Prediction of Resistance to<sup>177</sup>Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers
Oliver Sartor, Elisa M. Ledet, Minqui Huang, Jennifer Schwartz, Alex Lieberman, Brian Lewis, Jodi Lyn Layton, Pedro C. Barata, Albert Jang, Madeline Hawkins, Olivia Pocha, Sree M Lanka, Kendra Harris
Abstract
<sup>177</sup>Lu-PSMA-617 and <sup>177</sup>Lu-PSMA I&T (collectively termed <sup>177</sup>Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET–positive disease, but biomarkers for these agents remain incompletely understood. <b>Methods:</b> Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving <sup>177</sup>Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. <b>Results:</b> The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, <i>P</i> = 0.03). In particular, amplifications in <i>FGFR1</i> (25% vs. 0%, <i>P</i> = 0.01) and <i>CCNE1</i> (31.2% vs. 0%, <i>P</i> = 0.001) were more likely to be present in nonresponders. <i>CDK12</i> mutations were more likely to be present in nonresponders (25% vs. 3.6%, <i>P</i> = 0.05). <b>Conclusion:</b> Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for <sup>177</sup>Lu-PSMA–treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.