Patients with locally advanced or metastatic PDAC are generally considered non-curative and managed with palliative intent. Several trials have showed systemic chemotherapy improves overall survival in this setting. FOLFIRINOX was evaluated in the PRODIGE 4-ACCORD11 trial, comparing standard dose gemcitabine to FOLFIRINOX (5-Fluorouracil, Folinic acid, Irinotecan and Oxaliplatin) in patients with advanced PDAC. This phase 3, multicenter trial randomized 342 patients showed a median overall survival (mOS) benefit of 11.1 months vs. 6.8 months in favor of FOLFIRINOX [55]. In another phase 3 trial (MPACT), 861 patients were randomized to either nab-paclitaxel and gemcitabine (Gem-nabP) or gemcitabine alone [56]. mOS was superior in the Gem-nabP group (8.5 months vs 6.7 months) as well as progression-free survival (5.5 vs 3.7 months). There is no randomized head-to-head comparison of FOLFIRINOX and Gem-nabP, both are considered reasonable first-line treatments for unresectable PDAC. In clinical practice, FOLFIRINOX is generally reserved for fit patients whereas Gem-nabP is preserved for patients with mediocre performance, comorbidities or old age. There is evidence from retrospective data that FOLFIRINOX could improve OS, but causes more toxicity in vulnerable population [57]. Therefore, gemcitabine monotherapy or FOLFOX are considered reasonable treatments for PDAC patients with poorer performance status (ECOG ≥2). After progression on first-line gemcitabine-based therapy, nanoliposomal irinotecan in combination with 5FU compared to 5FU alone was shown in the NAPOLI-1 study to have survival advantage of a mOS of 6.1 months vs 4.2 months) in PDAC patients [58]. Now this combination is standard second-line therapy. About 5% of PDAC patients harbor germline BRCA mutations. Given the role of synthetic lethality and PARP inhibition in patients with DNA damage response (DDR) pathway aberrations, the POLO trial was conducted to investigate the efficacy of Olaparib (a PARP Inhibitor) as switch maintenance therapy in PDAC patients with germline BRCA mutations [59]. Based on the significant mPFS advantage and QOL results (7.4 months vs. 3.8 months, HR 0.53), Olaparib maintenance is now approved for BRCA mutated PDAC patients. In the randomized phase 2 SEQUENCE study, standard gem-nabP (Days 1,8 15) followed by mFOLFOX (on day 29 of 6 weeks cycles) compared to standard gem-nabP, was studied in 153 metastatic PDAC patients [60]. Results were intriguing with mOS 13.7 months vs 9.4 months, however grade 3 cytopenias were higher in the experimental arm. Patients receiving nab-P/Gem-mFOLFOX showed a significantly higher 12-month (55.3% vs. 35.4%), and 24- month (22.4% vs. 7.6%) survival. This could be a potential first-line option in metastatic PDAC treatment.