Metformin and renal dosimetry in patients undergoing [¹⁷⁷Lu]Lu-PSMA therapy: reduced kidney absorbed dose without impact on tumor dosimetry.

Abstract

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy (RPT) is an established treatment for advanced prostate cancer, but renal radiation exposure remains a major safety concern, as no clinically established nephroprotective strategy exists. Preclinical data suggest metformin to reduce renal radiopharmaceutical retention by interfering with tubular reabsorption. This study aimed to investigate the effect of metformin on renal and tumor dosimetry in PSMA RPT patients. 57 patients undergoing PSMA RPT were retrospectively analyzed (n=15 with metformin; n=42 without metformin). The mean kidney absorbed dose (AD) and mean tumor AD (up to three randomly selected osseous metastases per patient) were assessed by post-RPT dosimetry. Total tumor volume (TTV) was evaluated as a potential confounder. Patients on metformin showed a significantly lower mean kidney AD compared to patients without metformin (median 0.290 vs. 0.367 Gy/GBq; p=0.046). In multiple linear regression analysis, metformin use was independently associated with reduced mean kidney AD, whereas TTV was not a significant predictor. No significant difference in mean tumor AD was observed between groups (0.739 vs. 0.997 Gy/GBq; p=0.215), indicating preserved tumor targeting. No association between tumor burden and mean kidney AD was detected, suggesting independence from tumor sink effect. Metformin use was associated with a reduced mean kidney AD in patients undergoing PSMA RPT without affecting tumor ADs. Thus, metformin may represent a promising and widely available strategy to reduce renal radiation exposure and improve the therapeutic index of PSMA-targeted RPT. Prospective studies are warranted to validate these findings and define optimal treatment regimens.