PET-based risk stratification for adverse events under [225Ac]Ac-PSMA radioligand therapy

Actinium-225 prostate-specific membrane antigen radioligand therapy ([225Ac]Ac-PSMA RLT) is a promising salvage option for metastatic castration-resistant prostate cancer (mCRPC). This study aimed to identify predictive parameters for renal and hematological adverse events. Twenty-six patients undergoing [225Ac]Ac-PSMA-I&T RLT (mean 3 ± 1 cycles) were retrospectively included. All patients received pretherapeutic Fluor-18 ([18F]F)-PSMA-1007 positron emission tomography/computed tomography (PET/CT) to quantify renal standardized uptake values (SUV) through manual segmentation of both kidneys. Total and osseous PSMA-tumor volume (TV) were also calculated. Additionally, Technetium-99m ([99mTc]Tc)-mercaptoacetyltriglycine (MAG3) renal scintigraphy was performed to assess tubular extraction rates (TER). Standard laboratory values were evaluated at baseline, at and between treatment cycles, including estimated glomerular filtration rate (eGFR) and hemoglobin (Hb). Renal events were defined as an eGFR decline ≥ 20% (Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group recommendations), while anemia was classified according to common terminology criteria of adverse events (CTCAE) version 5. Both eGFR (P = 0.0018) and Hb (P = 0.0002) declined during therapy. Eight patients (31%) experienced renal events, and ten subjects (38%) developed grade 3 anemia. Renal SUV on [18F]F-PSMA-1007 PET/CT correlated with both eGFR and TER (r ≥ 0.413, P ≤ 0.036), suggesting that PET-based renal quantification may reflect renal function. SUV emerged as the strongest predictor of renal events (Odds Ratio [OR] = 0.095, P = 0.011) outperforming TER (P = 0.165) and baseline eGFR (P = 0.245). Based on Kaplan Meier analysis, low SUV was also associated with shorter renal event-free survival (P = 0.001). Baseline Hb (P = 0.002) was the strongest predictor of grade 3 anemia, while additional markers (platelets, white blood cell count, alkaline phosphatase, osseous PSMA-TV and lactate dehydrogenase; each P ≤ 0.037) also contributed. In line, baseline Hb emerged as the strongest predictor of anemia-free survival (P = 0.0007; osseous TV, P = 0.024). PET-derived renal SUV and osseous tumor volume are promising predictive markers for renal and hematological adverse events during [225Ac]Ac-PSMA-I&T RLT. These findings may support pretherapeutic risk stratification in this vulnerable patient population.