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.

Keywords: Poly (ADP-ribose) polymerase inhibitors (PARP inhibitors); adverse events; network meta-analysis; randomized controlled trials.

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.

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.

Figure 4

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

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.

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.