Pancreatic cancer has a high morbidity and mortality with the majority being PC ductal adenocarcinomas (PDAC). Whole genome sequencing provides a wide description of genomic events involved in pancreatic carcinogenesis and identifies putative biomarkers for new therapeutic approaches. However, currently, there are no approved treatments targeting driver mutations in PDAC that could produce clinical benefit for PDAC patients. A proportion of 5–10% of PDAC have a hereditary origin involving germline variants of homologous recombination genes, such as Mismatch Repair (MMR), STK11 and CDKN2A genes. Very recently, BRCA genes have been demonstrated as a useful biomarker for PARP-inhibitor (PARPi) treatments. In this study, a series of 21 FFPE PDACs were analyzed using OncoPan®, a strategic next-generation sequencing (NGS) panel of 37 genes, useful for identification of therapeutic targets and inherited cancer syndromes. Interestingly, this approach, successful also on minute pancreatic specimens, identified biomarkers for personalized therapy in five PDAC patients, including two cases with HER2 amplification and three cases with mutations in HR genes (BRCA1, BRCA2 and FANCM) and potentially eligible to PARPi therapy. Molecular analysis on normal tissue identified one PDAC patient as a carrier of a germline BRCA1 pathogenetic variant and, noteworthy, this patient was a member of a family affected by inherited breast and ovarian cancer conditions. This study demonstrates that the OncoPan® NGS-based panel constitutes an efficient methodology for the molecular profiling of PDAC, suitable for identifying molecular markers both for therapy and risk assessment. Our data demonstrate the feasibility and utility of these NGS analysis in the routine setting of PDAC molecular characterization.