A combination isotope approach towards improved PSMA-targeted radioligand therapy in a murine model of prostate cancer

Objectives: Radioligand therapy targeting prostate-specific membrane antigen (PSMA) is a promising treatment option for metastatic castration-resistant prostate cancer (mCRPC). Early clinical experiences with beta-emitter Lu-177 and alpha-emitter Ac-225 as single agents have demonstrated encouraging treatment responses; however, responses are not durable. Disease relapse may be caused by insufficient tumor dose delivery, though ²²⁵Ac injected activity is limited by salivary gland toxicity. Dual isotope combination may improve tolerability while retaining high tumor dose. The objective of this study was to directly compare alpha- vs beta-particle treatment, as well as a combination thereof, at different stages of disease in a metastatic mouse model of mCRPC.

Methods: To determine comparable injected activities from ¹⁷⁷Lu and ²²⁵Ac, biodistribution studies were carried out at five time points following treatment of C4-2 subcutaneous tumor-bearing NSG mice. Tumor doses were estimated by integrating time-activity curves according to standard medical internal radiation dose methods. To establish a metastatic model of disease, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle. Mice were treated at either 3 or 5 weeks after inoculation, with equivalent tumor dose-depositing activities of ¹⁷⁷Lu- or ²²⁵Ac-PSMA-617 or in scaled combination (n=10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole body tumor burden growth and overall survival.

Results: The dosimetry studies revealed that 35 MBq ¹⁷⁷Lu and 40 kBq ²²⁵Ac yield equivalent tumor doses in a subcutaneous C4-2 model. Untreated mice develop visceral metastases >200 μm by 3 weeks after intracardiac inoculation, increasing to millimeter scale by 5 weeks. Disease burden of mice treated at 3 weeks with ¹⁷⁷Lu was not significantly different from untreated mice, potentially due to off-target dose deposition from the greater penetration range of beta particles. However, both the single agent ²²⁵Ac-PSMA-617 and in combination with ¹⁷⁷Lu were associated with significant whole body tumor growth retardation and survival benefit. Preliminary results of an ongoing treatment study at 5 weeks after inoculation show increased ¹⁷⁷Lu efficacy against larger metastases.

Conclusions: Treatment of a metastatic model of prostate cancer with 40 kBq ²²⁵Ac-PSMA-617 or 20 kBq ²²⁵Ac in tandem with 17MBq ¹⁷⁷Lu results in significantly decreased tumor growth compared with a beta-emitter alone. This works suggests a preference for alpha emitters alone or in combination in the metastatic setting.