Tandem Isotope Therapy with ²²⁵Ac- and ¹⁷⁷Lu-PSMA-617 in a Murine Model of Prostate Cancer

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using ¹⁷⁷Lu or ²²⁵Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or "tandem" approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from ¹⁷⁷Lu- and ²²⁵Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of ¹⁷⁷Lu- or ²²⁵Ac-PSMA-617 alone or in combination (35 MBq of ¹⁷⁷Lu, 40 kBq of ²²⁵Ac, or 17 MBq of ¹⁷⁷Lu + 20 kBq ²²⁵Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of ¹⁷⁷Lu and 40 kBq of ²²⁵Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with ¹⁷⁷Lu was not significantly different from that of untreated mice. However, ²²⁵Ac-PSMA-617 both as a single agent and in combination with ¹⁷⁷Lu (17 MBq of ¹⁷⁷Lu + 20 kBq of ²²⁵Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for ¹⁷⁷Lu, 15.3 wk for ²²⁵Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between ²²⁵Ac alone and administration of half the ²²⁵Ac activity in tandem with ¹⁷⁷Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for ¹⁷⁷Lu, 14.6 wk for ²²⁵Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous ²²⁵Ac- and ¹⁷⁷Lu-PSMA-617 results in significantly decreased tumor growth compared with ¹⁷⁷Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of ¹⁷⁷Lu and ²²⁵Ac. Although the greatest benefits were observed with the single agent ²²⁵Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of ²²⁵Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of ²²⁵Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.