Safety profile of poly (ADP-ribose) polymerase (PARP) inhibitors in cancer: a network meta-analysis of randomized controlled trials

Introduction

In recent years, a deeper understanding of the molecular characteristics of tumors has driven the development of precise treatment. The novel and promising poly (ADP-ribose) polymerase (PARP) inhibitors have led to breakthroughs in cancer treatment (1,2). They were designed to exploit synthetic lethality and kill cells that have homologous recombination deficiency (3). Great effectiveness has been observed in BRCA-mutant tumors or tumors with deficiencies in the homologous recombination repair pathway (4).

Currently, PARP inhibitors have been employed in the treatment of breast and ovarian cancer, either alone or in combination with other therapies (2,5). According to NCCN guidelines, HER2-negative metastatic breast cancer patients with germline BRCA1/2 mutations could receive treatment with olaparib or talazoparib. Ovarian cancer patients with germline or somatic BRCA1/2 mutations are recommended to receive PARP inhibitors alone or combined with bevacizumab. To enhance the anti-tumor effectiveness, clinical scientists are also investigating the most potent synergistic efficacy partner of PARP inhibitors. The efficacy and safety of the combination therapy, including PARP inhibitors plus angiogenesis inhibitors (6,7), immune checkpoint inhibitors (8-10), cyclin dependent kinase (CDK) 4/6 inhibitors (11,12), phosphoinositide 3-kinase (PI3K) inhibitors (13), protein kinase B (AKT) inhibitors (14), mammalian target of rapamycin (mTOR) inhibitors (15), WEE1 inhibitors (16) or mitogen-activated protein kinase (MEK) inhibitors (17) are being evaluated through various clinical trials.

To further explore the therapeutic potential of PARP inhibitors, clinical trials in other tumors have also been conducted. On one hand, PARP inhibitors have shown effectiveness in patients carrying BRCA1/2 mutations beyond breast or ovarian cancer, such as prostate cancer (18) and pancreatic cancer (19). On the other hand, numerous clinical trials have sought to extend the promising function of PARP inhibitors to tumors with BRCAness (3,20). For example, the concept of combining PARP inhibitors with targeted therapy involving homologous recombination repair genes, including ATM, RAD51, CHEK2 and PTEN, has brought novel insights in cancer treatment (21-23).

However, despite the great effectiveness of PARP inhibitors, their toxicity profiles are not yet understood. Because of differences in their mechanisms, the various PARP inhibitor drugs differ in terms of safety (24-26). The safety profile of the combination therapy with other drugs, such as an angiogenesis inhibitor, also remains to be determined.

Since the traditional meta-analysis is limited to pairwise comparisons, it is impossible to determine the relative advantages of candidate therapies that have not yet been directly compared. By introducing indirect comparison, network meta-analysis can not only solve this limitation, but also improve the accuracy by combining direct and indirect estimations (27).

Here, we conducted a network meta-analysis of randomized controlled trials to compare the relative safety of PARP inhibitors alone, the combination of PARP inhibitors and angiogenesis inhibitors, and conventional therapy. We reported the results of both dose- and drug-based meta-analyses and ranked these treatment options on the basis of safety. The subgroup analysis was carried out according to different specific adverse events and cancer type (ovarian cancer). We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/atm-21-1883).

Methods

This network meta-analysis was conducted following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) and the PRISMA extension statement for network meta-analysis (28). A protocol was created in the Prospective Register of Systematic Reviews (PROSPERO CRD42020198263).

Date sources and searches

The databases of PubMed, Cochrane Library, and Web of Science were used to search for related studies. Randomized controlled trials published in English between January 2009 and February 2020 were eligible. Key words used in the search strategy included cancer, carcinoma, neoplasm, poly (ADP-ribose) polymerase inhibitors (BRCA mutation, PARP inhibitors, PARPis, PARPi), and specific PARPi drug names (fluzoparib, niraparib, olaparib, rucaparib, talazoparib, iniparib, and veliparib). The search strategy will be described in detail in the supplementary materials. Two independent investigators (SN-B, YP-Y) evaluated the data of the related publications after the primary screening of all eligible studies.

Study selection

Only prospective, phase II and III randomized controlled trials that compared two or three treatments in the following group were included: niraparib, talazoparib, olaparib, rucaparib, conventional therapy (chemotherapy), one PARP inhibitor with one angiogenesis inhibitor, or placebo. Studies that compared different doses of one PARP inhibitor were also included. Eligible studies must have toxicity regarding adverse events of all grades. Conference abstracts, posters, and ongoing randomized controlled trials were excluded. Trials wherein PARP inhibitors were used as neoadjuvant or adjuvant treatments were also excluded.

Data extraction and quality assessment

The primary outcome was the difference in adverse events between different PARP inhibitors. The study name, study ID, first author, year of publication, cancer type, study design, number of patients, treatments, region, version of the Common Terminology Criteria for Adverse Events (CTCAE), the frequency of each specific grade 1–5 and grade 3 or higher adverse events, and follow-up time were extracted and summarized. The CTCAE was used to evaluate adverse events. Adverse events of any grade indicated complete toxicity while grade 3 or higher adverse events indicated severe toxicity. We evaluated the full text, reference lists of the related publications, and supplementary materials from clinicaltrials.gov and other available sources to obtain the latest and complete data. For each study, both original and updated information were extracted and reviewed in this network meta-analysis.

Two independent investigators (SNB, YJH) assessed the risk of bias in the randomized trials using the Cochrane Collaboration’s tool. The considered sources of bias included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and others (29). Methodological quality was also evaluated using the modified Jadad quality scale (30). Scores ≥4 were considered to be of high quality (Supplementary materials, Table S1).

Data synthesis and statistical analysis

Direct and indirect data from all eligible trials, including odds ratios and 95% confidence intervals (CIs), were synthesized to evaluate the difference in safety between the various PARP inhibitors. The safety profiles of the PARP inhibitors were analyzed in both overview and detail, according to the number of general and specific adverse events. Both dose- and drug-based analyses compared and assessed grade 3 or higher adverse events. All reported P values were two-sided, and results with P<0.05 were considered significant. Odds ratios >1 represented a safety benefit for the control group.

To compare the different treatments, we generated a network diagram using STATA version 14.0 (StataCorp) (31). A Bayesian framework using Markov chain Monte Carlo methods in R version 4.0.2 and its appropriate packages was employed in both dose- and drug-based network meta-analyses (32). The drug based meta-analysis, wherein we combined different treatment arms with different doses of the same PARP inhibitor into one arm, was conducted after completing the dose-based meta-analysis. Studies that only had one treatment group after the combination were ruled out. To address inter-study heterogeneity, random effects and consistency models were employed to calculate odds ratios and 95% CIs (33). To achieve posterior distributions of model parameters, non-informative uniform and normal prior distributions were used. Besides, initial values of over-dispersion (with a scaling of 5) in four chains were also applied to fit the model (32). Overall, 100,000 iterations (including 100,000 tuning iterations) and a thinning interval of 10 for each chain were generated. The convergence of iterations was evaluated in accordance with the Brooks-Gelman-Rubin statistic (34). The safety of each treatment was assessed and ranked according to the odds ratio and posterior probabilities.

Consistency between direct and indirect evidence is imperative to achieve reliable results. The inconsistency of the entire network was assessed by node splitting analysis, wherein P<0.05 indicated significant inconsistency (35,36). The frequentist framework was also used in pairwise meta-analysis to estimate odds ratios and 95% CIs. We evaluated the inter-study heterogeneity using the χ² and I² tests. Statistical significance was set at P<0.05. The heterogeneity was considered to be low, moderate, and high when I² value was estimated to be under 25%, 25–50%, and more than 50%, respectively (37). The fixed effects model was used when there was no significant heterogeneity. Otherwise, the random effects model was used. Results from the network (indirect) and pairwise (direct results) meta-analysis were compared to check for inconsistency.

Subgroup analyses were carried out according to different specific adverse events and cancer types. To ensure the stability and reliability of the network meta-analysis, we also performed a sensitivity analysis by controlling the source of this study, including phase III randomized controlled trials, studies using the current recommended dosage of PARP inhibitors, and studies explicitly reporting grade ≥3 adverse events.

Results

Systematic review and characteristics

The initial search yielded 1,080 potentially relevant studies, of which 121 reports were assessed in full text, and 14 randomized controlled trials were declared eligible (Figure 1) (6,19,38-49). In the dose based-network meta-analysis, 13 randomized controlled studies (6,19,38,39,41-49), representing nine treatments with different doses [niraparib 300 mg once daily; talazoparib 1 mg once daily; olaparib 200, 300 or 400 mg twice daily; rucaparib 600 mg twice daily; one PARP inhibitor with one angiogenesis inhibitor; conventional therapy (chemotherapy) and placebo], (n=4,219) were evaluated (Figure 2A). Twelve randomized controlled trials (6,19,38,39,41-48), which included seven treatments [niraparib, talazoparib, olaparib, rucaparib, one PARP inhibitor with one angiogenesis inhibitor, conventional therapy (chemotherapy), and placebo], (n=4,121) were assessed in the drug-based network meta-analysis (Figure 2B). The main characteristics of all studies are shown in Table 1. Nine studies (64.3%) were phase III trials and, five (35.7%) were phase II. Twelve (85.7%) were multinational trials. Thirteen (92.9%) studies were two-arm trials, and one (7.2%) included three arms. Cancer types investigated in these studies included breast, ovarian, prostate, and pancreatic cancers. The modified Jadad scores indicated that 14 studies were of high quality (Supplementary materials, Table S1).

Figure 1 Flowchart of study selection.

Figure 2 Network plots of comparisons for dose (A) and drug (B) based network meta-analyses. Each circular node represents a type of treatment. The circle size is proportional to the total number of patients. The width of lines is proportional to the number of studies performing head-to-head comparisons in the same study. PARPi, poly (ADP-ribose) polymerase inhibitor; AI, angiogenesis inhibitor.

Table 1 Baseline characteristics of 14 studies for Bayesian network meta-analysis by cancer type
Full table

Dose based network meta-analysis

To investigate the safety profiles of differing doses of one PARP inhibitor, a dose-based network meta-analysis was conducted. The results obtained in the consistency model indicated that, in terms of grade 3–5 adverse events, there was no significant difference between varied olaparib doses (Supplementary materials, Figure S1). The node splitting analysis also demonstrated that there was no significant inconsistency (all P>0.05; Supplementary materials, Table S2). Therefore, there was no significant difference in the safety profile between different doses of one PARP inhibitor, and this was an important prerequisite for the drug-based network meta-analysis.

Drug based network meta-analysis

The drug-based network meta-analysis compares the risks of grade 3–5 adverse events between niraparib, talazoparib, olaparib, rucaparib, a PARP inhibitor with one angiogenesis inhibitor, conventional therapy (chemotherapy), and placebo. The results are shown in Figure 3A. Logically, the placebo group was found to have the lowest risk of grade 3–5 adverse events. The combination of one PARP inhibitor and one angiogenesis inhibitor was shown to cause more toxicity than all other treatments except niraparib and rucaparib. Olaparib was significantly safer than niraparib and rucaparib, but the difference between talazoparib was not significant. Niraparib had a higher risk of adverse events than talazoparib and olaparib, but it was not significantly different compared to rucaparib. It was also indicated that conventional therapy (chemotherapy) was significantly safer than niraparib and rucaparib but was not different from the other two PARP inhibitors.

Figure 3 Safety profile (A) and ranking histograms (B) according to the drug based network meta-analysis in the consistency model. Each cell of the safety profile contains the pooled odds ratios and 95% confidence intervals for grade 3–5 adverse events; significant results are in bold. Ranking histograms indicate the probability of the highest risk of grade 3–5 adverse events, the second highest, the third highest, and so on. PARPi, poly (ADP-ribose) polymerase inhibitor; AI, angiogenesis inhibitor.

The safety ranking for grade 3–5 adverse events, from the lowest to highest risk, was placebo, olaparib, conventional therapy (chemotherapy), talazoparib, rucaparib, niraparib, and one PARP inhibitor with one angiogenesis inhibitor (Figure 3B). Therefore, in clinical practice, when considering grade 3–5 adverse events, olaparib may be a better choice (probability =57%), followed by conventional therapy (50%), talazoparib (45%), rucaparib (75%), niraparib (77%), and a PARP inhibitor with one angiogenesis inhibitor (94%). The probabilities are detailed in the Supplementary materials, Table S3.

In addition to inducing synthetic lethality, PARP1 or PARP2 become trapped in DNA damage sites, leading to PARP-DNA complexes and interfering with DNA replication (25,50). The rank order of trapping potency is talazoparib >> olaparib = rucaparib > niraparib = veliparib in HeyA8 cells treated with 1 mmol/L methyl methanesulfonate. This difference is believed to be the main reason for the different recommended doses of existing PARP inhibitors, as PARP trapping appears to drive myelosuppresion (26).

The results of the three head-to-head comparisons are presented in Figure 4. Pairwise meta-analysis of two comparisons, which were olaparib and niraparib versus placebo, demonstrated that our network meta-analysis results were prominently consistent. No significant inter-study heterogeneity was found in any pairwise meta-analysis comparisons (I²=0%; P>0.05) (Supplementary materials, Figure S2).

Figure 4 Forest plots depicting the direct and indirect results of head-to-head comparisons.

Subgroup analysis based on specific adverse events

Based on specific grade 1–5 adverse events, the subgroup network meta-analysis included nine to 13 studies (3,372 patients to 4,211 patients). We evaluated the risk of all treatment groups for specific adverse events, including hematological disorders (anemia, neutropenia and thrombocytopenia), gastrointestinal disorders (nausea, vomiting, constipation), metabolism disorders (anorexia), and general disorders (fatigue) (Table 2). In terms of the safety of the PARP inhibitor monotherapy, no meaningful results were observed between the different PARP inhibitors. However, olaparib was safer than niraparib for constipation and thrombocytopenia. Compared to the combination of PARP inhibitor and angiogenesis inhibitor, niraparib was safer for anorexia, and olaparib was safer for anorexia and constipation. No differences were found between the combination and talazoparib or rucaparib. Interestingly, compared to conventional therapy, the risk for nausea, vomiting, and anemia was increased in almost all PARP inhibitors. Only olaparib was found to be safer than conventional therapy for neutropenia.

Table 2 Effect of treatment on each specific grade 1-5 adverse event
Full table

We also assessed the ranking profile of all treatment groups (Figure 5). The combination of PARP inhibitor and angiogenesis inhibitor had the highest risk for causing general, metabolic, and gastrointestinal disorders. Niraparib had a higher risk of causing hematological toxicities, including anemia, thrombocytopenia, and neutropenia. The main adverse events of rucaparib were gastrointestinal disorders. Talazoparib was the safest PARP inhibitors for gastrointestinal function. Moreover, olaparib, which has a narrow and mild toxicity profile, had the lowest risk for constipation and neutropenia, but a higher risk for anorexia. Interestingly, the conventional therapy had the lowest risk for fatigue, nausea, vomiting, anemia, and thrombocytopenia, but the highest risk for neutropenia.

Figure 5 Toxicity spectra and rankings in the subgroup analysis based on each specific grade 1-5 adverse event and cancer type. PARP inhibitor drugs are shown with a dark background. CT, conventional therapy; PARPi, poly (ADP-ribose) polymerase inhibitor; AI, angiogenesis inhibitor.

Subgroup analysis based on cancer type (ovarian cancer)

The approval of PARP inhibitors (olaparib, niraparib, and rucaparib) for recurrent epithelial ovarian cancer has emerged as a new and exciting treatment method. We therefore assessed the safety of different PARP inhibitors in ovarian cancer.

This subgroup analysis included nine studies (6,41-48), and only adverse events of grade 3 or higher were analyzed (Figure 6). This indicated that olaparib was safer than niraparib, rucaparib, and the combination of PARP inhibitor and angiogenesis inhibitor. Conventional therapy had lower risks for grade 3–5 adverse events than niraparib, rucaparib, and the combination of PARP inhibitor and angiogenesis inhibitor, but was not different from that of olaparib. No differences were observed between the combination of PARP inhibitor and angiogenesis inhibitor, and niraparib or rucaparib. The safety ranking, from the lowest to the highest risk, was placebo, conventional therapy, olaparib, rucaparib, niraparib, and one PARP inhibitor with one angiogenesis inhibitor. In conclusion, olaparib may be the safest option among the analyzed PARP inhibitors for the treating ovarian cancer.

Figure 6 Safety profiles in the subgroup analysis based on ovarian cancer. Each cell of the safety profile contains the pooled odds ratios and 95% confidence intervals for grade 3–5 adverse events; significant results are in bold. PARPi, poly (ADP-ribose) polymerase inhibitor; AI, angiogenesis inhibitor.

Sensitivity analysis

To ensure the reliability of this study, we conducted a sensitivity analysis on three subgroups: phase III studies (19,38,39,42-44,46-48), studies explicitly reporting grade ≥3 adverse events (6,19,38,39,42-48), and studies using the current recommended dosage of PARP inhibitors (6,19,38,39,42-44,46-48). Similar results were observed in these three subgroups.

The individual sensitivity analysis of nine phase III studies suggested that olaparib was safer than conventional therapy and all other PARP inhibitors. This finding was consistent with the drug-based network meta-analysis. Talazoparib, rucaparib, and niraparib caused more risks for adverse events than the conventional therapy. The combination of a PARP inhibitor and an angiogenesis inhibitor was absent in this analysis. Two additional sensitivity analyses, based on 11 studies explicitly reporting grade ≥3 adverse events and 10 studies using the current recommended dosage of PARP inhibitors, showed that the safety ranking from the lowest to the highest risk, was placebo, olaparib, conventional therapy, talazoparib, rucaparib, niraparib, and one PARP inhibitor plus one angiogenesis inhibitor (Supplementary materials, Table S4).

Discussion

The successful development of PARP inhibitors has become a milestone in cancer treatment. Despite their promising effectiveness in clinical practice, the toxicity profiles of different PARP inhibitors need to be clarified.

To the best of our knowledge, there have been relatively few network meta-analyses comparing the toxicity outcomes of PARP inhibitors for the treatment of advanced cancers. In this network meta-analysis, we included 14 randomized controlled studies (4,336 patients) to compare the safety profile of placebo, niraparib, talazoparib, olaparib, rucaparib, conventional therapy (chemotherapy), and one PARP inhibitor with one angiogenesis inhibitor. Because of the strict inclusion criteria and a reasonable study design, our network meta-analysis features good transitivity, and results achieved in this study can be interpreted appropriately (51,52). The sensitivity analysis further confirmed the reliability of our results, ensuring the homogeneity and consistency of our study.

In the dose-based safety analysis, no significant differences were found between different doses of one PARP inhibitor. The general safety profile ranking, from lowest to highest, was placebo, olaparib, conventional therapy (chemotherapy), talazoparib, rucaparib, niraparib, and one PARP inhibitor with one angiogenesis inhibitor in the drug-based analysis.

In the subgroup analyses according to different specific adverse events, the toxicity spectrum of each PARP inhibitor was different. Niraparib and rucaparib had higher risks for hematological and gastrointestinal toxicities, respectively. Talazoparib was safer for gastrointestinal function. Constipation and neutropenia were less observed in olaparib, but the risks for anorexia increased. The combination of PARP inhibitor and angiogenesis inhibitor increased the risk of general, metabolic, and gastrointestinal disorders. In addition, the subgroup analysis based on cancer type revealed that olaparib may be a better choice for treating ovarian cancer. Moreover, similar results were reported in the sensitivity analyses. Therefore, olaparib is considered a safer drug for cancer treatment because of its mild toxicity and narrow toxicity spectrum.

Limitations

This study had some limitations. First, inevitable confounding factors, based on clinical trial data, such as the difference in follow-up time and cancer type, were shown in this network meta-analysis. Second, the difference in common comparisons (conventional therapy) may have influenced the general function of the network meta-analysis, especially the exchangeability, thus undermining the balance of this study. Third, placebo-controlled trials tended to recruit more patients with mild diseases. Finally, this study did not include too many clinical trials, and the subgroup analysis of cancer type was limited to ovarian cancer. Given that NCT01116648 did not provide the number of patients who had grade ≥3 adverse events, we excluded it when analyzing the dose- and drug-based network meta-analysis. Since our findings were based on clinical trials, further studies are warranted in the clinical setting.

Conclusions

In this network meta-analysis, different toxicity spectra were observed among the different PARP inhibitors. After comparing various PARP inhibitors, conventional therapy (chemotherapy), and the combination of PARP inhibitor and angiogenesis inhibitor, olaparib was found to be the safer choice. The integration of evidence from this network meta-analysis can improve the management of adverse events and modify prescriptions for PARP inhibitors in the clinical setting. Since there have been no randomized controlled trials comparing the safety profile of PARP inhibitors directly, this study provides a useful guide for clinicians and researchers. Further studies are needed to explore the relative characteristics of PARP inhibitors.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Funding: This work was financially supported by the National Key Research and Development Program of China (ZDZX2017ZL-01), High-level Innovation Team of Nanjing Medical University (JX102GSP201727), Wu Jieping Foundation (320.6750.17006), Key Medical Talents (ZDRCA2016023), 333 Project of Jiangsu Province (BRA2017534 and BRA2015470), the Collaborative Innovation Center for Tumor Individualization Focuses on Open Topics (JX21817902/008) and Project of China Key Research and Development Program Precision Medicine Research (2016YFC0905901).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/atm-21-1883

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1883). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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