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

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors, which are among the most important breakthroughs in precision medicine, have played a crucial role in cancer treatment. Understanding the toxicity profiles of the different PARP inhibitors will improve strategic treatment in clinical practice. Methods: PubMed, Cochrane Library, and Web of Science were systematically searched to include related studies published in English between January 2009 and February 2020. Only prospective, phase II and III randomized controlled trials were included. The following treatment groups were analyzed: niraparib, talazoparib, olaparib, rucaparib, conventional therapy (chemotherapy), one PARP inhibitor with one angiogenesis inhibitor, and placebo. Baseline data and adverse event data were extracted from the Bayesian random-effects network meta-analysis.Results: Fourteen phase II and III randomized controlled trials (4,336 patients) were included. 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%). 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.Conclusions: This network meta-analysis suggested that the toxicity spectrum of each PARP inhibitor is different. Olaparib had the best safety profile among all PARP inhibitors because of its mild toxicity and narrow spectrum. This study may guide clinicians and support further research.

Adverse Event Profiles of PARP Inhibitors: Analysis of Spontaneous Reports Submitted to FAERS

“…We found that the overall signals for niraparib and rucaparib were stronger than those for olaparib, including symptoms of nausea, vomiting, diarrhea, and constipation, but olaparib had a strong signal in the ileus at the PT level. This was consistent with several systematic reviews (Bao et al, 2021). Gastrointestinal toxicity is one of the most frequent AEs associated with PARPis, often occurring early after treatment initiation.…”

“…In pivotal PARPi RCTs, the most common AEs that have led to dose modifications were hematologic toxicities; other common AEs associated with this class of therapy include gastrointestinal disorders, photosensitivity, and fatigue (Mirza et al, 2016;Pujade-Lauraine et al, 2017). A recent metaanalysis showed that niraparib and rucaparib had higher risks for hematological and gastrointestinal toxicities, and olaparib has a higher risk of serious adverse events (SAEs), such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (Bao et al, 2021;Morice et al, 2021). Unfortunately, there is little knowledge about differences between PARPis.…”

Utilization of Poly(ADP-Ribose) Polymerase Inhibitors in Ovarian Cancer: A Retrospective Cohort Study of US Healthcare Claims Data

“…Hematologic toxicities are a common class effect of PARPi, often occurring early after treatment initiation; they are also the most common cause of dose modification, interruption, and discontinuation [ 4 ]. In our study, rates of hematologic CEIs were consistent with RCT data [ 7 , 8 ] and were higher with niraparib, followed by rucaparib and then olaparib. Differences between PARPi in terms of tolerability and dose modifications in pivotal RCTs in the OC maintenance setting have recently been highlighted in an indirect treatment comparison [ 18 ].…”

“…Differences between PARPi in terms of tolerability and dose modifications in pivotal RCTs in the OC maintenance setting have recently been highlighted in an indirect treatment comparison [ 18 ]. Specifically, any grade 3–4 AEs were observed less frequently with olaparib than with niraparib and rucaparib [ 18 ], which is consistent with the results of a recent network meta-analysis of RCTs [ 7 ].…”

“…CEIs observed during the index period were consistent with the safety endpoints from pivotal RCTs with olaparib, niraparib, and rucaparib [ 7 , 8 , 13 – 17 , 30 , 31 ] and the limited real-world evidence published to date [ 19 – 21 , 23 ]. The most common CEIs observed included nausea, fatigue, vomiting, and hematologic toxicities such as anemia and thrombocytopenia.…”