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Introduction Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care. Patients may receive a sequence of both regimens as first- and second-line palliative treatment. However, there is no guidance regarding a preferred order. Methods Retrospective analysis of clinical characteristics, treatment trajectories and outcomes of patients with advanced PDAC treated at the West German Cancer Center Essen from 2014 to 2020 to inform treatment decisions with respect to predictive factors, impact of chemotherapy regimen sequence and maintenance treatment. Results We identified 170 patients with available follow-up. Of those, 160 (94.1%) pts received palliative CTX for primary metastatic, locally advanced or recurrent PDAC. Median PFS upon first palliative chemotherapy was 4.1 (3.1 – 5.9) months. First-line FOLFIRINOX associated with superior PFS (median 6.3 months) and OS (9.7 months, HR 0.7, p=0.03) as compared to gemcitabine/nab-paclitaxel or other regimens (PFS 3.0, OS 6.9 months). However, OS benefit of first-line FOLFIRINOX was lost in patients who received at least two treatment lines (median OS 12.1 vs. 13.1 months, p=0.43). A landmark analysis of patients with clinical benefit (defined at CR/PR/SD for at least 20 weeks) upon first-line therapy revealed improved OS (HR 0.53, p=0.02) for patients receiving continued deescalated maintenance therapy. Second-line regimens resulted in similar PFS (overall log-rank p=0.92, median PFS2 2.3 (1.8-2.9), per-regimen median between 1.8 and 3.9 months). A previously established systemic inflammation score proved to be strongly prognostic and allowed identification of a patient subgroup with dismal prognosis (OS 2.9 vs. 11.4 months, HR 5.23, p

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