Background: Different therapeutic options are available for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Platinum-based multi-agent chemotherapy regimens, such as FOLFIRINOX, are important elements in the multidisciplinary management of PDAC. Summary: At least one third of patients with metastatic PDAC are eligible for treatment with FOLFIRINOX. Eligibility criteria include good performance status and the absence of relevant comorbidities. However, chemotherapies can potentially be associated with serious adverse events, such as diarrhea or polyneuropathies. Here, we review relevant data from first-line, second-line, and maintenance therapy trials as well as real-world data. In addition, we address the management of possible adverse events. Key Messages: (1) Selection of a suitable treatment regime depends on patient performance status, comorbidities, and anticipated toxicity. (2) FOLFIRINOX is an appropriate treatment for patients up to 75 years of age with an ECOG PS of 0 or 1, without relevant comorbidities, normal or nearly normal bilirubin levels, and no significantly reduced DPD activity. (3) In particular, patients with germline BRCA1/2 (gBRCA1/2) or PALB2 mutations may benefit from first-line platinum-containing therapy. (4) Early and comprehensive testing of the patient’s mutational status could support the first-line treatment decision-making.

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