Prostate-Specific Membrane Antigen Radioligand Therapy Using 177 Lu-PSMA I&T and 177 Lu-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 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: 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&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. Results: The whole-body half-lives were shorter for 177Lu PSMA I&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&T (0.04 Gy/GBq vs. 0.03 Gy/GBq, p<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&T (0.77 Gy/GBq vs 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to parotid glands (0.5 Gy/GBq, P = 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&T, respectively. All tumor metastases exhibited a higher initial uptake when using 177Lu-PSMA I&T, as well as shorter tumor half-life as compared to 177Lu-PSMA-617 (p<0.00001). The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617 (5.8 Gy/GBq vs. 5.9 Gy/GBq, P = 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&T which 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. 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&T. The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&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.