Efficacy and safety of olaparib in advanced ovarian cancer: a meta-analysis

Abstract This study aimed to evaluate the efficacy and safety of olaparib for the treatment of advanced ovarian cancer. All studies that assessed the efficacy and safety of olaparib in advanced ovarian cancer were searched in PubMed, Embase, and Web of Science from their inception to 20 September 2022. The analysis included six studies and 2016 patients. Olaparib could significantly prolong the progression-free survival (PFS) of patients compared to that of the control group (HR = 0.49, 95% CI = 0.36 − 0.68). However, no statistically significant differences were detected in overall survival (OS) and objective response rate (ORR) between the olaparib and control groups. Olaparib treatment increased the number of grade ≥3 adverse events (AEs) in patients with advanced ovarian cancer compared with that in the control group. Olaparib significantly prolonged PFS in patients with advanced ovarian cancer; however, no statistically significant differences were detected in OS and ORR. In terms of safety, olaparib has manageable adverse effects.


Introduction
Ovarian cancer (OC) is the fifth most common cancer worldwide and is one of the most fatal gynaecological cancers in women (Siegel et al. 2022).According to GLOBOCAN 2020 data, there are 313,959 new cases of OC and 207,252 fatalities worldwide each year (Sung et al. 2021).Most OC cases (90%) are assumed to be caused by epithelial cells, and more than 70% are identified as high-grade OC, which usually manifests at an advanced stage (III and IV) (Moya-Alarc� on et al. 2022).The primary therapies for OC are usually surgery and platinum-based chemotherapy.Although patients often effectively respond to platinum-based compounds and taxane-based first-line chemotherapy, the majority will experience recurrence and resistance 12-18 months after the initial treatment (Kujawa and Lisowska 2015).Currently, great progress has been made in the treatment of recurrent OC, although the overall prognosis remains poor.
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a type of anticancer treatment that target cells deficient in homologous recombination repair (HRR), causing cell death via apoptosis once the DNA repair pathway is suppressed (Patel et al. 2011, Zheng et al. 2020).Olaparib is an effective, orally accessible PARPi that targets PARP-1, À 2, and À 3 in cells with a homologous recombination deficit, including those with BRCA1/ 2 mutations, to mediate this synthetic lethality (Guo et al. 2018).As an important new anticancer drug, olaparib has been used for the treatment of OC, gastric cancer, and other cancers (Robson 2017;Bang et al. 2017, Pujade-Lauraine et al. 2017).Olaparib maintenance therapy for advanced OC has been shown to reduce tumour size, prolong progression-free survival (PFS), and improve objective response rates (Ledermann et al. 2014, Oza et al. 2015, Moore et al. 2018).It is important to summarise these results to provide clinicians with an evidencebased reference.Therefore, we performed a meta-analysis of all published randomised controlled trials (RCTs) to evaluate the efficacy and safety of olaparib in advanced OC.

Materials and methods
The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.

Search strategy
A comprehensive search of relevant literature from PubMed, EMBASE, and Web of Science was conducted and included the keywords: 'Olaparib', 'AZD 2281', 'Ovarian Neoplasms', and 'OC' published before 20 September 2022.The search was limited to English language.We also checked the reference lists for screening full-text studies to identify other potentially eligible trials.

Eligibility criteria
The inclusion criteria for this study were: (1) a randomised controlled study of olaparib in the treatment of advanced OC; (2) patients in the experimental group received olaparib, and patients in the control group received placebo or other therapies; and (3) the study reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).Literature review articles, animal studies, case reports, and observational studies were excluded.

Data selection and quality
Two researchers independently screened the literature and extracted data.The following information was extracted: first author, study design, interventions, number of patients, age, BRCA status, Eastern Cooperative Oncology Group (ECOG) performance status, and outcome measures.If any disagreement was encountered during the screening and extraction processes, a consensus was reached through discussion, and thirdparty opinions were sought if necessary.The risk of bias in RCTs was assessed using the Cochrane Risk of Bias tool, with scores for each aspect as low, high, or unclear risk of bias.

Statistical analysis
Stata SE 15.0 software (College Station, TX, USA) was used for the statistical analysis.The risk of bias of the included studies was assessed using RevMan 5.3 software.The outcomes of AEs were assessed using relative risk (RR) with 95% confidence interval (CI).Odds ratios (OR) and 95% confidence intervals (CI) were used for ORR.Hazard ratios (HR) with 95% CI were used to estimate OS and PFS.I 2 statistics were used to assess heterogeneity.If I 2 < 50% and p > 0.05, the fixedeffects model was used for analysis; otherwise, the randomeffects model was used.Publication bias was measured using Egger's test.Statistical significance was set at p < 0.05.In addition, the authors of the included studies were contacted for missing values where required.

Results
A total of 3314 studies were selected after systematic exploration.Duplication resulted in exclusion of 970 records.The titles and abstracts of 2310 articles were reviewed, and only 24 articles were eligible for full-text review.Finally, six studies were included in this meta-analysis (Kaye et al. 2012, Ledermann et al. 2012, Oza et al. 2015, Pujade-Lauraine et al. 2017, Moore et al. 2018, Ray-Coquard 2019), as shown in Figure 1.
The six included studies included 2016 patients, with 1274 and 742 in the experimental and control groups, respectively.The number of participants in this study ranged from 97 to 806.The included patients were mostly between 53 and 65 years old.The ECOG performance status of the patients was �2.The detailed baseline characteristics are shown in Table 1.The risk of bias for each study is shown in Figure 2.

OS
Five studies reported OS data.No heterogeneity was detected among the six included studies (I 2 ¼0%, p ¼ 0.56), and a combined analysis was performed using a fixed-effects model.The OS of the patients in the olaparib group was not significantly different from that in the control group (HR ¼ 0.90, 95% CI ¼ 0.75À 1.08) (Figure 3).

PFS
Six studies reported the PFS.Heterogeneity results were I 2 ¼85.3%, p < 0.001.Thus, a random effects model was used  for analysis.The results showed that olaparib could significantly prolong the PFS of patients compared with that of the control group (HR ¼ 0.49, 95% CI ¼ 0.36À 0.68) (Figure 4).

ORR
Three studies were selected because the heterogeneity test showed I 2 ¼0% p ¼ 0.611, a fixed-effects model was used for  analysis.The olaparib group had a higher ORR than that of the control group, although the difference was not statistically significant (OR ¼ 1.39, 95% CI ¼ 0.86À 2.25) (Figure 5).

AEs
The outcomes of AEs were reported in all six RCTs.No heterogeneity was detected among studies (I 2 ¼0%, p ¼ 0.987), and a fixed-effects model was utilised for analysis.No significant difference was observed in the incidence of AEs between olaparib and control groups (RR ¼ 1.01, 95% CI ¼ 0.99À 1.03) (Figure 6(a)).Five studies reported an incidence of grade �3 AEs.The heterogeneity test showed I 2 ¼85.4%, p < 0.001, and the random effects model was used for analysis.The incidence of grade �3 AEs was substantially higher in the olaparib group than that in the control group, and the difference was statistically significant (RR ¼ 1.7, 95% CI ¼ 1.51À 1.92) (Figure 6(b)).

Publication bias
Publication bias was objectively assessed using Egger's test.

Discussion
OC is the leading cause of gynaecological cancer fatalities, and its incidence and mortality rates are rising globally (Wang et al. 2022).It is likely that 70% of the patients with OC have advanced disease when they are diagnosed, which contributes to the poor prognosis (Jelovac and Armstrong 2011).In advanced OC, first-line treatment involves cytoreductive surgery and adjuvant chemotherapy (including platinum drugs).It is unavoidable that incompletely resected disease progresses or relapses after cytoreduction.A reduced immune surveillance and a drug-resistant cell population may be a contributing factor to the resistance of OC to chemotherapy (Lagan� a et al. 2015, Fagotti et al. 2020).
Olaparib, the first oral PARPi, was approved by the FDA for patients with BRCA1 or BRCA2 detrimental germline mutations and advanced OC who had previously received three or more chemotherapy regimens (Agency 2014, FDA 2014).Olaparib inhibits PARP proteins, which are essential components of the mechanisms for repairing single-strand DNA damage (Reinbolt and Hays 2013).Tumour cells lack two crucial repair pathways because of PARP suppression and BRCA1/2 mutation, which results in a substantial buildup of DNA damage and tumour cell death (Jelovac and Armstrong 2011).This meta-analysis summarises the efficacy and safety of olaparib in the treatment of advanced OC.
In this meta-analysis, we found that olaparib was associated with remarkably prolonged PFS compared to that of the control group.The OS and ORR in the olaparib group were not significantly different from those in the control group.Compared with previous meta-analyses, this study analysed a total of six RCTs and 2016 patients to evaluate the efficacy of olaparib in terms of PFS, OS, and ORR, making the conclusions more reliable and convincing.
Olaparib is an orally active PARP inhibitor that is selective for cells lacking homologous recombination, such as those with homozygous BRCA1/2 deficiency (Farmer et al. 2005).Preclinical evidence has revealed that olaparib could boost the effectiveness of DNA-damaging chemotherapies in OC, platinum-based medicines, such as carboplatin (Evers et al. 2008, Rottenberg et al. 2008).This meta-analysis found that olaparib substantially prolonged PFS compared to that in the control group.However, the OS of patients in the olaparib group was not significantly different from that of the patients in the control group.Olaparib administration resulted in a substantially prolonged PFS.However, after the PFS period, the tumour progression aggravated and led to rapid death of the patients, and the OS was not significantly different from that of the control group.In addition, the ORR results of this study also showed that the olaparib group had a higher ORR than that of the control group, although the difference was not statistically significant.The results further suggest that olaparib treatment of advanced OC may achieve remission in certain cases but does not stabilise the disease.Therefore, combining olaparib with other drugs before tumour progression may prolong the patient survival.Studies have evaluated olaparib in combination with other drugs for advanced OC (Ray-Coquard 2019, Shah et al. 2021), but none of them reported OS results.In the future, we hope to conduct more studies on olaparib combined with other drugs for the treatment of advanced OC to our hypothesis.We expect that the results of this meta-analysis will provide clinicians with new ideas for the treatment of advanced OC.
With regard to safety, this study found no significant difference in the incidence of AEs between the olaparib and control groups.However, the incidence of grade �3 AEs was significantly higher in the olaparib group than that in the control group.
This study has some limitations.Five RCTs were included in this meta-analysis, which were of high quality.However, the number of included trials was small and needs to be further supplemented.Second, heterogeneity was observed in the outcome measures of PFS and grade �3 AEs, which may be attributed to the different doses of olaparib administered in the included studies.Finally, both phase II and III trials were included in this study, which may be a potential source of bias.

Conclusion
Our analysis showed that olaparib substantially prolonged PFS in patients with advanced OC; however, no statistically significant differences were detected in OS and ORR.In terms of safety, the incidence of AEs in the olaparib group was not significantly different from that in the control group; however, grade �3 AEs were associated with olaparib.Clinicians should consider potential AEs associated with these interventions in clinical practice because AEs are usually manageable.

Figure 1 .
Figure 1.The flow diagram of the study selection process.

Figure 2 .
Figure 2. (a) The risk of bias summary.The risk judgement for each bias item is presented as a percentage of all included studies.(b) The risk of bias graph.The risk judgement for each bias item is presented as a percentage of all included studies.

Figure 3 .
Figure 3. Forest plot of the HR and 95% CI of the overall survival (OS).

Figure 4 .
Figure 4. Forest plot of the HR and 95% CI of the progression-free survival (PFS).

Figure 5 .
Figure 5. Forest plot of the odds ratio (OR) and 95% CI of objective response rate (ORR).

Table 1 .
Characteristics of included studies.