Optimizing the Schedule of PARP Inhibitors in Combination with (177)Lu-DOTATATE: A Dosimetry Rationale

(177)Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair (177)Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance (177)Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with (177)Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during (177)Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of (177)Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to (177)Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of (177)Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and (177)Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).