Heidi Fettke, Louise Kostos, Maria Docanto, Patricia Bukczynska, Nicole Ng, Elizabeth Medhurst, Miyah Awad, James P Buteau, Sebastián Casanueva Eliceiry, Sathya Manoharan, Siavash Foroughi, Jason A. Steen, Tú Nguyen‐Dumont, Michael S. Hofman, Arun Azad
In the context of prostate-specific membrane antigen (PSMA)-targeted radioligand treatment with [ 177 Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer, our data illustrate the potential utility of both pretreatment and on-treatment measurement of circulating tumour DNA to optimise patient selection, improve therapeutic monitoring, and dissect mechanisms of resistance. 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. 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. 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. 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.