PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology

Background: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials.Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Devel-opment and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recom-mendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2-(clinical question 2) advanced BC.Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/ HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration.Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.