Peptide receptor radionuclide therapy in neuroendocrine tumours: advances, combination strategies, and future directions

Abstract Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that 177 LuLu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle–emitting therapies ( 225 Ac, 212 Pb, 213 Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)–targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.