Comparison of novel PSMA-targeting [¹⁷⁷Lu]Lu-P17-087 with its albumin binding derivative [¹⁷⁷Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study

Purpose

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [¹⁷⁷Lu]Lu-P17-087, and its albumin binder modified derivative, [¹⁷⁷Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3).

Methods

Patients with PSMA-positive tumors were enrolled after [⁶⁸Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [¹⁷⁷Lu]Lu-P17-087 and four other patients received [¹⁷⁷Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups.

Results

Patients showed no major clinical side-effects under this low dose treatment. As expected [¹⁷⁷Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [¹⁷⁷Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [¹⁷⁷Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [¹⁷⁷Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively.

Conclusion

[¹⁷⁷Lu]Lu-P17-088 and [¹⁷⁷Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy.

Trial registration

¹⁷⁷Lu-P17-087/¹⁷⁷Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022).

URL of registry

https://classic.clinicaltrials.gov/ct2/show/NCT05603559.