Tracing the global evolution of PSMA-targeted radioligand therapy in prostate cancer: clinical advancements, future directions, and challenges.

Prostate-specific membrane antigen-targeted radioligand therapy (PSMA RLT) has recently emerged as a promising treatment for patients with metastatic prostate cancer. Building on the success of PSMA PET diagnostics, PSMA RLT has attracted interest from both research institutions and pharmaceutical companies, leading to a progressive increase in clinical trials over the past decade. In 2022, the first PSMA RLT agent, [Lu]Lu-PSMA-617, was approved by the FDA and EMA for the treatment of mCRPC patients progressing after standard therapies. Since then, the number of centers offering PSMA RLT has grown rapidly worldwide. In March 2025, the FDA expanded the indication for [Lu]Lu-PSMA-617 to include taxane chemotherapy-naïve mCRPC patients. Current research studies are focusing on expanding the indications for PSMA RLT, developing new PSMA-targeting agents, exploring alternative radionuclides such as alpha and Auger electron emitters, and investigating combination strategies. Despite these advancements, several significant challenges remain in clinical implementation, global access, and availability. To present, there is high variability among different countries and institutions in patient selection and treatment protocols. Moreover, the distribution of centers offering the treatment is highly heterogeneous, with significant disparities across different countries. Furthermore, workforce shortages are already hindering its widespread diffusion and are expected to limit its expansion, particularly in low and middle-income countries. Many barriers need to be overcome in the coming years to standardize treatment protocols, guarantee fair global access to the treatment, and achieve widespread accessibility. Addressing these challenges is crucial to maximize the potential of PSMA RLT as a leading treatment for prostate cancer.