A systematic review and meta-analysis of randomized controlled trials to evaluate the risk of gastrointestinal and hepatic toxicities in patients with recurrent ovarian cancer treated with poly adenosine diphosphate ribose polymerase inhibitors maintenance

Background: Inhibition of poly adenosine diphosphate ribose polymerase (PARP) enzymes resulted in synthetic lethality in ovarian cancer cells by terminating an alternative DNA repair pathway in homologous recombination deficient tumors. Many PARP inhibitors have shown to improve survival with noteworthy safety concerns. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention GI toxicities and elevation of liver function tests (LFT) either aspartate or alanine aminotransferase as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Results: Three phase III RCTs with 1401 patients were eligible. The study arms used olaparib or niraparib or rucaparib while the control arms utilized placebo. The randomization ratio was 2:1 in all studies. The RR of all-grade side effects were as follows: diarrhea, 1.29 (95% CI: 1.05 – 1.58, P = 0.015); dyspepsia, 1.73 (95% CI: 1.20 – 2.49, P = 0.003); nausea, 2.11 (95% CI: 1.86 – 2.40, P < 0.001); vomiting, 2.20 (95% CI: 1.76 – 2.75, P < 0.001); dysgeusia, 4.38 (95% CI: 3.00 – 6.41, P < 0.001); and elevated LFT, 4.74 (95% CI: 2.82 – 7.95, P < 0.001). The RR of high-grade side effects were as follows: diarrhea, 1.225 (95% CI: 0.992 – 1.512, P = 0.060); nausea, 4.35 (95% CI: 1.45 – 13.06, P = 0.009); vomiting, 3.39 (95% CI: 1.19 – 9.63, P = 0.02); and elevated LFT, 10.19 (95% CI: 2.47 – 42.06, P = 0.001). Conclusions: Our meta-analysis demonstrated that PARP inhibitors increased the risk of all grades of GI and hepatic toxicities with a relative risk of 10.19 for grade 3 and 4 elevated LFT. These toxicities have significant impact on patients’ quality of life and may ultimately affect patients’ compliance. Timely intervention with proper supportive care is necessary. Legal entity responsible for the study: Kyaw Zin Thein/ Texas Tech University Health Sciences Center. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.