Comprehensive Analysis of Adverse Events Induced by PARP Inhibitors Using JADER and Time to Onset

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against breast cancer susceptibility gene (BRCA) mutations. Clinical trials have reported hematologic toxicity and gastrointestinal symptoms as class effects of PARP inhibitors. However, information on adverse events (AEs) in a Japanese clinical cohort is currently lacking. In this study, we conducted a comprehensive survey of the AEs of two PARP inhibitors, olaparib and niraparib, using the Japanese Adverse Reaction Reporting (JADER) database provided by the Pharmaceuticals and Medical Devices Agency (PMDA). Moreover, we also analyzed the course and time to the onset of AEs. Signals were detected for 15 and 11 AEs for olaparib and niraparib, respectively. Most occurred within the first month of treatment with either agent. These results may indicate the importance of early response and monitoring after beginning PARP inhibitor therapy. The results of this study may be useful for managing side effects and suggesting supportive care for patients using PARP inhibitors in the future.

Keywords: Japanese Adverse Drug Event Reporting (JADER); Poly (ADP-ribose) polymerase (PARP) inhibitor; niraparib; olaparib; pharmacovigilance; spontaneous reporting system.

Figure 1

Box chart for time to onset of AEs associated with olaparib. (A) Hematological-related AEs: anemia (n = 327), myelodysplastic syndrome (n = 18), acute myeloid leukemia (n = 4), myelosuppression (n = 15), neutrophil count decreased (n = 31), platelet count decreased (n = 41), pancytopenia (n = 14); (B) gastrointestinal disorders: ileus (n = 5), nausea (n = 27), vomiting (n = 14); (C) others: malignant neoplasm progression ( n = 24), fatigue (n = 8), interstitial lung disease (n = 67), malaise (n = 13), death (n = 2). Box plots show the 25th quartile, 75th quartile, and median (the horizontal line inside the box). The whiskers reach the maximum and minimum values within 1.5 times the inner quartile point’s length. The box’s outside values represent the median number of days before each AE occurred.

Figure 2

Box chart for time to onset of AEs associated with niraparib. (A) Hematological-related AEs: thrombocytopenia (n = 34), platelet count decreased (n = 65), anemia (n = 30), myelosuppression (n = 8), neutrophil count decreased (n = 23); (B) gastrointestinal disorders: ileus (n = 10); (C) others: ovarian cancer recurrent (n = 20), ovarian cancer (n = 28), disease progression (n = 43), condition aggravated (n = 8), renal impairment (n = 32). Box plots show the 25th quartile, 75th quartile, and median (the horizontal line inside the box). The whiskers reach the maximum and minimum values within 1.5 times the inner quartile point’s length. The box’s outside values represent the median number of days before each AE occurred.