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 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.

Keywords: 177Lu; 177Lu-PSMA I&T; 177Lu-PSMA-617; PSMA radioligand therapy; dosimetry; prostate-specific membrane antigen; theranostics.

Graphical abstract

FIGURE 1.

Flowchart of Bad Berka dose protocol. ROI = region of interest; VOI = volume of interest.

FIGURE 2.

PRLT posttherapy scans and SPECT maximum-intensity-projection (MIP) image. (A) Scans after ¹⁷⁷Lu-PSMA I&T. (B) Scans after ¹⁷⁷Lu-PSMA-617. p.i. = after injection.

FIGURE 3.

Biodistribution and dosimetry results for normal organs in patients treated with different PSMA ligands. (A) Kinetics: median uptakes in percentage administered activity. (B) Median effective half-life in hours. (C) Median residence time in hours. (D) Mean absorbed doses in Gy/GBq.

FIGURE 4.

Kinetics of metastases and comparative results from 96 metastases (bone, lymph node, liver, lung, and other) of patients treated with ¹⁷⁷Lu-PSMA I&T and from 179 tumor lesions (bone, lymph node, liver, lung, and other) of patients treated with ¹⁷⁷Lu-PSMA-617. (A) Median kinetics of all types of metastases. (B) Median kinetics of bone metastases. (C) Median kinetics of lymph node metastases. After administration of therapeutic activity, higher initial uptakes and faster washout for ¹⁷⁷Lu-PSMA I&T were observed in bone and lymph node lesions. In contrast, curves of ¹⁷⁷Lu-PSMA-617 showed initial increase until 3 h after injection. %IA = percentage injected activity.

FIGURE 5.

Comparative dosimetry results of metastases. (A) Median effective half-life. (B) Median residence time. (C) Mean absorbed dose.

FIGURE 6.

Comparison of laboratory parameters (hemoglobin, leukocyte, platelet, and serum creatinine) before therapy, after 2 cycles, and after 2–6 cycles with long-term follow up (FU) (observation period, 3.2–48.5 mo; mean ± SD, 17.4 ± 11.9 mo; median, 13.2 mo) for ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 PRLT.