Leveraging DNA repair deficiency to personalize radiopharmaceutical therapy in prostate cancer

Abstract

Radiopharmaceutical therapies targeting prostate-specific membrane antigen (PSMA) have transformed the management of metastatic prostate cancer, yet inter-patient variability in therapeutic response remains a critical challenge. Emerging evidence indicates that defects in DNA repair pathways, including homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRd), sensitize tumor cells to ionizing radiation by impairing damage resolution. Ongoing research explores the potential of integrating genomic profiling of DNA repair defects to optimize patient selection and personalize radiopharmaceutical strategies such as 177Lu-PSMA and alpha-emitting conjugates. Clinical efforts to combine targeted radiation with synthetic lethality approaches are ongoing. Tailoring radiopharmaceutical therapy to individual tumor DNA repair profiles offers a promising paradigm to improve outcomes and expand therapeutic windows in advanced prostate cancer.