**Abstract**

Metastatic and local advanced unresectable pancreatic cancers are lethal conditions that always carry a poor prognosis with rare exceptions. Currently, the mainstay of therapy is cytotoxic chemotherapy plus best supportive care. First-line therapy for patients with a good performance status includes FOLFIRINOX or gemcitabine plus nab-paclitaxel regimens. Patients carrying a deleterious germline BRCA mutation can be treated with maintenance olaparib after FOLFIRINOX. Patients with a poor performance status, but still fit enough for chemotherapy, may be treated with single agent gemcitabine. Second-line therapy will depend on previous therapy and current performance status. Options for patients treated with gemcitabine-based regimens are 5-fluorouracil plus leucovorin plus either nanoliposomal irinotecan, irinotecan or oxaliplatin. Patients that were treated with first line FOLFIRINOX may benefit from a gemcitabine-based chemotherapy, but evidence from randomized trials is lacking. Other options like immunotherapy and targeted therapies yield benefit only in very selected cases, and it is still an area of research.

**Keywords:** metastatic pancreatic cancer, unresectable pancreatic cancer, local advanced pancreatic cancer, FOLFIRINOX, nab-paclitaxel, gemcitabine, nanoliposomal irinotecan, olaparib, BRCA pancreatic cancer
