Tumor sink effect in PSMA-targeted theranostics: intra-patient evaluation of a cohort receiving 225Ac/177Lu-PSMA tandem radioligand therapy.

Background: This study aims to further strengthen the evidence of tumor sink effect (TSE) and to confirm this phenomenon in patients undergoing ²²⁵Ac/¹⁷⁷Lu-PSMA tandem radioligand therapy.

Methods: The study included a total of N.=31 mCRPC patients who undergone two cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT, with at least one cycle being augmented by [²²⁵Ac]Ac-PSMA-617. For pre- and post-therapeutic [⁶⁸Ga]Ga-PSMA-11 PET/CT scans the standardized uptake value (SUVmean) of the liver, kidneys, parotid glands, and spleen as well as the total lesion PSMA (TLP) were assessed and compared.

Results: The mean TLP value decreased by 31.32% after two cycles of PSMA-RLT. Overall, significant increases in SUVmean were noted in the spleen (P=0.002) and liver (P=0.009). Especially, responders exhibited significant SUVmean increases in the spleen (P<0.001, baseline mean: 5.35 vs. follow-up mean: 7.28), liver (P=0.001, 4.21 vs. 5.00), and kidney (P=0.003, 17.30 vs. 20.43). Correlation analysis revealed significant relationships between change in TLP and change in SUVmean in the parotid gland (r=0.408, P=0.023) and spleen (r=0.410, P=0.022). The strength of TSE varied with tumor size, with an increase in tumor burden leading to a stronger TSE.

Conclusions: This analysis demonstrates the presence of the TSE in mCRPC patients undergoing the innovative ²²⁵Ac/¹⁷⁷Lu-PSMA tandem radioligand therapy concept. TSE may hold significant clinical implications and may play a role towards more individualized RLT.