.42) 11/787 (1.40) 1.69 0.87–3.29 0.12 Any grade diarrhea 6 394/1325 (29.74) 214/787 (27.19) 1.08 0.94–1.24 0.29 Grade ≥ 3 diarrhea 6 32/1325 (2.42) 22/787 (2.80) 0.82 0.49–1.37 0.44 Any grade decreased appetite 4 215/1013 (21.22) 105/484 (21.69) 0.99 0.80–1.21 0.89 Grade ≥ 3 decreased appetite 4 7/1013 (0.69) 2/484 (0.41) 1.49 0.36–6.13 0.58 Quality of included studies The ‘Risk of bias graph’ revealed that this meta-analysis had moderate risk of selection bias, because 3 out of 10 clinical trials were single-arm studies (Supplementary Fig. 1). We performed the funnel plots to detect the publication bias, the results suggested that there was a relatively low risk publication bias (Supplementary Fig. 2). Discussion The results of this study highlight that compared with chemotherapy, PARP inhibitors can safely and significantly improve the ORR and PFS in patients with advanced/metastatic TNBC. Furthermore, exploratory analysis showed that the BRCA mutated patients could derive more benefits from PARP inhibitors compared with BRCA wild-type patients. However, we did not observe any difference in tumor control between HRD positive patients and non-HRD patients. Based on those recent clinical evidences, BRCA mutation, rather than HRD status, can be used as a predictive biomarker for response to PARP inhibitors in the advanced/metastatic TNBC setting. Preclinical studies showed that PARP inhibitors have greater efficacy in BRCA -deficient cells when compared with wild-type cells.( 26 , 27 ) In the clinical setting, a proof-of-concept trial by Tutt showed that PARP inhibition treatment has a favourable therapeutic index in BRCA -mutated advanced breast cancer patients.( 28 ) Based on these results, over the past years, several clinical trials have been conducted and are currently evaluating the role of different PARP inhibitors in this population. Specifically, olaparib has been approved in BRCA -mutated HER2-negative metastatic breast cancer patients as the first targeted therapy based on the results of the OlympiAD study.( 14 ) In view of this meta-analysis, our conclusion also confirmed that patients with BRCA mutations might be prime candidates for PARP inhibition treatment. However, our analysis also found that PARP inhibitors could provide significant improvement in PFS for unselected patients, regardless of BRCA mutational status. Similarly, in the phase II and III clinical trials for metastatic TNBC patients irrespective of BRCA status,( 16 , 17 ) the gain in PFS was obtained in the PARP inhibition group compared with the chemotherapy group. In addition, those with BRCA mutation account for only a small proportion of breast cancer patient.( 29 ) Hence, only using BRCA status as a predictive biomarker for PARP inhibitors sensitivity is insufficient and may miss many potential responders. The major question for oncologists is how to go about practically selecting advanced/metastatic TNBC patients who will benefit from PARP inhibitor therapy? Following large-scale sequence analysis, besides BRCA1/2 gene, many other HRD-mutation genes ( ATM , CHK1/2 , and PTEN ) were found to be correlated with PARP inhibition sensitivity, and could be utilized as alternative biomarkers for identifying vulnerable population.( 30 – 32 ) In clinical situations, HRD status has a good predictive power for the benefits of PARP inhibitors in several cancer types, like ovarian cancer, prostate cancer, and gastric cancer.( 33 ) However, in this study, we did not observe any improvement in ORR for HRD positive patients compared with HRD negative patients. It should be noted that there were only two relevant studies in this subgroup analysis with small sample size, which has less statistical power and is difficult to draw strong conclusions. In the future, more clinical trials are needed to evaluate the predictive value of HRD in the TNBC setting, and explore new biomarkers for determining optimal patients who are more likely to benefit from PARP inhibitors. As PARP inhibitors has gradually been approved for clinical applications worldwide, the evaluation of safety and tolerance of PARP inhibitors in patients is very of value and indispensable. Our pooled analysis of 1346 advanced/metastatic breast cancer patients treated with PARP inhibitors from seven randomized controlled trials showed that the three most common AEs of grade 3 and above were neutropenia (47.03%), thrombocytopenia (30.32%), and anemia (27.56%), suggesting the risks of hematologic toxicities caused by PARP inhibition treatment are more common and serious. Similarly, a meta-analysis of eight clinical trials also found that olaparib could significantly increase the risk of severe neutropenia in cancer patients.( 34 ) This may be because PARP inhibitor not only can interfere with DNA repair in cancer cells, but also may interfere with rapidly dividing blood cells, thus leading to myelosuppression. Notably, our meta-analysis showed that the PARP inhibitors did not increase the incidence of grade ≥ 3 AEs except for the risk of thrombocytopenia when compared with chemotherapy. Overall, PARP inhibitors seem to be generally safe and tolerable for advanced/metastatic breast cancer patients, but the high risk of PARP inhibitor-related hematologic toxicities is a trouble that cannot be ignored and should be considered in clinical application. There are several limitations in the present meta-analysis. First, the potential bias of this study included heterogenous inclusion criteria, patients and treatment schedule in the included trials, for example, age, race, disease status, and interventional arm, these confounding variables were not stratified properly and incorporated into the meta-analysis. In addition, there are few comparative studies on the efficacy of PARP inhibitors between HRD-positive patients and HRD-negative patients, which makes it difficult to fully assess the benefit of PARP inhibitors based on patients’ HRD status. Therefore, it is warranted to conduct randomized controlled trials with longer clinical follow-up in the future. Conclusions Our findings confirm that the addition of PARP inhibitor is a more effective, well tolerable and useful treatment in advanced/metastatic TNBC patients when compared with chemotherapy. We also support the view that BRCA status can be used as a predictive biomarker for PARP inhibitor sensitivity to guide clinical decision-making. However, the predictive value of HRD status still needs further evaluation in future studies. Hematologic toxicities are common adverse events, thus regular hematological monitoring is warranted for patients treated with PARP inhibitors. Abbreviations AEs: adverse events; CI: confidence interval; FDA: Food and Drug Administration; HR: hazard ratio; HRD: homologous recombination deficiency; HRR: homologous recombination repair; ORR: overall response rate; PARP: Poly (ADP-ribose) polymerase; PFS: progression-free survival; PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis; RR: risk ratio; TNBC: triple-negative breast cancer Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the key program of the Science and Technology Department of Sichuan Province [grant number: 2017SZ0005 to HZ]; and the 135 project for disciplines of excellence, West China Hospital, Sichuan University [grant number: ZYGD18012 to HB]. Authors' contributions XL, KW, and XRZ conceived and designed the analysis; XL, and KW collected the data; XL, KW, and DZ analyzed the data; and CXL, YF, XL, and HZ interpreted the data. All authors were involved in the drafting, critical review, and approval of the final manuscript and the decision to submit for publication. Acknowledgements Not applicable. References Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama. 2006;295(21):2492-502. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. 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Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol. 2019. Shimomura A, Yonemori K, Yoshida M, Yoshida T, Yasojima H, Masuda N, et al. Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy. Transl Oncol. 2019;12(10):1386-94. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-7. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-21. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235-44. Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(13):1460-8. Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010;116(22):4578-87. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-15. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6-7):315-22. Yi T, Feng Y, Sundaram R, Tie Y, Zheng H, Qian Y, et al. Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas. Int J Cancer. 2019;145(5):1209-20. Guo XX, Wu HL, Shi HY, Su L, Zhang X. The efficacy and safety of olaparib in the treatment of cancers: a meta-analysis of randomized controlled trials. Cancer Manag Res. 2018;10:2553-62. Supplementary Files SupplementaryFigure1.tif SupplementaryFigure1.tif SupplementaryFigure1.tif SupplementaryFigure2.tif SupplementaryFigure2.tif SupplementaryFigure2.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-116023","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":5347784,"identity":"eda0c5e9-2173-4179-bd54-9bd85cbb4712","order_by":0,"name":"Xu Liu","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Liu","suffix":""},{"id":5347785,"identity":"8a3bc579-ad18-4eec-8202-97c5a769d923","order_by":1,"name":"Kan Wu","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kan","middleName":"","lastName":"Wu","suffix":""},{"id":5347786,"identity":"b71dd970-13a3-42a8-80d9-2ac6122c367a","order_by":2,"name":"Dan Zheng","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Zheng","suffix":""},{"id":5347787,"identity":"d536bc14-add8-45e4-b51e-0c9ed4ee9116","order_by":3,"name":"Chuanxu Luo","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chuanxu","middleName":"","lastName":"Luo","suffix":""},{"id":5347788,"identity":"d28bc0ba-690a-4791-b87f-384374c1cf46","order_by":4,"name":"Yu Fan","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Fan","suffix":""},{"id":5347789,"identity":"e018e063-ff18-41f5-b2cd-3846c25fd524","order_by":5,"name":"Xiaorong Zhong","email":"","orcid":"","institution":"West China School of Medicine: Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaorong","middleName":"","lastName":"Zhong","suffix":""},{"id":5347790,"identity":"6527bca5-ba30-4b60-8bb7-d74877fdc43c","order_by":6,"name":"Hong Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBACAwYeEGUD4fGQoCWNdC2HSdBizn/24OOCX+ft+WckMD5428Ygb05Ii2XDuWTjmX23E2fcSGA2nNvGYLizgZDDDvaYSfP23E4wkEhgk+ZtY0gwOEBIy2Ee89+8PefsgVrYfxOn5RiPGTPPjwOMG4C2MBOn5QyPsTRvQ3LijDMPmyXnnJMw3EBQy/kzhp95/tjZ87cnH/zwpsxGnqAtYMDYBiYbgIQEMepB4A+xCkfBKBgFo2BEAgAvzTyHdSDWeQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5802-330X","institution":"West China Hospital, Sichuan University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2020-11-25 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3","display":"","copyAsset":false,"role":"figure","size":180334,"visible":true,"origin":"","legend":"Forest plots of pooled analyses for PARP inhibitors vs control treatment on progression-free survival in: (a) total patients, (b) BRCA mutated patients, (c) unselected patients.","description":"","filename":"OnlineFigure3.Png","url":"https://assets-eu.researchsquare.com/files/rs-116023/v1/fa6789ab7ca6eccc63172ef8.Png"},{"id":3934572,"identity":"ba8525b2-2fab-4dce-840d-d43232039f85","added_by":"auto","created_at":"2020-12-01 20:07:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":102515,"visible":true,"origin":"","legend":"Forest plots of pooled analyses for the effect of PARP inhibitors on ORR in: (a) BRCA mutated vs BRCA wild-type patients, (b) HRD vs non-HRD patients.\nAbbreviation: ORR, overall response rate; HRD, homologous recombination 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4","display":"","copyAsset":false,"role":"figure","size":102515,"visible":true,"origin":"","legend":"Forest plots of pooled analyses for the effect of PARP inhibitors on ORR in: (a) BRCA mutated vs BRCA wild-type patients, (b) HRD vs non-HRD patients.\nAbbreviation: ORR, overall response rate; HRD, homologous recombination deficiency.\n","description":"","filename":"OnlineFigure4.Png","url":"https://assets-eu.researchsquare.com/files/rs-116023/v1/e9d3e428fa60f4f56d379bb1.Png"},{"id":13621095,"identity":"67c32eea-4d5b-4d53-a36a-c8bc69afbc75","added_by":"auto","created_at":"2021-09-17 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20:07:21","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3244912,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-116023/v1/a9190887dd0d888c0c6696a2.tif"},{"id":3934566,"identity":"5e2b815d-17d7-4122-aa68-cc85ac4b7d15","added_by":"auto","created_at":"2020-12-01 20:07:15","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3244912,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-116023/v1/c5ce0c70bb83495d7a575e5c.tif"},{"id":3934560,"identity":"b07d5149-5e15-458c-961f-cfb1c98fc3d5","added_by":"auto","created_at":"2020-12-01 20:07:14","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3244912,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-116023/v1/0fe5861d987b706c31b56def.tif"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEfficacy and Safety of PARP\u0026nbsp;Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, accounting for 15 to 20% of all cases of breast cancer.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Cytotoxic chemotherapy is currently the mainstay of treatment for TNBC due to lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Unfortunately, TNBC is frequently resistant to chemotherapy and eventually evolves lethal metastatic disease, with a median survival of approximately 1\u0026nbsp;year.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Notably, more than one-third of TNBC patients will have distant metastases,(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) and no standard of care therapy exists for metastatic TNBC (mTNBC) patients.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Therefore, development of new therapeutic approach for patients with mTNBC are urgently needed.\u003c/p\u003e \u003cp\u003eWith the advancement of genomics analysis, new druggable targets are being identified, which may contribute to broadening the novel therapeutic scenario for mTNBC. Among patients with TNBC, about 10\u0026ndash;30% cases present with \u003cem\u003eBRCA1\u003c/em\u003e or \u003cem\u003eBRCA2\u003c/em\u003e gene mutations.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) On the other hand, approximately 70% of \u003cem\u003eBRCA1\u003c/em\u003e-mutated breast cancers are triple negative phenotype.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e genes are involved in the homologous recombination repair (HRR) pathway and responsible to repair DNA double-strand breaks. HRR pathway also contains many other genes such as \u003cem\u003eATM, PALB2, RAD51, CDK12, CHK1/2\u003c/em\u003e. Alterations on these genes can lead to homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase (PARP) is an important enzyme in the repair of DNA single-strand breaks.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Thus, inactivation of PARP in tumors with HRD will increase genomic instability, ultimately result in cell death. Preclinical studies have shown that cancer cells with functional \u003cem\u003eBRCA1\u003c/em\u003e or \u003cem\u003eBRCA2\u003c/em\u003e mutation are sensitive to PARP inhibition,(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) providing a strong rationale for treating mTNBC with PARP inhibitors.\u003c/p\u003e \u003cp\u003eThere are currently several PARP inhibitors being tested in clinical trials for mTNBC patients. Based on the promising results observed in clinical trials, olaparib has been approved by the Food and Drug Administration (FDA) for the treatment of patients with germline \u003cem\u003eBRCA\u003c/em\u003e-mutated, HER2-negative metastatic breast cancer.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Whereas, several clinical trials suggested that PARP inhibitors also conferred a survival benefit in metastatic TNBC patients irrespective of \u003cem\u003eBRCA\u003c/em\u003e status.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Thus, in this systematic review and meta-analysis, we aimed to comprehensively evaluate the efficacy and safety of PARP inhibitors in advanced or metastatic TNBC based on available clinical trial results. We also explored biomarkers to identify the subgroups of patients who could most benefit from PARP inhibitors.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eOn August 2020, A systematic literature search was performed by two independent reviewers through PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) The search terms are as following: ((\u0026ldquo;Poly(ADP-ribose) Polymerase inhibitors\u0026rdquo; OR \u0026ldquo;PARP inhibitors\u0026rdquo;) OR \u0026ldquo;Olaparib\u0026rdquo; OR \u0026ldquo;rucaparib\u0026rdquo; OR \u0026ldquo;talazoparib\u0026rdquo; OR \u0026ldquo;veliparib\u0026rdquo; OR \u0026ldquo;niraparib\u0026rdquo; OR \u0026ldquo;iniparib\u0026rdquo;) AND (\u0026ldquo;breast\u0026rdquo;) AND (\u0026ldquo;randomized controlled trial\u0026rdquo; OR \u0026ldquo;clinical trial\u0026rdquo;).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eInclusion criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Phase II and Phase III clinical trials evaluating the efficacy of PARP inhibitor as single-agent or in combination with other anticancer drugs in patients with advanced or metastatic TNBC were considered for inclusion. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The eligible studies mentioned objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or safety outcomes. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Only English-language articles were included.\u003c/p\u003e \u003cp\u003eExclusion criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Phase I clinical trial, case reports, editorials, review articles, retrospective studies were excluded; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Single-arm studies that did not report \u003cem\u003eBRCA\u003c/em\u003e or HRD status were not included. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Clinical trials focused on neoadjuvant therapy. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Finally, for the continuously updated and published follow-up data, the latest results were considered for analysis. The selected studies were identified based on inclusion and exclusion criteria by two independent reviewers (X. Liu and K. Wu).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eTwo authors (Xu. Liu and K. Wu) independently extracted data from eligible studies included in the meta-analysis. The following data was included: first author's information, year of publication, study design, trial phase, ClinicalTrial.gov Number, sample size, \u003cem\u003eBRCA\u003c/em\u003e or HRD status, type of intervention/control, efficacy results (ORR and PFS) and numbers of adverse events (AEs) in each arm. If the PFS was only represented by Kaplan-Meier curve, the Engauge digitizer 4.1 software was used to digitize and extract the data (only in one study(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eThe potential risks of bias in the selected studies was independently assessed by two reviewers (Xu. Liu and K. Wu), using the Cochrane Risk of bias tool, which included selection bias, performance bias, detection bias, attrition bias, reporting bias, and other possible sources of bias. The risk of bias was graded as high, low or unclear risk. Disagreement was resolved through consensus or a third reviewer (X.R. Zhong).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy objectives\u003c/h2\u003e \u003cp\u003eThe objectives of this study were to compare the antitumor efficacy and safety between the PARP inhibitor group and the chemotherapy group. The primary outcomes of this meta-analysis were ORR and PFS, AEs were the secondary outcomes. We also performed exploratory subgroup analyses to investigate treatment activity of PARP inhibitors in the \u003cem\u003eBRCA\u003c/em\u003e mutated vs \u003cem\u003eBRCA\u003c/em\u003e wild-type group, and HRD group vs non-HRD group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe hazard ratio (HR) with its 95% confidence interval (CI) was calculated to compare the PFS. The risk ratios (RR) and 95% CI was calculated to measure the ORR and AEs. A two-sided p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. The statistical heterogeneity was assessed using the I\u003csup\u003e2\u003c/sup\u003e statistic and chi-squared tests. When heterogeneity was observed (I\u003csup\u003e2\u003c/sup\u003e value\u0026thinsp;\u0026gt;\u0026thinsp;50% and p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05), a random effects model was applied; otherwise a fixed effect model was used. Funnel plot was used to detect potential publication bias. All statistical analyses were performed using Review Manager software version 5.3.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and characteristics\u003c/h2\u003e \u003cp\u003eAfter the electronic databases searches, a total of 2689 records were initially retrieved (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After removing duplicates and screening titles and abstracts, only 27 full-text articles were further assessed for their eligibility based on inclusion/exclusion criteria. After full-text review, 17 published articles were excluded for the following reasons: 5 articles did not report the related outcomes of this study population; five studies reported the results from the same population; 4 were clinical trials for neoadjuvant therapy in TNBC; two single-arm studies did not report HRD or \u003cem\u003eBRCA\u003c/em\u003e mutation status; one single-arm study only reported \u003cem\u003eBRCA\u003c/em\u003e mutation. Ultimately, 10 clinical trials were included for final pooled analysis, including 7 randomized controlled trials(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and 3 single-arm studies.(\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) For BROCADE study,(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) they randomly set up two comparison groups: veliparib with carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel, and veliparib plus temozolomide versus placebo plus carboplatin/paclitaxel, we only evaluated veliparib plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel in order to avoid statistical influences on research weights.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe main features of the selected studies and enrolled patients were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All clinical trials reported the antitumor efficacy of PARP inhibitors in patients with advanced or metastatic TNBC, ranging from 21 to 519 patients per study. Globally, a total of 1495 patients were included in the meta-analysis, of whom 735 patients harbored somatic or germline \u003cem\u003eBRCA1/2\u003c/em\u003e mutations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the selected studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy Name (NCT number)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal no. of TNBC patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo.of \u003cem\u003eBRCA\u003c/em\u003emut patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo.of \u003cem\u003eBRCA\u003c/em\u003ewt patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo.of HRD patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGelmon et al. (2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNCT00679783\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOlaparib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO\u0026rsquo;Shaughnessy et al. (2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNCT00540358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIniparibs\u0026thinsp;+\u0026thinsp;gemcitabine and carboplatin vs gemcitabine and carboplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO\u0026rsquo;Shaughnessy et al. (2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNCT00938652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIniparibs\u0026thinsp;+\u0026thinsp;gemcitabine and carboplatin vs gemcitabine and carboplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e519\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKummar et al. (2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNCT01306032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVeliparib\u0026thinsp;+\u0026thinsp;cyclophosphamide vs cyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRobson et al. (2017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOlympiAD NCT02000622\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOlaparib vs standard therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLitton et al. (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEMBRACA NCT01945775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTalazoparib vs standard single-agent therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHan et al. (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBROCADE NCT01506609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVeliparib\u0026thinsp;+\u0026thinsp;carboplatin/paclitaxel vs placebo\u0026thinsp;+\u0026thinsp;carboplatin/paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVinayak et al. (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTOPACIO NCT02657889\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNiraparib\u0026thinsp;+\u0026thinsp;pembrolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShimomura et al. (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEO UMIN000018721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOlaparib\u0026thinsp;+\u0026thinsp;Eribulin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDi\u0026eacute;ras et al. (2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBROCADE3 NCT02163694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVeliparib\u0026thinsp;+\u0026thinsp;carboplatin-paclitaxel vs placebo\u0026thinsp;+\u0026thinsp;carboplatin/paclitaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eNCT ClinicalTrials.gov identifier, TNBC Triple-negative breast cancer, \u003cem\u003eBRCA\u003c/em\u003emut \u003cem\u003eBRCA\u003c/em\u003e mutation, \u003cem\u003eBRCA\u003c/em\u003ewt \u003cem\u003eBRCA\u003c/em\u003e wild type, HRD homologous recombination deficiency.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy of PARP inhibitors in advanced/metastatic TNBC\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003ePARP inhibitors vs control\u003c/h2\u003e \u003cp\u003eTo evaluate the effect of PARP inhibitors on the patients with advanced/metastatic TNBC, we first conducted a pooled analysis comparing the antitumor efficacy between the PARP inhibitor group and the chemotherapy group. Seven randomized controlled trials were pooled into the analysis of ORR or PFS,(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) which included 778 advanced/metastatic TNBC patients who received PARP inhibitors (Olaparib, iniparibs, veliparib or talazoparib) and 568 participants who were administered with chemotherapies. In the whole population, the pooled RR showed that PARP inhibitor treatment significantly improved the incidence of achieving ORR compared to chemotherapy (RR\u0026thinsp;=\u0026thinsp;2.00, 95% CI: 1.14\u0026ndash;3.50, p\u0026thinsp;=\u0026thinsp;0.02) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The pooled analysis for PFS indicated that the PARP inhibitor group had a better PFS when compared with the chemotherapy group (HR\u0026thinsp;=\u0026thinsp;0.68, 95% Cl: 0.59\u0026ndash;0.77, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWith regard to the clinical benefit of PARP inhibitors in patients with \u003cem\u003eBRCA\u003c/em\u003e mutation, four randomized controlled trials were eligible for the analysis of ORR or PFS.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) The studies above showed that compared with chemotherapy, the PARP inhibitor treatment significantly improved ORR (RR\u0026thinsp;=\u0026thinsp;3.63, 95% CI: 2.18\u0026ndash;6.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), and PFS (HR\u0026thinsp;=\u0026thinsp;0.61, 95% CI: 0.50\u0026ndash;0.74, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in the germline/somatic \u003cem\u003eBRCA\u003c/em\u003e mutated patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eThree clinical trials focused on the efficacy of PARP inhibitors in advanced or metastatic TNBC irrespective of \u003cem\u003eBRCA\u003c/em\u003e or HRD status,(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) we performed a pooled analysis in this unselected population. Results showed that no significant difference in terms of the ORR was observed between the PARP inhibitor group and the chemotherapy group (RR\u0026thinsp;=\u0026thinsp;1.22, 95% CI: 0.99\u0026ndash;1.52, p\u0026thinsp;=\u0026thinsp;0.07) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). However, PARP inhibitors had significant improvements in PFS (HR\u0026thinsp;=\u0026thinsp;0.74, 95% CI: 0.62\u0026ndash;0.89, p\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis of the efficacy of PARP inhibitors\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eBRCA mutated vs BRCA wild-type\u003c/h2\u003e \u003cp\u003eTo further compare the efficacy of PARP inhibitors in the \u003cem\u003eBRCA\u003c/em\u003e mutated and \u003cem\u003eBRCA\u003c/em\u003e wild-type populations, we subsequently conducted an exploratory analysis directly comparing these two groups. Three studies mentioned ORR in two subgroups and were incorporated into this analysis.(\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Subgroup analysis demonstrated that PARP inhibitors could provide a significant improvement in ORR to the \u003cem\u003eBRCA\u003c/em\u003e mutated patients in comparison to the \u003cem\u003eBRCA\u003c/em\u003e wild-type patients, with a RR of 2.85 (95% CI: 1.34\u0026ndash;6.06, p\u0026thinsp;=\u0026thinsp;0.007) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eHRD vs non-HRD\u003c/h2\u003e \u003cp\u003eIt is still unclear whether, in addition to \u003cem\u003eBRCA\u003c/em\u003e mutations, HRD status can be used as a biomarker to predict PARP inhibitors sensitivity in the advanced/metastatic TNBC setting. Therefore, we performed subgroup analyses of the HRD positive group vs. the non-HRD group to address this question. Two articles were eligible for this analysis, and only ORR data was available in two studies with less statistical power.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Interestingly, there were not significant differences in ORR when comparing the HRD positive subgroup to the non-HRD subgroup (RR\u0026thinsp;=\u0026thinsp;1.82, 95% CI: 0.81\u0026ndash;4.08, p\u0026thinsp;=\u0026thinsp;0.14) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events of PARP inhibitor\u003c/h2\u003e \u003cp\u003eIn this study, seven randomized controlled trials that reported AEs were used to risk analysis. The comparative safety profile in terms of AEs of interest was shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. On the whole, the results showed that the incidence of AEs in the PARP inhibitor group was similar to that in the chemotherapy group, regardless of any grade AEs (98.94% vs. 98.98%, RR\u0026thinsp;=\u0026thinsp;1.00, 95% CI: 0.99\u0026ndash;1.01, p\u0026thinsp;=\u0026thinsp;0.66), and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs (76.32% vs. 79.68%, RR\u0026thinsp;=\u0026thinsp;0.97, 95% CI: 0.88\u0026ndash;1.07, p\u0026thinsp;=\u0026thinsp;0.54). Notably, PARP inhibitor weakly increased the overall risk to suffer serious AEs compared with chemotherapy (26.88% vs. 24.57%, RR\u0026thinsp;=\u0026thinsp;1.18, 95% CI: 1.00\u0026ndash;1.38, p\u0026thinsp;=\u0026thinsp;0.05). In PARP inhibitor group, for any grade events, the five most common AEs were nausea (64.00%), neutropenia (60.30%), thrombocytopenia (59.20%), anemia (59.17%) and fatigue (51.70%); and for grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, they were neutropenia (47.03%), thrombocytopenia (30.32%), anemia (27.56%), leukopenia (14.78%) and fatigue (5.13%). The pooled data showed that compared with the chemotherapy group, the PARP inhibitor group had an increased incidence of AEs in terms of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 thrombocytopenia (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), any grade nausea (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and any grade vomiting (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of the adverse events (AEs).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of studies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eAdverse events/total patients (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePARP inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1311/1325 (98.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e779/787(98.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.99\u0026ndash;1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e809/1060 (76.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e541/679 (79.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.88\u0026ndash;1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e799/1325 (60.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e533/787 (67.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.78\u0026ndash;1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e633/1346 (47.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e430/805 (53.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.69\u0026ndash;1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade anemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e784/1325 (59.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e407/787 (51.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.97\u0026ndash;1.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e371/1346 (27.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e158/805 (19.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.86\u0026ndash;2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade thrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e663/1120 (59.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e359/696 (51.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.99\u0026ndash;1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 thrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e346/1141 (30.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e149/714 (20.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.26\u0026ndash;1.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade leukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e346/1325 (26.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e209/787 (26.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.82\u0026ndash;1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 leukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e199/1346 (14.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e121/805 (15.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.81\u0026ndash;1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade fatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e685/1325 (51.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e415/787 (52.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.97\u0026ndash;1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 fatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68/1325 (5.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44/787 (5.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.72\u0026ndash;1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade nausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e848/1325 (64.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e439/787 (55.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.09\u0026ndash;1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 nausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30/1325 (2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21/787 (2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.49\u0026ndash;1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade constipation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e406/1120 (36.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e245/696 (35.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.99\u0026ndash;1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 constipation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/1120 (0.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/696 (0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.35\u0026ndash;4.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e424/1325 (32.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e224/787 (28.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.01\u0026ndash;1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32/1325 (2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11/787 (1.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.87\u0026ndash;3.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade diarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e394/1325 (29.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e214/787 (27.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.94\u0026ndash;1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 diarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32/1325 (2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22/787 (2.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.49\u0026ndash;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade decreased appetite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215/1013 (21.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e105/484 (21.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.80\u0026ndash;1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 decreased appetite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/1013 (0.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/484 (0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.36\u0026ndash;6.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eQuality of included studies\u003c/h2\u003e \u003cp\u003eThe \u0026lsquo;Risk of bias graph\u0026rsquo; revealed that this meta-analysis had moderate risk of selection bias, because 3 out of 10 clinical trials were single-arm studies (Supplementary Fig.\u0026nbsp;1). We performed the funnel plots to detect the publication bias, the results suggested that there was a relatively low risk publication bias (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe results of this study highlight that compared with chemotherapy, PARP inhibitors can safely and significantly improve the ORR and PFS in patients with advanced/metastatic TNBC. Furthermore, exploratory analysis showed that the \u003cem\u003eBRCA\u003c/em\u003e mutated patients could derive more benefits from PARP inhibitors compared with \u003cem\u003eBRCA\u003c/em\u003e wild-type patients. However, we did not observe any difference in tumor control between HRD positive patients and non-HRD patients. Based on those recent clinical evidences, \u003cem\u003eBRCA\u003c/em\u003e mutation, rather than HRD status, can be used as a predictive biomarker for response to PARP inhibitors in the advanced/metastatic TNBC setting.\u003c/p\u003e \u003cp\u003ePreclinical studies showed that PARP inhibitors have greater efficacy in \u003cem\u003eBRCA\u003c/em\u003e-deficient cells when compared with wild-type cells.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) In the clinical setting, a proof-of-concept trial by Tutt showed that PARP inhibition treatment has a favourable therapeutic index in \u003cem\u003eBRCA\u003c/em\u003e-mutated advanced breast cancer patients.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) Based on these results, over the past years, several clinical trials have been conducted and are currently evaluating the role of different PARP inhibitors in this population. Specifically, olaparib has been approved in \u003cem\u003eBRCA\u003c/em\u003e-mutated HER2-negative metastatic breast cancer patients as the first targeted therapy based on the results of the OlympiAD study.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) In view of this meta-analysis, our conclusion also confirmed that patients with \u003cem\u003eBRCA\u003c/em\u003e mutations might be prime candidates for PARP inhibition treatment. However, our analysis also found that PARP inhibitors could provide significant improvement in PFS for unselected patients, regardless of \u003cem\u003eBRCA\u003c/em\u003e mutational status. Similarly, in the phase II and III clinical trials for metastatic TNBC patients irrespective of \u003cem\u003eBRCA\u003c/em\u003e status,(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) the gain in PFS was obtained in the PARP inhibition group compared with the chemotherapy group. In addition, those with \u003cem\u003eBRCA\u003c/em\u003e mutation account for only a small proportion of breast cancer patient.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Hence, only using \u003cem\u003eBRCA\u003c/em\u003e status as a predictive biomarker for PARP inhibitors sensitivity is insufficient and may miss many potential responders.\u003c/p\u003e \u003cp\u003eThe major question for oncologists is how to go about practically selecting advanced/metastatic TNBC patients who will benefit from PARP inhibitor therapy? Following large-scale sequence analysis, besides \u003cem\u003eBRCA1/2\u003c/em\u003e gene, many other HRD-mutation genes (\u003cem\u003eATM\u003c/em\u003e, \u003cem\u003eCHK1/2\u003c/em\u003e, and \u003cem\u003ePTEN\u003c/em\u003e) were found to be correlated with PARP inhibition sensitivity, and could be utilized as alternative biomarkers for identifying vulnerable population.(\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) In clinical situations, HRD status has a good predictive power for the benefits of PARP inhibitors in several cancer types, like ovarian cancer, prostate cancer, and gastric cancer.(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) However, in this study, we did not observe any improvement in ORR for HRD positive patients compared with HRD negative patients. It should be noted that there were only two relevant studies in this subgroup analysis with small sample size, which has less statistical power and is difficult to draw strong conclusions. In the future, more clinical trials are needed to evaluate the predictive value of HRD in the TNBC setting, and explore new biomarkers for determining optimal patients who are more likely to benefit from PARP inhibitors.\u003c/p\u003e \u003cp\u003eAs PARP inhibitors has gradually been approved for clinical applications worldwide, the evaluation of safety and tolerance of PARP inhibitors in patients is very of value and indispensable. Our pooled analysis of 1346 advanced/metastatic breast cancer patients treated with PARP inhibitors from seven randomized controlled trials showed that the three most common AEs of grade 3 and above were neutropenia (47.03%), thrombocytopenia (30.32%), and anemia (27.56%), suggesting the risks of hematologic toxicities caused by PARP inhibition treatment are more common and serious. Similarly, a meta-analysis of eight clinical trials also found that olaparib could significantly increase the risk of severe neutropenia in cancer patients.(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) This may be because PARP inhibitor not only can interfere with DNA repair in cancer cells, but also may interfere with rapidly dividing blood cells, thus leading to myelosuppression. Notably, our meta-analysis showed that the PARP inhibitors did not increase the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs except for the risk of thrombocytopenia when compared with chemotherapy. Overall, PARP inhibitors seem to be generally safe and tolerable for advanced/metastatic breast cancer patients, but the high risk of PARP inhibitor-related hematologic toxicities is a trouble that cannot be ignored and should be considered in clinical application.\u003c/p\u003e \u003cp\u003eThere are several limitations in the present meta-analysis. First, the potential bias of this study included heterogenous inclusion criteria, patients and treatment schedule in the included trials, for example, age, race, disease status, and interventional arm, these confounding variables were not stratified properly and incorporated into the meta-analysis. In addition, there are few comparative studies on the efficacy of PARP inhibitors between HRD-positive patients and HRD-negative patients, which makes it difficult to fully assess the benefit of PARP inhibitors based on patients\u0026rsquo; HRD status. Therefore, it is warranted to conduct randomized controlled trials with longer clinical follow-up in the future.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eOur findings confirm that the addition of PARP inhibitor is a more effective, well tolerable and useful treatment in advanced/metastatic TNBC patients when compared with chemotherapy. We also support the view that \u003cem\u003eBRCA\u003c/em\u003e status can be used as a predictive biomarker for PARP inhibitor sensitivity to guide clinical decision-making. However, the predictive value of HRD status still needs further evaluation in future studies. Hematologic toxicities are common adverse events, thus regular hematological monitoring is warranted for patients treated with PARP inhibitors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs: adverse events; CI: confidence interval; FDA: Food and Drug Administration; HR: hazard ratio; HRD: homologous recombination deficiency; HRR: homologous recombination repair; ORR: overall response rate; PARP: Poly (ADP-ribose) polymerase; PFS: progression-free survival; PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis; RR: risk ratio; TNBC: triple-negative breast cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the key program of the Science and Technology Department of Sichuan Province [grant number: 2017SZ0005 to HZ]; and the 135 project for disciplines of excellence, West China Hospital, Sichuan University [grant number: ZYGD18012 to HB].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXL, KW, and XRZ conceived and designed the analysis; XL, and KW collected the data; XL, KW, and DZ analyzed the data; and CXL, YF, XL, and HZ interpreted the data. All authors were involved in the drafting, critical review, and approval of the final manuscript and the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCarey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama. 2006;295(21):2492-502.\u003c/li\u003e\n\u003cli\u003eSorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(14):8418-23.\u003c/li\u003e\n\u003cli\u003eLebert JM, Lester R, Powell E, Seal M, McCarthy J. Advances in the systemic treatment of triple-negative breast cancer. 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Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol. 2015;137(2):343-50.\u003c/li\u003e\n\u003cli\u003ePommier Y, O'Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med. 2016;8(362):362ps17.\u003c/li\u003e\n\u003cli\u003eRobson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. The New England journal of medicine. 2017;377(6):523-33.\u003c/li\u003e\n\u003cli\u003eResearch C for DE and. Approved Drugs - FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm59 2357.htm (accessed 23 May 2018).\u003c/li\u003e\n\u003cli\u003eO'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. The New England journal of medicine. 2011;364(3):205-14.\u003c/li\u003e\n\u003cli\u003eO'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(34):3840-7.\u003c/li\u003e\n\u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336-41.\u003c/li\u003e\n\u003cli\u003eKummar S, Wade JL, Oza AM, Sullivan D, Chen AP, Gandara DR, et al. Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. Invest New Drugs. 2016;34(3):355-63.\u003c/li\u003e\n\u003cli\u003eLitton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. The New England journal of medicine. 2018;379(8):753-63.\u003c/li\u003e\n\u003cli\u003eHan HS, Dieras V, Robson M, Palacova M, Marcom PK, Jager A, et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Ann Oncol. 2018;29(1):154-61.\u003c/li\u003e\n\u003cli\u003eDieras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2020;21(10):1269-82.\u003c/li\u003e\n\u003cli\u003eGelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. The Lancet Oncology. 2011;12(9):852-61.\u003c/li\u003e\n\u003cli\u003eVinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, et al. Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol. 2019.\u003c/li\u003e\n\u003cli\u003eShimomura A, Yonemori K, Yoshida M, Yoshida T, Yasojima H, Masuda N, et al. Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy. Transl Oncol. 2019;12(10):1386-94.\u003c/li\u003e\n\u003cli\u003eBryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-7.\u003c/li\u003e\n\u003cli\u003eFarmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-21.\u003c/li\u003e\n\u003cli\u003eTutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235-44.\u003c/li\u003e\n\u003cli\u003eTung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(13):1460-8.\u003c/li\u003e\n\u003cli\u003eWeston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010;116(22):4578-87.\u003c/li\u003e\n\u003cli\u003eMcCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-15.\u003c/li\u003e\n\u003cli\u003eMendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6-7):315-22.\u003c/li\u003e\n\u003cli\u003eYi T, Feng Y, Sundaram R, Tie Y, Zheng H, Qian Y, et al. Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas. Int J Cancer. 2019;145(5):1209-20.\u003c/li\u003e\n\u003cli\u003eGuo XX, Wu HL, Shi HY, Su L, Zhang X. The efficacy and safety of olaparib in the treatment of cancers: a meta-analysis of randomized controlled trials. Cancer Manag Res. 2018;10:2553-62.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metastatic triple-negative breast cancer, PARP inhibitor, BRCA mutation, Homologous recombination deficiency, Efficacy, Safety","lastPublishedDoi":"10.21203/rs.3.rs-116023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-116023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003ePoly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBC). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eOn August 2020, we searched all published phase II/III clinical studies of PARP inhibitors in advanced/metastatic TNBC patients. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points included overall response rate (ORR), progression-free survival (PFS) and adverse events.\u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eTen clinical trials were identified, with a total of 1495 patients included. Pooled analyses showed that the addition of PARP inhibitors could provide a significant improvement of ORR (risk ratio [RR]=2.00, 95% confidence interval [CI]: 1.14–3.50, p=0.02) and PFS (hazard ratio [HR]=0.68, 95 %Cl: 0.59-0.77, p\u0026lt;0.0001) compared to chemotherapy in the whole population. In subgroup analysis, \u003cem\u003eBRCA\u003c/em\u003e mutated patients have a higher objective response to PARP inhibitor, with a RR of 2.85 (95%CI: 1.34–6.06, p=0.007) compared to \u003cem\u003eBRCA\u003c/em\u003e wild-type patients. However, no significant differences in ORR were observed between homologous recombination deficiency (HRD) positive and non-HRD subgroup (RR=1.82, 95%CI: 0.81–4.08, p=0.14). Hematologic toxicities were common adverse events of PARP inhibitors.\u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003ePARP inhibitors are an effective option for the treatment of advanced or metastatic TNBC patients. \u003cem\u003eBRCA\u003c/em\u003e mutated patients could derive more benefits from PARP inhibitors when compared to \u003cem\u003eBRCA\u003c/em\u003e wild-type patients.\u0026nbsp;In clinical application, hematological toxicity related to PARP inhibitors should be monitored regularly.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of PARP\u0026nbsp;Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-01 20:07:11","doi":"10.21203/rs.3.rs-116023/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7b4994a-50da-427e-bce4-db422b226af9","owner":[],"postedDate":"December 1st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":1238321,"name":"Cancer Biology"},{"id":1238322,"name":"Oncology"}],"tags":[],"updatedAt":"2020-12-01T20:07:13+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-01 20:07:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-116023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-116023","identity":"rs-116023","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}