Response to RL-225Ac in prostate cancer: effect of prior treatment with RL-177Lu: a systematic review of the literature.

Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen ligands (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). Compared to β-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alphas could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA radioligand therapy (RLT) in mCRPC.

The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus and Web of Science databases, and articles up to Aug 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format or discussing a topic out of scope. Data on efficacy, toxicity and health-related quality of life were extracted from the individual articles. The I2 index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA RLT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-Scale.

The study included 12 articles; one series was performed prospectively. In total, data of 329 patients were analyzed. About 33% (n=132) of the included men were pretreated with 177Lu-PSMA RLT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA RLT. >25% PSA decline after 225Ac-PSMA RLT was lower in individuals who received prior 177Lu-PSMA RLT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median PFS and OS for pretreated vs. not pretreated individuals was 4.3 vs. 14.3 months and 11.1 vs. 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I2 =99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups.

225Ac-PSMA RLT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted RLT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA RLT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA RLT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA RLT in men refractory to 177Lu-PSMA RLT. This article is protected by copyright. All rights reserved.

The Prostate. 2023 Mar 24 [Epub ahead of print]

Judith Stangl-Kremser, Andres Ricaurte-Fajardo, Kritika Subramanian, Joseph R Osborne, Michael Sun, Scott Tagawa, Neil H Bander

Department of Urology, Weill Cornell Medicine, New York, NY., Department of Radiology, Division of Molecular Imaging and Therapeutics, Weill Cornell Medicine, New York, NY., Department of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY.