Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry

The objective of this study was to determine the safety, kinetics, and dosimetry of the ¹⁷⁷Lu-labeled prostate-specific membrane antigen (PSMA) small molecules ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46-90 y) with progressive mCRPC and PSMA expression verified by ⁶⁸Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4-7.6 GBq) of ¹⁷⁷Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5-9.0 GBq) of ¹⁷⁷Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for ¹⁷⁷Lu-PSMA I&T (35 h) than for ¹⁷⁷Lu-PSMA-617 (42 h). The mean whole-body dose of ¹⁷⁷Lu-PSMA-617 was higher than that of ¹⁷⁷Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of ¹⁷⁷Lu-PSMA-617, the renal dose was lower for ¹⁷⁷Lu-PSMA-617 than for ¹⁷⁷Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using ¹⁷⁷Lu-PSMA I&T than when using ¹⁷⁷Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either ¹⁷⁷Lu-PSMA I&T or ¹⁷⁷Lu-PSMA-617 PRLT. Conclusion: Both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. ¹⁷⁷Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did ¹⁷⁷Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.