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

1204 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.