Safety and hematological toxicities of PARP inhibitors in patients with cancer: a systematic review of randomized controlled trials and a pharmacovigilance analysis

ABSTRACT

Introduction

This study aimed to estimate the toxicities of PARP inhibitors (PARPis), based on randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS) database.

Methods

Four electronic databases were searched from inception to 16 April 2024, for RCTs of approved PARPis. The primary and secondary outcomes were grade 3–5 adverse events (AEs) and grade 3–5 hematological AE, respectively. We conducted network meta-analyses to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of outcomes. A disproportionality analysis was conducted to estimate the signals of hematological AEs associated with PARPis from the FAERS database.

Results

Overall, 27 RCTs involving 11,067 patients with cancer were included. Olaparib had the best safety profile for any grade 3–5 AEs and hematological AEs among four approved PARPis. Olaparib did not increase the risk of thrombocytopenia (RR: 1.48; 95%CI: 0.64–3.39), but other PARPis did. Furthermore 14,780 hematological AE reports associated with PARPis were identified in the FAERS database, and all PARPis were associated with strong hematological AE signals. Hematological AEs mainly occurred within the first 3 months (80.84%) after PARPi initiation.

Conclusion

Olaparib had the best safety profile among five PARPis. PARPi-associated hematological AEs mainly occurred within the first 3 months.

Registration

PROSPERO (CRD42022385274).

KEYWORDS:

• PARP inhibitors
• adverse events
• hematological toxicities
• network meta-analysis
• pharmacovigilance
• FAERS database

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors substantially contributed to the conception and design of the review article and interpreting the relevant literature, participated in the study throughout and agreed to be accountable for all aspects of the work. L Fang and HY Ding are the guarantors of the entire manuscript. L Fang, HY Ding contributed to critical revision of the manuscript for important intellectual content. MF Dai, X Wang, WX Xin contributed to material preparation, data collection, analysis and interpretation. SS Kong and WX Xin and WB Xu verified the underlying data. The first draft of the manuscript was written by MF Dai and all authors reviewed and commented on it critically for important intellectual content and made revisions. All authors read and approved the final manuscript.

Data availability statement

All data generated or analyzed during this study are included in this published article and its Supplementary Material.

Acknowledgments

We extend our heartfelt gratitude to Professor Zhi-Chun Gu of the Department of Pharmacy, Renji Hospital, for his invaluable assistance in data analysis and interpretation of results of this study.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14737140.2024.2357822.

Additional information

Funding

This study was funded by the Medical Health Science and Technology Project of Zhejiang Province [2023KY606, 2023KY608], Project of Clinical Comprehensive Pharmaceutical Evaluation from Zhejiang Pharmaceutical Association [2022ZYYL20], Special Research Program of Pharmacoeconomics and Health Technology Assessment Committee of Zhejiang Pharmaceutical Association [2022ZYJ10; 2022ZYJ18], and 2022 Bethune Qiusuo Pharmaceutical Research Capacity Building Project [Z04JKM2021005].