ARIEL3 Investigators Clarify the Effects of Rucaparib on the Liver


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Jonathan A. Ledermann, MD

Jonathan A. Ledermann, MD

Robert L. Coleman, MD

Robert L. Coleman, MD

PRIMARY RESULTS from the randomized, placebo-controlled, phase III study ARIEL3—presented at the European Society for Medical Oncology (ESMO) 2017 Congress and published recently in The Lancet1—demonstrated that maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib (Rubraca) significantly improved progression-free survival compared with placebo in patients with recurrent ovarian carcinoma who had achieved a complete or partial response to platinum-based therapy. 

In an article published in the October 10 issue of The ASCO Post,2 Sandro Pignata, MD, was cited as saying: “There are some differences in toxicity among PARP inhibitors … including ‘small’ differences in fatigue, nausea, and anemia. Thrombocytopenia is more frequent than typical with niraparib [Zejula], and liver toxicity is more frequent than typical with rucaparib.” 

In ARIEL3, common laboratory abnormalities observed in the rucaparib group included elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST)—seen at any grade in 34% of the rucaparib group vs 4% of the placebo group, and at grade 3 in 10% vs 0%, respectively. There were no grade 4 or 5 cases in either group. 

Defining Terms 

WE BELIEVE there is an important distinction to be made between elevations in ALT and AST levels and liver toxicity. The two terms are not interchangeable. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)3—criteria that were applied in ARIEL3—grade ALT and AST elevations based entirely on laboratory test results. CTCAE terminology does not include “liver toxicity” but does refer to “hepatic failure,” which describes serious physiologic consequences of liver damage. 

In ARIEL3, observed elevations in ALT and AST were not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity and generally resolved over time. Only two rucaparib-treated patients (0.5%) discontinued treatment due to elevations in ALT or AST. Importantly, there were no cases of hepatic failure reported with rucaparib treatment, and no cases were found to meet Hy’s law criteria for drug-induced liver injury.4,5 

Elevations in ALT and AST have also been observed with other PARP inhibitors.6 Although the mechanism of action of ALT and AST elevations associated with PARP inhibitors is not known, it is possible that these laboratory abnormalities may be part of an adaptive response to PARP inhibition by these agents. Further research is needed to elucidate the underlying mechanism, but in our experience, the elevations observed with rucaparib are self-limiting and not symptomatic of toxic effects to the liver or hepatic failure and thus should not be equated with liver toxicity. ■

Jonathan A. Ledermann, MD

University College London Cancer Institute and UCL Hospitals, London

Robert L. Coleman, MD

Department of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center, Houston 

DISCLOSURE: Dr. Ledermann has served in an advisory role for Clovis Oncology, AstraZeneca, Pfizer, and Roche; served on speakers bureaus for AstraZeneca and Pfizer; and received research grants from AstraZeneca. Dr. Coleman has received grants from AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, and AbbVie and has been an advisor to AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, Tesaro, GamaMabs, Pfizer, Genmab, Gradalis, Bayer, and AbbVie. 

REFERENCES 

1. Coleman RL, Oza AM, Lorusso D, et al: Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:1949-1961, 2017. 

2. Expert Point of View: Sandro Pignata, MD, in Goodman A: Strong showing for rucaparib maintenance therapy for platinum-sensitive ovarian cancer. Available at www.ascopost.com/issues/october-10-2017/expert-point-of-view-sandro-pignata-md. Accessed October 27, 2017. 

3. NCI Term Browser, CTCAE. Available at nciterms.nci.nih.gov/ncitbrowser/ pages/vocabulary.jsf?dictionary=CTCAE&version=4.03. Accessed October 27, 2017. 

4. Temple R: Hy’s law: Predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15:241-243, 2006. 

5. Guidance for industry. Drug-induced liver injury: Premarketing clinical evaluation. Available at www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/Guidances/UCM174090.pdf. Accessed October 27, 2017. 

6. Zejula (niraparib) capsules (prescribing information). Available at http:// zejula.com/application/files/4115/0422/0987/Zejula_niraparib_Full_Prescribing_Information.pdf. Accessed October 27, 2017.



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