Safety of the Combination of External Beam Radiotherapy with ¹⁷⁷Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer

The VISION trial of ¹⁷⁷Lu-PSMA-617 (LuPSMA) demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer when compared with the best standard of care. The practice patterns for and safety of the combination of external beam radiotherapy (EBRT) and LuPSMA in the real-world setting are unknown. Here, we characterize the toxicities and efficacy of the combination of EBRT and LuPSMA among patients with metastatic castration-resistant prostate cancer. <b>Methods:</b> The records of all patients treated with LuPSMA at an urban academic institution between 2022 and 2024 were retrospectively extracted from the electronic medical record. Patients were stratified on the basis of their receipt of EBRT. Treatment characteristics of both systemic therapy and EBRT were extracted. Provider-reported toxicities after LuPSMA and EBRT were assessed. Overall survival was assessed using Kaplan-Meier analysis. <b>Results:</b> The records of 113 patients were included in the analysis, including 92 patients who received EBRT and LuPSMA and 21 patients who received LuPSMA alone. The median age was 71.5 and 75 y in the combination therapy and the monotherapy groups, respectively. All patients were heavily pretreated. There were significantly higher rates of prior taxane-based chemotherapy in the combination group compared with those who received LuPSMA alone (92.4% vs. 76.2%; <i>P</i> = 0.045). In total, 207 EBRT courses were delivered among 92 patients. Of these courses, 164 (79.2%) were administered before the start of LuPSMA and 15 (7.2%) occurred between cycles of LuPSMA. Thirty-six patients (39.1%) received periconcurrent LuPSMA (i.e., within 3 mo of receiving EBRT). Most EBRT courses were palliative in intent. There were no significant differences in fatigue, dry eye, and cytopenias after administration of LuPSMA alone compared with periconcurrent LuPSMA and EBRT. There were higher rates of thrombocytopenia (any grade) in patients who received EBRT within 3 mo of LuPSMA relative to those who received EBRT more than 3 mo before LuPSMA (60.6% vs. 34.0%; <i>P</i> = 0.03). The median follow-up was 6.8 mo, during which there were no differences in overall survival between patients treated with prior EBRT relative to those who had never received EBRT (<i>P</i> = 0.10). There were also no differences in overall survival in patients treated with EBRT within 3 mo of LuPSMA relative to those who had never received EBRT (<i>P</i> = 0.10). <b>Conclusion:</b> Receipt of EBRT during or within 3 mo of LuPSMA was not associated with increased toxicity compared with LuPSMA alone and was not associated with receiving fewer cycles of LuPSMA. There were no differences with respect to overall survival between patients who received prior EBRT or EBRT within 3 mo and those who had never received EBRT. Treatment with EBRT in combination with LuPSMA can be incorporated as needed for primarily palliative purposes.