Current Developments in Combining External-Beam Radiotherapy and ¹⁷⁷Lu-Labeled PSMA Ligands for Prostate Cancer Treatment

The combination of external-beam radiotherapy (EBRT) and ¹⁷⁷Lu-labeled prostate-specific membrane antigen (PSMA) ligands may improve the outcome for specific prostate cancer indications. This review aims to introduce the concept of this combined treatment, provide an overview of preclinical and clinical studies (as well as ongoing trials), and address current challenges and future directions to investigate this emerging therapeutic approach. <b>Methods:</b> A comprehensive search was conducted in online research databases (including PubMed) and trial databases (including ClinicalTrials.gov) to gather all relevant preclinical and clinical studies and ongoing trials on the combination of EBRT and ¹⁷⁷Lu-labeled PSMA ligands. <b>Results:</b> One completed preclinical study demonstrated increased tumor growth delay and survival with combined EBRT and [¹⁷⁷Lu]Lu-PSMA-617, compared with monotherapies, and one an additive effect. Four clinical reports published results on this combination, including series showing tumor regression in metastatic lesions and a pilot study demonstrating an increased biologically effective dose. Ten ongoing prospective clinical trials with varying designs, patient populations (de novo oligometastatic, oligorecurrent, and locally recurrent), treatment schedules ([¹⁷⁷Lu]Lu-PSMA ligands neoadjuvant, adjuvant, concurrent with EBRT), and radiation doses and fractionation schemes were identified. <b>Conclusion:</b> The combination of EBRT and [¹⁷⁷Lu]Lu-PSMA ligands holds promise to improve tumor control without increasing toxicity across various stages of prostate cancer. However, optimal treatment scheduling, dosing regimens, the role of dosimetry, and specific clinical indications require further investigation through robust preclinical and clinical research to guide future clinical trials.