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      Efficacy and safety of PARP inhibitors as the maintenance therapy in ovarian cancer: a meta-analysis of nine randomized controlled trials

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          Abstract

          Purpose: Poly ADP ribose polymerase (PARP) inhibitors can effectively kill cancer cells by restraining the activity of DNA repair enzymes and utilizing the characteristics of BRCA mutations. This article evaluates the efficacy and safety of PARP inhibitors (PARPis) in the maintenance treatment of ovarian cancer.

          Method: We searched for clinical trials in electronic databases. PARPis efficacy were evaluated by the hazard ratios (HR) and its 95% confidence intervals (95% CI) of overall survival (OS) and progression-free survival (PFS) between the PARPis groups and placebo groups, while the PARPis’ safety was assessed by relative risk (RR) values of adverse events (AEs) between the two arms.

          Results: The immature OS data manifested that patients with BRCA mutation receiving PARPis therapy versus placebo therapy appeared to have longer OS (HR = 0.78, 95%CI = 0.61–1.01; P = 0.06). Compared with placebo group, PARP group had a significant advantage in PFS in ovarian cancer patients with BRCA wild-type (BRCAwt), BRCA mutation (BRCAm), BRCA status unclassified, BRCA1 mutation subgroup and the BRCA2 mutation subgroup (BRCAwt: HR = 0.53, 95%CI = 0.42–0.68, P < 0.00001; BRCAm: HR = 0.30, 95%CI = 0.26–0.34, P < 0.00001; BRCA status unclassified: HR = 0.52, 95%CI = 0.41–0.66, P < 0.00001; BRCA1m: HR = 0.38, 95%CI = 0.29–0.48, P < 0.00001; BRCA2m: HR = 0.23, 95%CI = 0.10–0.57, P = 0.001). Our analysis revealed the incidence rates for AEs of grade ≥3 (grades 3 to 4) and serious AEs in PARPis group were 55.19% and 26.29%, respectively.

          Conclusion: Our meta-analysis demonstrates that PARPis therapy can significantly improve PFS in ovarian cancer patients, but it has no benefit in OS. However, the therapy is associated with a significant increase in the risk of AEs of grade ≥ 3 and serious AEs.

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          Most cited references15

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          Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

          Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
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            Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.

            Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Five-year overall mortality. The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
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              Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.

              To define a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in epithelial ovarian cancer (EOC). A publicly available microarray data set including 61 patients with EOC with either sporadic disease or BRCA(1/2) germline mutations was used for development of the BRCAness profile. Correlation with platinum responsiveness was assessed in platinum-sensitive and platinum-resistant tumor biopsy specimens from six patients with BRCA germline mutations. Association with poly-ADP ribose polymerase (PARP) inhibitor responsiveness and with radiation-induced RAD51 foci formation (a surrogate of homologous recombination) was assessed in Capan-1 cell line clones. The BRCAness profile was validated in 70 patients enriched for sporadic disease to assess its association with outcome. The BRCAness profile accurately predicted platinum responsiveness in eight out of 10 patient-derived tumor specimens, and between PARP-inhibitor sensitivity and resistance in four out of four Capan-1 clones. [corrected] When applied to the 70 patients with sporadic disease, patients with the BRCA-like (BL) profile had improved disease-free survival (34 months v 15 months; log-rank P = .013) and overall survival (72 months v 41 months; log-rank P = .006) compared with patients with a non-BRCA-like (NBL) profile, respectively. The BRCAness profile maintained independent prognostic value in multivariate analysis, which controlled for other known clinical prognostic factors. The BRCAness profile correlates with responsiveness to platinum and PARP inhibitors and identifies a subset of sporadic patients with improved outcome. Additional evaluation of this profile as a predictive tool in patients with sporadic EOC is warranted.
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                Author and article information

                Contributors
                Journal
                Biosci Rep
                Biosci. Rep
                bsr
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                27 March 2020
                18 March 2020
                : 40
                : 3
                : BSR20192226
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Second Road 58, Guangzhou 510080, Guangdong, P. R. China
                [2 ]School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055
                Author notes
                Correspondence: Shanyang He ( hsy5g777@ 123456sina.com )
                [*]

                These authors have contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-3768-2389
                http://orcid.org/0000-0002-3793-569X
                Article
                BSR20192226
                10.1042/BSR20192226
                7080644
                32096544
                1d550ecb-d3e3-4edc-b42a-e87db6eae2a1
                © 2020 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 11 July 2019
                : 21 January 2020
                : 24 February 2020
                : 25 February 2020
                Page count
                Pages: 10
                Categories
                Cancer
                Pharmacology & Toxicology
                Mutation
                Research Articles

                Life sciences
                adverse events,brca,efficacy and safety,ovarian cancer,parp inhibitors
                Life sciences
                adverse events, brca, efficacy and safety, ovarian cancer, parp inhibitors

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