Comparative Analysis of Morphological and Functional Effects of ²²⁵Ac- and ¹⁷⁷Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with ²²⁵Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of ¹⁷⁷Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of ²²⁵Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (−10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (−20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUV_mean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUV_mean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.