Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Abstract

Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT-nonresponding lesions by targeted next-generation sequencing. <b>Methods:</b> Of 60 patients treated with ²²⁵Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. <b>Results:</b> In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting <i>TP53</i> (<i>n</i> = 3), <i>CHEK2</i> (<i>n</i> = 2), <i>ATM</i> (<i>n</i> = 2), and <i>BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB,</i> and <i>PMS1</i> (<i>n</i> = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in <i>ATM, BRCA1, MSH2, SLX4, ERCC,</i> and various <i>FANC</i> genes were detected. <b>Conclusion:</b> Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair-targeting agents such as poly(ADP-ribose)-polymerase inhibitors.