Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) is still one of the most lethal malignant diseases with a devastating 5‑year overall survival of only 4–5%. Indeed, long-term survival was not affected by the introduction of new systemic cytotoxic chemotherapies which remain the key cornerstone in the treatment of metastatic PDAC. In the first-line setting, FOLFIRINOX based upon the results of the PRODIGE/ACCORD trial and gemcitabine with albumin-bound paclitaxel (GNP) based upon the MPACT trial have both been approved as therapeutic options for patients with no significant comorbidities and good performance status. As there is no direct comparison between these regimens, the choice in first-line treatment depends on the toxicity profile, patient’s preferences and reimbursability. In the second-line setting, the results of the NAPOLI-1 trial have led to the approval of nanoliposomal irinotecan (nal-iri) in combination with 5‑fluorouracil (5-FU) for the treatment of patients with mPDAC progressing under gemcitabine-based chemotherapy and therefore this regimen is the first to be approved for use in second-line therapy.