Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA617: Dosimetry, toxicity and duration of tumor-control

Objectives: To evaluate 225Ac-PSMA617 for PSMA-targeting alpha-therapy of advanced-stage mCRPC patients. Methods: A protocol for synthesis and quality control of 225Ac-PSMA617 was developed and an appropriate starting activity for clinical application of 225Ac-PSMA617 was defined by preliminary dosimetry modeling. The treatment protocol was refined by an empirical dose escalation with n=14 patients and consecutively an additional group of n=40 was treated following this protocol. PSA and radiological response were assessed. Duration of response was compared to the duration of tumor control of preceding treatment lines. Lab tests and clinical exam was done to assess toxicity. Results: 225Ac-PSMA617 was routinely synthesized with a radiochemical purity exceeding 98%. Assuming a RBE of 5, a mean dose of 2.3 Sv for salivary glands, 0.7 Sv for kidneys and 0.05 Sv for red marrow were estimated for 1 MBq of 225Ac-PSMA617; comparable to an activity of 1 GB of 177Lu-PSMA617. In dose-escalation phase, severe xerostomia became dose-limiting and defined the MTD even before relevant hematological toxicity was observed. 100 kBq/kg BW 225Ac-PSMA617 administered every 2 months was chosen as treatment protocol. From 40 patients intended to treat, 31 patients were treated “per-protocol”, while 5 patients discontinued due to non-response and 4 patients due to xerostomia. In patients surviving at least eight weeks, a PSA decline >50% was observed in 24/38 (63%) and any PSA response in 33/38 (87%) of patients. Median duration of tumor control under 225Ac-PSMA-617 last-line therapy was 9.0 months; 5 patients presented with enduring responses of > 2 years. No grade-3/4 hematological toxicity was observed for patients with grade-0/1 values at baseline, regardless of the extent of bone involvement. PFS under PSMA-TAT was longer than the mean duration of tumor control under preceding treatment lines. Conclusion: First clinical results imply that PSMA-targeting alpha-radiation therapy with 225Ac-PSMA617 benefits from favorable low hematological toxicity even in “superscan”-pattern patients and also presents remarkable anti-tumor activity in regard to objective response and PFS. Swimmer-plot analysis indicates promising duration of tumor-control, especially taking into account the unfavorable prognostic profile of the selected advanced-stage patients.JRC.G.I.5-Advanced Nuclear Knowledg