Cardiovascular toxicities reported with Poly ADP Ribose Polymerase (PARP) inhibitors in the FDA Adverse Event Reporting System

Background Poly ADP Ribose Polymerase inhibitors (PARPi) are approved for the maintenance treatment of adult patients with ovarian and breast cancer and for the treatment of prostate cancer in different setting. These oral targeted agents exploit cancer cells' intrinsic vulnerabilities (e.g. BRCA1/2 mutations), but are also associated with a variety of off-target toxicities, including haematological, gastrointestinal, and renal events. Recently, rare cardiovascular (CV) events have started to accrue, especially regarding thromboembolism. However, ESC Cardio-Oncology guidelines do not specifically address CV toxicities. Purpose To describe the spectrum of CV toxicities reported with PARPi in the real-life observational setting. Methods Deduplicated individual case safety reports (ICSRs) for licensed PARPs were identified from the Food and Drug Administration Adverse Event Reporting System (FAERS). Based on the Medical Dictionary for Regulatory Activities (MedDRA) terminology, major adverse CV events were identified based on a composite query including Standardized MedDRA Queries and Preferred Terms. Disproportionality analysis, using Information Component (IC) with a 95% confidence interval (CI) >0, was performed for CV events with at least 3 reports. Sensitivity analyses restricted the comparator to other anticancer drugs to minimize confounding by indication and channelling bias. Results Of 30,202 PARPi-associated reports, 6,922 involved CV ICSRs, with 68% submitted by consumers, and 87% originated from North America. Patients were predominantly females (92%), median age 66 years (Interquartile range [IQR] 58–73). Median time to onset was 28 days (IQR 4-117). Main co-reported drugs were ondansetron (19%) and paracetamol (17%). Among cardiac co-medications, metoprolol (13%) and apixaban (7%) were more frequently reported, with negligible use of class I-III antiarrhythmics and digoxin. Reported toxicities varied across PARPi: hypertension with veliparib (34%), increased blood pressure with niraparib (32%) and rucaparib (12%), pulmonary embolism with talazoparib (12%), and thrombosis with olaparib (9%). Disproportionality analysis included significant reporting (SDR) for deep vein thrombosis (IC 2.12) with veliparib and cardiac flutter (IC 2.88) with niraparib. Talazoparib was linked to pulmonary embolism (IC 1.56), while rucaparib was associated with lymphoedema (IC 1.92). Olaparib showed increased reporting for thrombosis (IC 0.67). Sensitivity analyses yielded comparable ICs. Conclusion The spectrum of CV toxicities reported with PARPi is heterogeneous and deserves urgent clarification through prospective studies to identify drug- and patients-related risk factors and clarify a potential class effect. Although causality cannot be firmly inferred, we call for increased awareness by cardio-oncologists, who should proactively monitor CV events to optimize patient safety.Analysis Faers Analysis vs L01