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Introduction: Targeted alpha-radiation therapy (TAT) with 225 Ac-labeled prostate-specific membrane antigen (PSMA) ligands is a promising novel treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. However, limited data are available on efficacy, quality of life (QoL), and pretherapeutic biomarkers. The aim of this study was to evaluate the efficacy of 225 Ac-PSMA TAT and impact on QoL in advanced mCRPC, and to explore predictive biomarkers on pretherapeutic metastatic tissue biopsies., Methods: Observational cohort study including consecutive patients treated with 225 Ac-PSMA TAT between February 2016 and July 2018. Primary endpoint was overall survival (OS). Furthermore, prostate-specific antigen (PSA) changes, radiological response, safety, QoL, and xerostomia were evaluated. Biopsies were analyzed with immunohistochemistry and next-generation sequencing., Results: Thirteen patients were included. Median OS was 8.5 months for the total cohort and 12.6 months for PSMA radioligand therapy-naïve patients. PSA declines of ≥90% and ≥50% were observed in 46% and 69% of patients, respectively. Six patients were radiologically evaluable; 50% showed partial response. All patients showed >90% total tumor volume reduction on PET imaging. Patients experienced clinically relevant decrease of pain and QoL improvement in physical and role functioning domains. Xerostomia persisted during follow-up. Patients with high baseline immunohistochemical PSMA expression or DNA damage repair alterations tended to have longer OS., Conclusions: TAT with 225 Ac-PSMA resulted in remarkable survival and biochemical responses in advanced mCRPC patients. Patients experienced clinically relevant QoL improvement, although xerostomia was found to be nontransient. Baseline immunohistochemical PSMA expression and DNA damage repair status are potential predictive biomarkers of response to 225 Ac-PSMA TAT., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: [ 177 Lu]Lu-PSMA-617 radioligand therapy ( 177 Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177 Lu-PSMA in pateints with low-volume mHSPC., Patients and Methods: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [ 68 Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177 Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS., Results: All patients received two cycles of 177 Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease., Conclusions: 177 Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC., (©2021 American Association for Cancer Research.)