Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with 225Ac-PSMA-617 targeted alpha-radiation therapy

Targeted alpha-radiation therapy (TAT) with 225Ac-labeled prostate-specific membrane antigen (PSMA)-ligands is a promising novel treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. Limited data is available on efficacy, quality of life (QoL) and pretherapeutic biomarkers. The objective was to evaluate the efficacy of 225Ac-PSMA TAT and impact on QoL in advanced mCRPC, and to explore predictive biomarkers on pre-therapeutic metastatic tissue biopsies. Design, setting and participants: Observational cohort study including consecutive patients treated with 225Ac-PSMA TAT between February 2016 and November 2017. 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. We used Kaplan-Meier estimates for OS. 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 large improvement of physical and role functioning and clinically relevant decrease of pain. Xerostomia persisted during follow-up. Patients with high baseline PSMA expression or DNA damage repair alterations tended to have longer OS. The small sample size limits the interpretation of the results. TAT with 225Ac-PSMA resulted in remarkable survival and biochemical responses in advanced mCRPC patients. Patients experienced large QoL improvement, although xerostomia was found to be non-transient. Larger prospective studies on 225Ac-PSMA TAT are warranted, including evaluation of pretherapeutic biomarkers. In this observational study, we examined outcomes of 225Ac-PSMA TAT in end-stage mCRPC patients. Patients experienced decrease of pain and improvement of functioning. Dry mouth symptoms were non-transient at follow-up. These findings warrant further evaluation of 225Ac-PSMA TAT in larger prospective clinical trials.

VAN DER DOELEN M.J.;  MEHRA N;  VAN OORT Inge;  LOOIJEN-SALAMON Monika;  JANSSEN M.J.R.;  CUSTERS Jose;  SLOOTBEEK P.H.J.;  KROEZE Leonie;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  HABERKORN Uwe;  KRATOCHWIL Clemens;  NAGARAJAH J;  GERRITSEN W.R.; 

2022-03-28

ELSEVIER SCIENCE INC

JRC121092

1078-1439 (online),   

https://www.sciencedirect.com/science/article/pii/S1078143920306311,    https://publications.jrc.ec.europa.eu/repository/handle/JRC121092,   

10.1016/j.urolonc.2020.12.002 (online),