Metformin effects on renal function in mCRPC during PSMA radiopharmaceutical therapy (RPT): A retrospective analysis.

Abstract

203 Background: Preclinical research indicates that metformin may mitigate renal accumulation of lutetium-177-labeled PSMA radioligands in metastatic castration-resistant prostate cancer (mCRPC) by inhibiting organic cation transporters in the kidneys, thereby offering potential protection against radiopharmaceutical-induced nephrotoxicity. Methods: In this IRB-exempt retrospective analysis, 181 mCRPC patients treated with PSMA-RPT were identified from UCLA electronic health record database (2016–2025) and stratified by metformin exposure. Data on their age at treatment onset, hypertension diagnosis, treatment cycles, estimated glomerular filtration rate (eGFR), serum creatinine (Cr), and prostate-specific antigen (PSA) were collected. The study protocol was reviewed by the Internal Scientific Peer Review Committee. Inclusion required documented baseline and post-treatment eGFR and Cr. Primary endpoints were absolute changes in eGFR (|ΔeGFR|) and Cr (|ΔCr|) from baseline to first post-treatment assessment. Missing data was addressed using complete-case analysis. Two-sided t-tests were performed at α = 0.05. Multivariate analysis of variance (MANOVA) was conducted to evaluate ΔeGFR and ΔCr from metformin exposure, with age, hypertension, treatment cycles, and PSA as predictors. Results: Metformin-exposed patients (n=23), compared to controls (n=158), exhibited better baseline renal function (eGFR 89.6 ± 11.0 vs 81.7 ± 18.8 mL/min/1.73 m², p =0.048; creatinine 0.82 ± 0.18 vs 0.98 ± 0.30 mg/dL, p =0.009) despite significantly higher hypertension prevalence (47.8% vs 23.4%, p=0.019). In univariate analyses of posttreatment changes, metformin exposure was significantly associated with lower eGFR decline (-2.2 ± 16.8 vs -9.2 ± 27.1 mL/min/1.73 m², p =0.048) and creatinine increase (0.003 ± 0.20 vs 0.124 ± 0.32 mg/dL, p =0.042). However, metformin showed no significant multivariate effect on posttreatment ΔeGFR and ΔCr (Wilks’ λ = 0.944, F (2,92) = 2.72, p = 0.071). Conclusions: Renal preservation observed in the unadjusted analysis was likely attributable to confounding factors such as indication bias. Future research will address this limitation through a randomized, placebo-controlled trial with standardized metformin dosing, serial assessment of renal biomarkers, and quantitative PET SUV with predefined imaging outcomes. Variable Metformin (n = 23) Control (n = 158) p -value Age (years), mean ± SD 74.4 ± 8.1 72.9 ± 9.2 0.45 Hypertension (%) 47.8 23.4 0.019* Baseline eGFR (mL/min/1.73 m²), mean ± SD 89.6 ± 11.0 81.7 ± 18.8 0.048* Baseline serum creatinine (mg/dL), mean ± SD 0.82 ± 0.18 0.98 ± 0.30 0.009* Baseline PSA (ng/mL), mean ± SD 189.3 ± 358.7 266.5 ± 603.3 0.55 Treatment cycles, mean ± SD 3.7 ± 2.2 3.6 ± 2.1 0.85 Posttreatment ΔeGFR (mL/min/1.73 m²), mean ± SD -2.2 ± 16.8 -9.2 ± 27.1 0.048* Posttreatment ΔCr (mg/dL), mean ± SD 0.003 ± 0.20 0.124 ± 0.32 0.042* * p <0.05.