Radiopharmaceutical Therapy Meets Radiobiology: Implications for Trial Design and DNA Repair Inhibitor Combinations

Radiopharmaceutical therapy (RPT) delivers protracted, low absorbed dose rate radiation over time, with cellular DNA repair capacity potentially limiting its efficacy. This article explores how lessons from radiobiology—particularly regarding DNA damage response (DDR)—inform the rational design of ¹⁷⁷Lu-labeled RPT (¹⁷⁷Lu-RPT)–based clinical trials, with emphasis on combinations with DDR inhibitors and replication stress response (RSR) inhibitors. <b>Methods:</b> We integrate preclinical and clinical data on both the induction and repair of DNA damage in the context of ¹⁷⁷Lu-RPT and on their combination with inhibitors of DDR/RSR pathways. <b>Results:</b> At the low absorbed dose rates typical of ¹⁷⁷Lu-RPT (&lt;0.1 Gy/h), sublethal DNA damage is largely repaired during exposure, minimizing the quadratic component (β) of the linear quadratic model and making intrinsic radiosensitivity (α) the main determinant of cell killing. This raises questions regarding the biologic factors underlying intrinsic radiation sensitivity, as well as the influence of the activity administered per cycle and the number of treatment cycles. <b>Conclusion:</b> Despite the attenuated β-component, the efficacy of ¹⁷⁷Lu-RPT could be improved by combining it with DDR and RSR inhibitors to disrupt the DNA repair processes that occur simultaneously with irradiation, provided that such combinations are rationally designed and sequenced. Optimal combinations will require integration of tumor- and patient-specific radiosensitivity profiles and incorporation of dosimetry and biomarker endpoints into trial designs.