Radioligand therapy using combination of Ac-225 and Lu-177 labelled PSMA ligands for progressive end-stage metastatic prostate cancer: effective trade-off between response and toxicity

Objectives: The alpha emitter Ac-225 labelled with PSMA-617 has revealed encouraging results in end-stage prostate cancer (PC) with disseminated metastases and progression under treatment with Lu-177. However, xerostomia is dose limiting and might necessitate cessation of Ac-225 PSMA-617 therapy. We studied the efficacy and toxicity of tandem PSMA radioligand therapy (PRLT), concurrently administering both Lu-177 and Ac-225 labelled PSMA-617.

Methods: Tandem PRLT, concurrently applying 3-5 MBq of Ac-225 PSMA-617 and 3.5-7.5 GBq Lu-177 PSMA-617, was performed in 30 patients with end stage PC. Ga-68 PSMA PET/CT, patient questionnaires, PSA and evaluation of other laboratory parameters at least 8 weeks after 1 cycle of the combined treatment, were evaluated in 23 patients.

Results: There was no severe xerostomia and no discontinuation of treatment. G3 thrombocytopenia and G2 anemia / leucocytopenia were noted in 2 patients with progressive disease. Otherwise, there was no worsening of counts even in patients with pre-existing anemia or pancytopenia. No nephrotoxicity or any other organ toxicity occurred. Pain decreased in severity with improvement in the global health status / Karnofsky performance score, particularly significant in 3 patients presenting in a poor general condition. Decline in PSA was seen in 13 (56.5%) patients, by > 99% in 3 (13%) and by >50% in 10 (43.5%) patients. Excellent response with nearly complete remission was observed on Ga-68 PSMA PET/CT in 3 patients. On PET/CT, partial remission was noted in 12 (52%) patients, PD in 10 (43.5%), and mixed response (4.5%) in 1 patient. 5 patients died, median overall survival was 33 weeks, and median progression-free survival 21 weeks.

Conclusions: TANDEM-PLRT, concomitantly administering Ac-225 and Lu-177 PSMA-617, seems to be feasible, safe and effective in end-stage metastatic prostate cancer, refractory to Lu-177 PSMA. The administered radioactivity of Ac-225 PSMA can be lowered and the risk of dose-limiting toxicity (xerostomia, xerophthalmia etc.) be minimized. There might be a potential synergistic effect using two radionuclides with different emission characteristics.