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

Abstract

The objective of this study was to determine the safety, kinetics and dosimetry of ¹⁷⁷Lu labeled prostate specific membrane antigen (PSMA) small molecules ¹⁷⁷Lu-PSMA-I&amp;T and ¹⁷⁷Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). <b>Methods:</b> A total of 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. 51 patients received 6.1±1.0 GBq (range, 3.4-7.6 GBq) ¹⁷⁷Lu-PSMA I&amp;T and 87 patients received 6.5±1.1 GBq (range, 3.5-9.0 GBq) ¹⁷⁷Lu-PSMA-617. Dosimetry was performed in all patients on the identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. <b>Results:</b> The whole-body half-lives were shorter for ¹⁷⁷Lu PSMA I&amp;T (35 h) as compared to ¹⁷⁷Lu PSMA-617 (42 h). The mean whole-body dose of ¹⁷⁷Lu-PSMA-617 was higher as compared to ¹⁷⁷Lu-PSMA-I&amp;T (0.04 Gy/GBq vs. 0.03 Gy/GBq, p&lt;0.00001). Despite the longer half-life of ¹⁷⁷Lu-PSMA-617, the renal dose of ¹⁷⁷Lu-PSMA-617 was lower than for ¹⁷⁷Lu-PSMA-I&amp;T (0.77 Gy/GBq vs 0.92 Gy/GBq, <i>P</i> = 0.0015). Both PSMA small molecules demonstrated a comparable dose to parotid glands (0.5 Gy/GBq, <i>P</i> = 0.27). Among all normal organs, lacrimal glands exhibited the highest mean absorbed dose of 5.1 Gy/GBq and 3.7 Gy/GBq for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&amp;T, respectively. All tumor metastases exhibited a higher initial uptake when using ¹⁷⁷Lu-PSMA I&amp;T, as well as shorter tumor half-life as compared to ¹⁷⁷Lu-PSMA-617 (p&lt;0.00001). The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&amp;T and ¹⁷⁷Lu-PSMA-617 (5.8 Gy/GBq vs. 5.9 Gy/GBq, <i>P</i> = 0.96). All patients tolerated the therapy without any acute adverse effects. There was a small, statistically significant reduction in hemoglobin, leukocyte counts and platelet counts after ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&amp;T which did not need any clinical intervention. No nephrotoxicity was observed after either ¹⁷⁷Lu-PSMA I&amp;T or ¹⁷⁷Lu-PSMA-617 PRLT. <b>Conclusion:</b> Both ¹⁷⁷Lu-PSMA I&amp;T and ¹⁷⁷Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. Highest absorbed dose amongst healthy organs were observed for the lacrimal and parotid glands, however, not resulting in any significant clinical sequel. ¹⁷⁷Lu-PSMA-617 demonstrated higher whole-body and lacrimal glands absorbed dose, but lower renal doses as compared to ¹⁷⁷Lu-PSMA-I&amp;T. The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&amp;T and ¹⁷⁷Lu-PSMA-617. There was a large inter-patient variability of the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.