Veliparib‑Induced Toxicity in Cancer Patients: A Systematic Review and Meta‑Analysis

Abstract In this study, we investigate the veliparib‑induced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could increase the risk of hematologic and gastrointestinal toxicities. Anemia, neutropenia, thrombocytopenia, and nausea were the most common toxicities. Patients diagnosed with gastrointestinal tumors tend to have a higher risk of high-grade neutropenia; patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the ≥ second line setting. Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia. Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue.


Introduction
Poly ADP-ribose polymerase (PARP) is a class of enzymes involved in some cellular processes.PARP plays a vital role in recognizing singlestrand DNA breaks and their activation lead to DNA repair mechanisms.There have been six primary pathways of DNA damage repair identified, which are variably used to address singlestrand DNA damage (SSBs) and double-strand DNA breaks (DSB) from a variety of mechanisms of injury.Homologous recombination (HR) and nonhomologous end joining (NHEJ) recombination are the two major pathways responsible for repairing DSB (1).Key tumor suppressor proteins involved in SSBs repair by HR are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes.PARP inhibitors were used as a treatment option for tumors that were mainly caused by DNA repair defects and to improve the therapeutic effect of radiotherapy or chemotherapy.Veliparib (ABT-888) is a potent PARP-1/2 inhibitor, and it has displayed promising results in cancer therapy and is currently under clinical trials (2).Numerous studies have highlighted the radiosensitizing properties of veliparib across various solid tumors, and it could enhance the antitumor activity of radiotherapy and reduced PARP levels in tumors at a low dose (3).In preclinical studies, veliparib could augmented radiation-induced lethality in cultured glioblastoma cells and exhibite similar combinatorial efficacy with radiation when paired with oxaliplatin, 5-fluorouracil, or irinotecan in cultured colorectal carcinoma cells (4).Therefore, cancer patients receiving radiotherapy or chemotherapy may benefit from the addition of veliparib to their treatment.In clinical studies, veliparib monotherapy has demonstrated antineoplastic activity in BRCA-mutated cancers, and it has also demonstrated promising results in combination with DNA-damaging therapies (5, 6).
Although veliparib shows activity for treating certain types of tumors, it can also result in doseindependent or dose-dependent adverse events (AEs), including gastrointestinal disorders, blood and lymphatic system disorders, nervous system disorders, infections and other AEs.Some of these AEs are frequently associated with the application of veliparib in clinical treatment, thus requiring appropriate management to avoid dose reductions or treatment discontinuations.However, these AEs have been less well studied.Therefore, we performed the present meta-analysis of randomized controlled trials (RCTs) to summarize the incidence and characteristics of veliparib-induced toxicity in cancer patients.

Methods
In this study, the methods for literature searches, article selection, data extraction and risk of bias assessment were in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (7).

Literature search
MEDLINE/PubMed, Embase and Cochrane Library were searched for potentially eligible publications from January 1966 to September 2023.The literature search was limited to human studies published in English.Databases were searched using combinations of the following keywords: 'veliparib', 'ABT-888', 'tumor', 'cancer', 'randomized controlled trials', and 'RCT'.The details of search strategy were provided in Supplementary search strategy.

Selection criteria
The inclusion criteria were as follows: (1) patients receiving veliparib for treating cancers; (2) randomized controlled trials; (3) available data including events or event rate and sample size of AEs.Veliparib in both control and treatment arms were excluded.Duplicate publications or unpublished studies were excluded.

Data extraction
The data extraction of all studies was performed independently by two of the authors, and any disagreements were resolved by consensus.The following properties were collected from each study: country, first author, year of publication, treatment line, names of the trial, median age of the participants, trial phase, cancer type, sample size and source of study subjects, treatment regimen, treatment duration, number and type of AEs in each arm.The assessment of the AEs were performed in accordance with the National Cancer Institute's common terminology criteria for adverse events (CTCAE, version 3/4).In this study, we separated AEs into all grade (grades 1-5) and high grade (grades 3-5) for our analysis.

Quality assessment
Cochrane Collaboration's Risk Bias Tool was used for assessing risk of bias, and the quality of the studies were assessed in accordance with the Jadad ranking system (8).The following components were assessed: allocation concealment, randomization, blinding, incomplete outcome data, loss-to-follow-up, intention-to-treat (ITT) analyses, and other sources of bias.Any disagreements were resolved by discussion among the investigators.The risk of bias was categorized as three levels: high risk, low risk, and unclear.

Data analysis
Summary risk ratio (RR) and their 95% CI were calculated for each type of AEs.The RR was used to compute dichotomous data by Mantel-Haenszel method.Statistical heterogeneity was quantified using the I 2 statistic.Heterogeneity was considered statistically significant If I 2 was more than 50%, and the meta-analysis was conducted using the random-effects model.Otherwise, the fixed-effect model was adopted.Subgroup analyses were used to analysis whether the RRs of AEs varied by cancer types (gastrointestinal tumors vs. breast cancer vs. lung cancer), median age (<60 vs. �60 years), line of therapy (first line vs. �second line), and dosage (<100 mg/BID vs. �100 mg/BID).Trial-specific RRs of heterogeneity were combined to calculate summary estimates by the random-effects model, and subgroup difference was considered statistically significant if I 2 > 50%.Publication bias was analyzed using funnel plot.Review Manager (Version 5.4) was used to conduct all the statistical analyses.

Results
Our search strategy identified 221 studies from databases and registers.The reasons for exclusion/inclusion and selection process are presented in Figure 1.At the end of the selection process, 22 RCTs (9-29) were included in our meta-analysis, including 5 phase III trials, 16 phase II trials, and one phase I trial.

Characteristics of included studies
Overall, 22 trials comprising 6538 patients receiving veliparib were included in this meta-analysis.
Underlying tumors included non-small cell lung cancer (NSCLC), ovarian cancer, small cell lung cancer (SCLC), colorectal cancer, breast cancer, melanoma, pancreas adenocarcinoma, and glioblastoma.Thirteen of the included studies were two-arm study, and nine were three-arm study.The number of participants in our study was ranged from 30 to 1124, and the median age of the participants were ranged from 44 and 69 years.The characteristics of the included trials are presented in Tables 1.
The risk of bias was summarized in both a risk of bias graph (Figure 2A) and risk of bias summary (Figure 2B).The quality assessment of the included trials are presented in Supplementary Table 1.All of the 22 included trials reported the randomization methods.Seven of the included  WBRT: whole-brain radiation therapy; BID: twice daily; QD: once daily; mFOLFIRI, irinotecan þ folinic acid þ 5-FU infusion; FOLFIRI: irinotecan þ folinic acid þ 5-FU bolus þ 5-FU infusion; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer.studies were open-label studies, thirteen were double-blind studies, and one was single-blind study.All the 22 included studies were judged as studies with a low risk of bias and had an acceptable degree of quality (Jadad score � 3/5).

All-grade adverse events
Adverse events data were available for all the included studies, and the pool results of all-grade AEs were presented in Haematological and gastrointestinal events were the most reported veliparib-induced AEs (19).For all-grade adverse events, the pooled incidence of anemia was 53.81%, neutropenia was 58.10%, thrombocytopenia was 44.73%, and nausea was 51.79% (Table 2).Neutropenia was the most common all-grade AE for veliparib.There were statistically significant heterogeneities among the studies (anemia, neutropenia, thrombocytopenia, nausea), and thus randomeffects model was applied (Figure 3).Different treatment regimen or cancer types were included in the present meta-analysis, which may bring about heterogeneities.Therefore, subgroup analyses were conducted by these differences.

High-grade adverse events
AEs data were available for all the 22 included trials, and the pool results of high-grade AEs were presented in For high-grade adverse events, the pooled incidence of anemia was 21.79%, neutropenia was 45.80%, and thrombocytopenia was 16.89% (Table 3).Neutropenia was the most common high-grade AE for veliparib.Statistically significant heterogeneities were observed among these studies (neutropenia and thrombocytopenia), and thus the random-effects model was used (Figure 4).Different treatment regimen or tumor types were included in our analysis, thus subgroup analyses were performed by these differences.

Subgroup analysis
As can be seen from our results, anemia, neutropenia, thrombocytopenia, and nausea were the most common AEs for veliparib.Therefore, subgroup analyses were conducted to analysis whether the RRs of these AEs varied by type of cancer, median age, and line of therapy.

Subgroup analysis according to the tumor type
In order to explore the relationship between veliparib-induced AEs and cancer types, we analyzed the risk of AEs in patients with gastrointestinal tumors, breast cancer, and lung cancers (Table 4).Significant group differences were observed in the RRs of high-grade neutropenia (I 2 ¼ 64.4%) with aspect of the tumor type.Patients with gastrointestinal tumors tend to associate with a higher risk of high-grade neutropenia than those with other tumor types.No significant group difference was detected in the RRs of anemia, thrombocytopenia, and nausea by tumor type.

Subgroup analysis according to the median age
The risk of AEs might be related to patients' age; thus, studies were further analyzed according to median age.No significant group difference was observed in the RRs of anemia, neutropenia, thrombocytopenia, and nausea by median age (Table 4).

Subgroup analysis according to line of therapy
As line of therapy may influence the incidence of AEs, and studies were further stratified according to line of therapy (Table 4).Significant group Patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the � second line setting.No significant group difference was observed in the RRs of thrombocytopenia and nausea by line of therapy.

Subgroup analysis according to dosage
The risk of AEs might be relate to the dosage of veliparib, studies were further analyzed according to different dosages.Significant group differences were found in the RRs of all-grade anemia (I 2 ¼ 66.7%).Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia.No significant group difference was observed in the RRs of neutropenia, thrombocytopenia, and nausea by different dosages (Table 4).

Publication bias
Funnel plots of the studies were used in the meta-analysis to evaluate the RRs of any AEs (Figure 5).No significant publication bias was found for the RRs of all-grade and high-grade any AEs in this study.

Discussion
PARP inhibitors have emerged as one of the most promising targeted therapies for breast cancer, ovarian cancer, prostate cancer, and other cancer types (30).Veliparib is an oral PARP-1/ PARP-2 inhibitor that has demonstrated activity as a monotherapy or in combination with standard chemotherapy in clinical trials.Although PARP inhibitors exhibit a low toxicity profile due to their specific mechanism of action, they are not completely benign and overall show a class effect toxicity profile (31).Our study provides a comprehensive meta-analysis on the toxicity profiles in cancer patients receiving veliparib.Our meta-analysis of data from 22 RCTs has demonstrated a significantly increased risk of hematologic toxicities and gastrointestinal toxicities with the use of veliparib.Anemia, neutropenia, thrombocytopenia, and nausea were the most   common AEs for veliparib.A previous network meta-analysis reported that the four approved PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) may increase the risk of some hematologic and gastrointestinal toxicities, including anemia, thrombocytopenia, neutropenia, and dyspnea (32).Our results show that veliparib-induced AEs was generally consistent with the AEs of these approved PARP inhibitors.
To the best of our knowledge, our research is the first and most comprehensive meta-analysis estimating the risk of veliparib-induced toxicity in cancer patients.Hematologic toxicities are a very common class effect of PARP inhibitors, which might be the on-target adverse effects related to PARP inhibition and myelosuppression.They tend to occur early after treatment begins with recovery after a few months, which was the most common reason of treatment interruption, dose modification, and discontinuation (31).Our study suggested that veliparib could significantly increase the risk of all-grade and high-grade hematologic toxicities, such as anemia, neutropenia, leukopenia, febrile neutropenia, and thrombocytopenia in cancer patients.Neutropenia, anemia, and thrombocytopenia were the most common hematologic toxicities.Therefore, cancer patients receiving veliparib or those who experience a dose modification should have a complete blood count with differential monthly to monitor hematologic toxicities.Our exploratory subgroup analysis by tumor type implied that patients diagnosed with gastrointestinal tumors tend to associate with a higher risk of neutropenia than those with other tumor types, which could be due to the fact that different tumors have different pathogeneses and different spectra of patient comorbidities.Therefore, physicians should pay special attention to gastrointestinal tumor patients when they were treated with veliparib.Moreover, our subgroup analysis according to line of therapy suggested that patients in the first-line setting tend to associate with a higher risk of high-grade anemia and neutropenia than those in the � second line setting.Thus, clinicians should be aware of veliparib-induced anemia and neutropenia in previously untreated patients.In addition, the subgroup analysis according to different dosages implied that patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia.Therefore, physicians should pay more attention to the patients who receive higher dosage of veliparib.
Gastrointestinal events are common for all PARP inhibitors, with nausea being the most prevalent.Gastrointestinal events can decrease patient compliance with oral therapy or delay treatment, thus decreasing the efficacy of anticancer treatment (32).
Our study suggested that the use of veliparib could increase the risk of nausea, diarrhea and constipation.Nausea was the most common gastrointestinal event.Patients treating with veliparib should be informed about the high risk of nausea and prevent its occurrence.Daily antihistamine and prokinetic are generally helpful to reduce the symptoms of nausea (33).Other frequent gastrointestinal events were constipation and diarrhea, which can be treated by Over-the-counter (OTC) drugs, such as loperamide for diarrhea, or polyethylene glycol 3350 or senna for constipation.
Other toxicities such as nervous system toxicities, pain, infections, electrolyte and metabolic disorders are not reported as common AEs associated with veliparib, but their occurrence cannot be entirely overlooked.Our results suggested that veliparib could increase the risk of all-grade insomnia, which was generally mild but can have a negative impact on quality of life.Since insomnia was not serious, symptomatic treatments could lead to resolution.Respiratory AEs are not commonly side-effects with PARP inhibitors, but they should not be ignored.Our results indicated that veliparib could increase the risk of dyspnea, but it was generally mild and reported as highgrade in 1% of patients.Moreover, our results showed that veliparib could increase the risk of all-grade pneumonia, which was 2.30 times more likely to occur than the controls.However, pneumonitis occurred in <4% of patients receiving veliparib.Treatment for veliparib-induced pneumonitis could refer to the accepted guidelines for drug-induced pneumonitis.Fatigue is also a commonly reported toxicity, and it might be related to previous treatment but can be increased by veliparib.Our study suggested that the risk of high-grade fatigue could be increased with the use of veliparib.For mild-to-moderate fatigue, a short-dose interruption at the same dose may relieve this symptom; but for severe fatigue, a dose reduction may be beneficial (34).A previous network meta-analysis investigated the safety and discontinuation of treatment due to PARP inhibitors-induced AEs.Significant differences were found in the AE spectrum and AE related treatment modification, and thus the investigators suggested that prompt dose personalization might obtain maximal benefit in the PARP inhibitors therapy (32).
Our study has several limitations.First, individual participant data were not available and only aggregated data from published clinical trial were used.Therefore, late effects of AEs manifested by previous treatment could not be considered here.Second, there were high heterogeneity for some analyses, which may be due to the inclusion of different tumor types or treatment schedule of veliparib.Therefore, we included RCTs with baseline comparability to reduce the potential impact of these factors.Third, the international studies were conducted by different experimenter from different institutions.Furthermore, the AEs were defined by different versions of CTCAE criteria, which may influence the co-primary endpoint.Therefore, the incidence of AEs may suffer from potential bias.
In conclusion, our meta-analysis suggested that veliparib could increase the risk of hematologic toxicities and gastrointestinal toxicities.Anemia, neutropenia, thrombocytopenia, and nausea were the most common AEs for veliparib.Patients diagnosed with gastrointestinal tumors tend to have a higher risk of neutropenia; patients in the first-line setting tend to associate with a higher risk of high-grade anemia and neutropenia than those in the � second line setting.Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia.Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue in cancer patients.Although veliparib was associated with several kinds of AEs, our study suggested that veliparib is a relatively safe agent.These AEs should be considered in the context of the benefits of veliparib for treating cancers.

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.For this type of study, formal consent is not required.

Figure 1 .
Figure 1.Flow chart showing the selection of studies included in the present review.

Figure 2 .
Figure 2. A summary of the risk of bias of the included studies (A.risk of bias graph; B. risk of bias summary).

Figure 3 .
Figure 3. Forest plots for the risk ratio of all-grade adverse events.

Figure 4 .
Figure 4. Forest plots for the risk ratio of high-grade adverse events.

Figure 5 .
Figure 5. Funnel plots for all-grade and high-grade any adverse events.

Table 1 .
Characteristics of the included studies.

Table 2 .
Summary risk ratio (RRs) of all-grade adverse events.

Table 3 .
Summary risk ratio (RRs) of high-grade adverse events.

Table 4 .
Summary risk ratio (RRs) of adverse events associated with veliparib in the subgroup analysis.