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.

Abstract

The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]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. We used a customized 78-gene panel to analyse circulating tumour DNA (ctDNA) from 150 patients with mCRPC included in a prospective [¹⁷⁷Lu]Lu-PSMA-617 registry. Undetectable ctDNA was a significant and positive prognostic biomarker at both baseline (before treatment) and at week 6 (before cycle 2 of [¹⁷⁷Lu]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. Our data highlight the potential utility of ctDNA in optimising patient selection, improving therapeutic monitoring, and dissecting genomic mechanisms of resistance to [¹⁷⁷Lu]Lu-PSMA-617, and further prospective validation is warranted.