BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) accounts for the vast majority of cases of pancreatic cancer and is a lethal cancer that is often diagnosed as late-stage disease with a historically poor prognosis, as reflected in its status as the third leading cause of cancer-related deaths in the United States. OBJECTIVE: To review the landmark clinical trials of approved chemotherapy regimens, immunotherapies, and targeted therapies for PDAC and discuss the notable investigational agents currently in clinical trials that have shown survival benefits in patients with PDAC. DISCUSSION: Chemotherapy regimens, such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) or nab-paclitaxel plus gemcitabine, have improved survival in phase 3 trials and are recommended as a first-line treatment for locally advanced or metastatic PDAC. In patients with recurrent disease, salvage chemotherapy has either limited or conflicting data. Approved immunotherapies and targeted therapies include pembrolizumab, olaparib, and 3 tyrosine kinase inhibitors (larotrectinib, entrectinib, and erlotinib), but all targeted therapies are limited in clinical use and are reserved for patient populations with specific genetic mutations. The therapeutic approaches currently in early-phase development for PDAC include dual immune checkpoint inhibition, monoclonal antibodies, cellular therapy, oncolytic adenoviruses, oligonucleotides, and multiple small-molecule inhibitors. Combinations of immunotherapies that target the programmed cell death (PD)-1 or PD ligand 1 are being explored in the induction and maintenance settings. Single agents under investigation are often combined with standard chemotherapy in the treatment of locally advanced or metastatic PDAC. The Precision Promise adaptive clinical trial platform is an innovative and efficient approach to testing multiple novel therapies simultaneously. CONCLUSION: Of the notable investigational agents for PDAC, early clinical data demonstrate improvements in tumor response and survival benefit in locally advanced or metastatic disease. Emerging immunotherapies and targeted therapies are at the forefront of drug development and may transform the approach to the treatment of patients with PDAC. [ABSTRACT FROM AUTHOR]