Baseline and Early On-treatment Circulating Tumour DNA Fraction Are a Key Prognostic Biomarker in Metastatic Castration-resistant Prostate Cancer Treated with [(177)Lu]Lu-PSMA-617
- Author(s)
- Fettke, H; Kostos, L; Docanto, M; Bukczynska, P; Ng, N; Medhurst, E; Awad, M; Buteau, JP; Eliceiry, SC; Manoharan, S; Foroughi, S; Steen, J; Nguyen-Dumont, T; Hofman, MS; Azad, AA;
- Journal Title
- European Urology
- Publication Type
- Oct 29
- Abstract
- BACKGROUND AND OBJECTIVE: The prostate-specific membrane antigen (PSMA)-targeted radioligand [(177)Lu]Lu-PSMA-617 is an approved treatment for metastatic castration-resistant prostate cancer (mCRPC). However, identification of genomic biomarkers associated with treatment efficacy remains a critical unmet need. METHODS: We used a customized 78-gene panel to analyse circulating tumour DNA (ctDNA) from 150 patients with mCRPC included in a prospective [(177)Lu]Lu-PSMA-617 registry. KEY FINDINGS AND LIMITATIONS: Undetectable ctDNA was a significant and positive prognostic biomarker at both baseline (before treatment) and at week 6 (before cycle 2 of [(177)Lu]Lu-PSMA-617). Quantification of the baseline ctDNA fraction enhanced prognostic stratification irrespective of high or low PSMA expression on position emission tomography imaging. Undetectable ctDNA at week 6 was linked to a superior treatment benefit independent of prostate-specific antigen response. FOLH1 alterations were identified as a potential novel therapeutic resistance mechanism. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our data highlight the potential utility of ctDNA in optimising patient selection, improving therapeutic monitoring, and dissecting genomic mechanisms of resistance to [(177)Lu]Lu-PSMA-617, and further prospective validation is warranted.
- Publisher
- Elsevier
- Keywords
- Circulating tumour DNA; Liquid biopsy; Lutetium; Prostate cancer; Prostate-specific membrane antigen radioligand; Theranostics
- Research Division(s)
- Clinical Discovery and Translation
- PubMed ID
- 41168066
- Publisher's Version
- https://doi.org/10.1016/j.eururo.2025.08.015
- Open Access at Publisher's Site
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Creation Date: 2025-11-03 09:22:04
Last Modified: 2025-11-03 09:23:54