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ABSTRACT Introduction Pancreatic ductal adenocarcinoma (PDAC) has a 5-year overall survival rate of 10%, emphasizing the need for more effective therapies, especially in metastatic disease. The immunosuppressive tumor microenvironment, poor vascularization, and dense tumor stroma typical for PDAC are hurdles that need to be overcome by novel drugs. Investigations are moving toward more targeted treatments including immunotherapy and cell-based approaches. Areas covered This article reviews emerging drugs in clinical development for metastatic PDAC, focusing on cellular therapies and novel treatments targeting metabolism, tumor stroma, oncogenic pathways and immunosuppression. With immunotherapy and CAR T-cell therapy on the rise in hematological malignancies, the transfer to solid tumors remains intriguing. Multiple exciting clinical trials investigating innovative therapeutic strategies for PDAC are currently ongoing and reviewed herein. ClinicalTrials.gov, conference abstracts and PubMed were searched in August 2021 and assessed for information on ongoing and published clinical studies. Expert opinion With many challenges to overcome, the optimal therapy for patients with metastatic PDAC is likely to consist of a combination of different agents. We are slowly moving from entity-dependent approaches to ones more focused on molecular and pathological features. Increasingly personalized treatment plans tailored to each patient may be the future of PDAC therapy.