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The biology of metastatic pancreatic neuroendocrine tumors (panNET) may alter over time. It remains to be defined if, how, and when this patient group should be recommended to re-evaluate the characteristics of their disease. This prospective single-center, longitudinal cohort study at Uppsala University Hospital, Sweden (NCT03130205), included metastatic panNET patients with progressive disease to participate in a standardized re-characterization protocol: clinical and biochemical analyses, core-needle biopsy, and dual-positron emission tomography/computed tomography (PET/CT) (¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and Gallium-68 DOTATOC (⁶⁸Ga-DOTATOC)) with NETPET score assessments. At further disease progression, a second re-characterization was offered. The proportion of patients with a clinically significant change is reported and defined as information that could lead to a change in the therapeutic algorithm proposed in the European Neuroendocrine Tumor Society (ENETS) guidelines. Between 2017 and 2021, 21 patients with progressive metastatic panNETs were included. Before inclusion, 19 tumors were grade (G) 1 or 2, and two were G3. Sixteen patients underwent biopsy with collection of adequate tumor material, of whom 81.3% (n = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (n = 8/16). Twelve and 15 patients were positive on ¹⁸F-FDG- and ⁶⁸Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (n = 2), P2b (n = 12), and P3b (n = 1). A clinically significant change was noted among 62% (n = 13/21) of patients at first re-characterization, leading to therapy change in 7 positron emission tomography/computed tomography (PET/CT) patients. After the second re-characterization, a significant clinical change occurred in 43% (n = 3/7) with a shift in therapy for one patient. This study shows that a considerable number of progressive metastatic panNETs experience significant changes in their disease characteristics over time. This may result in a revised treatment plan and highlights the need to re-evaluate all relevant aspects of panNET disease. Such comprehensive re-characterization is particularly crucial in the context of clinical trial inclusion.