Prediction of Resistance to¹⁷⁷Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers

¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T (collectively termed ¹⁷⁷Lu-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. Methods: Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving ¹⁷⁷Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. Results: The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, P = 0.03). In particular, amplifications in FGFR1 (25% vs. 0%, P = 0.01) and CCNE1 (31.2% vs. 0%, P = 0.001) were more likely to be present in nonresponders. CDK12 mutations were more likely to be present in nonresponders (25% vs. 3.6%, P = 0.05). Conclusion: Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for ¹⁷⁷Lu-PSMA–treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.