Relative Efficacy of (225)Ac-PSMA-617 and (177)Lu-PSMA-617 in Prostate Cancer Based on Subcellular Dosimetry

OBJECTIVES: Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) with alpha-emitting (225)Ac-PSMA-617 has shown clinical efficacy even in cases of failed therapy with beta-emitting (177)Lu-PSMA-617. We investigated the efficacy of (225)Ac-PSMA-617 relative to (177)Lu-PSMA-617 using subcellular dosimetry. METHODS: A 3-dimensional model of prostate cancer was constructed. For each decay, the absorbed and equivalent radiation dose to the cell nuclei was calculated. The relative efficacy per administered activity was calculated by taking into account the differences in residence time and tumor uptake. RESULTS: As the tumor size increased, the absorbed dose from (225)Ac-PSMA-617 increased linearly (R2: 0.99) and reached an asymptote near the maximum alpha range (85 µm), whereas the absorbed dose from (177)Lu-PSMA-617 continued to increase linearly (R2: 0.99). The equivalent dose per decay was 2,320, 2,900, and 823-fold higher in favor of (225)Ac-PSMA-617 compared to (177)Lu-PSMA-617 in a single cell, 100 µm-radius micrometastasis, and macroscopic tumor, respectively. Per administered activity, the relative efficacy of (225)Ac-PSMA-617 compared to (177)Lu-PSMA-617 in respective tumor sizes was at least 3,480, 4,350, and 1,230-fold higher, and possibly 11,800, 14,900, and 4,200-fold higher considering differences in tumor uptake. CONCLUSION: At commonly administered 1,000-fold lower activity of (225)Ac-PSMA-617 relative to (177)Lu-PSMA-617, the equivalent radiation dose deposited by (225)Ac-PSMA-617 is higher in measurable disease and much higher in microscopic disease compared to (177)Lu-PSMA-617.