Baseline and Early On-treatment Circulating Tumour DNA Fraction Are a Key Prognostic Biomarker in Metastatic Castration-resistant Prostate Cancer Treated with [177Lu]Lu-PSMA-617

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; ProsTIC Registry Investigators

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; ProsTIC Registry Investigators;
Details: Publication Year 2026-07,Volume 90,Issue #1,Page 74-84
Journal Title: European Urology
Publication Type: Research article
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: Humans; Male; *Prostatic Neoplasms, Castration-Resistant/blood/radiotherapy/pathology/genetics; *Circulating Tumor DNA/blood; *Dipeptides/therapeutic use; *Biomarkers, Tumor/blood/genetics; *Radiopharmaceuticals/therapeutic use; Lutetium/therapeutic use; Prognosis; Prospective Studies; Aged; *Heterocyclic Compounds, 1-Ring/therapeutic use; Radioisotopes/therapeutic use; Glutamate Carboxypeptidase II/genetics; Middle Aged; Prostate-Specific Antigen/blood; *Glycopeptides/therapeutic use; Antigens, Surface; Aged, 80 and over; *Heterocyclic Compounds/therapeutic use; Circulating tumour DNA; Liquid biopsy; Lutetium; Prostate cancer; Prostate-specific membrane antigen radioligand; Theranostics
Department(s): Laboratory Research; Medical Oncology; Cancer Imaging
Publisher's Version: https://doi.org/10.1016/j.eururo.2025.08.015
Open Access at Publisher's Site: https://doi.org/10.1016/j.eururo.2025.08.015
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-04 05:58:02

Last Modified: 2026-08-04 12:07:24