Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA-617: Dosimetry estimate and empirical dose finding

To develop a treatment protocol for 225Ac-PSMA-617 alpha-radiation therapy in advanced stage, metastatic castration-resistant prostate cancer patients with PSMA-positive tumor phenotype. Methods: A dosimetry estimate was calculated based on time-activity-curves derived from serially performed 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of instable daughter nuclides. Salvage therapies empirically conducted with 50kBq/kg (n=4), 100kBq/kg (n=4), 150kBq/kg (n=2), 200kBq/kg (n=4) 225AcPSMA-617 were evaluated retrospectively regarding toxicity and treatment response. 8 out of 14 patients received further cycles in either 2 or 4 months intervals with identical or de-escalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biological effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys and 0.05 Sv for red marrow that are composed of 99.4% alpha, 0.5% beta and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100kBq/kg per cycle. At 100kBq/kg duration of PSA-decline was <4 months, but if therapy was repeated every 2 months patients experienced additive anti-tumor effects. Treatment activities of 50kBq/kg were without toxicity but induced insufficient anti-tumor response in these high tumor burden patients. Remarkable anti-tumor activity by means of objective radiological response or tumor marker decline was observed in 9/11 evaluable patients. Conclusion: For advanced stage patients a treatment activity of 100kBq/kg 225Ac-PSMA-617 per cycle repeated every 8 weeks presents a reasonable trade-off between toxicity and biochemical response.