Peptide Receptor Radionuclide Therapy (PRRT) shifts to earlier, biology-driven strategy for GEP-NETs

Advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) pose significant treatment challenges, often progressing despite conventional therapies. Historically, systemic radionuclide therapy, specifically peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues like [¹⁷⁷Lu]Lu-DOTATATE, has been a cornerstone, primarily as a second-line option for somatostatin receptor-positive NETs. However, the existing treatment paradigm has been limited by its late-line application, potentially delaying optimal patient outcomes. This review addresses the evolving landscape, exploring how recent clinical and translational advances are expanding PRRT's therapeutic scope and justifying a reassessment of its strategic use.

This review synthesized findings from recent pivotal randomized phase III trials evaluating peptide receptor radionuclide therapy (PRRT) in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). It specifically examined evidence supporting a broader application of PRRT, including its use in selected high-grade well differentiated NETs, and analyzed studies directly comparing PRRT with targeted therapies to redefine optimal therapeutic sequencing. The review also considered emerging theranostic platforms and the development of next-generation agents, such as alpha-emitting radionuclides, which are entering late-phase development.

The review highlights that recent randomized phase III trials now support a significantly broader and more strategic application of PRRT. This includes its use in selected high-grade well differentiated NETs, expanding beyond its traditional role. > Direct comparisons between PRRT and targeted therapies have begun to redefine optimal therapeutic sequencing, suggesting PRRT may be utilized earlier in the treatment paradigm. Furthermore, the review identifies promising advances in radiosensitizing combinations and next-generation theranostic platforms, particularly those incorporating alpha-emitting radionuclides, which are currently progressing into late-phase development. These developments signify a shift towards a more flexible, biology-driven treatment approach for GEP-NETs, moving it from a late-line option to a more integrated strategy with important implications for clinical practice.