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

177Lu-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 177Lu-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 177Lu-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 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-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 177Lu-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 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-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 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).

[1]  K. O'Byrne,et al.  PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance , 2020, Frontiers in Cell and Developmental Biology.

[2]  D. Bushnell,et al.  Overview and Current Status of Peptide Receptor Radionuclide Therapy. , 2020, Surgical oncology clinics of North America.

[3]  J. Beauregard,et al.  Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours , 2019, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  P. Bernhardt,et al.  Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases , 2019, The Journal of Nuclear Medicine.

[5]  R. Shah,et al.  Potentiation of 177Lu-octreotate peptide receptor radionuclide therapy of human neuroendocrine tumor cells by PARP inhibitor , 2018, Oncotarget.

[6]  H. Lundqvist,et al.  Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity , 2018, European Journal of Nuclear Medicine and Molecular Imaging.

[7]  M Båth,et al.  Fast GPU-based Monte Carlo code for SPECT/CT reconstructions generates improved 177Lu images , 2018, EJNMMI Physics.

[8]  P. Bernhardt,et al.  Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments. , 2017, Cancer biotherapy & radiopharmaceuticals.

[9]  Val Gebski,et al.  Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[10]  J. Strosberg,et al.  Radionuclide Therapy for Neuroendocrine Tumors , 2017, Current Oncology Reports.

[11]  Ola Nilsson,et al.  NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors , 2016, The Journal of Nuclear Medicine.

[12]  J. Berlin,et al.  Phase 3 Trial of 177Lu‐Dotatate for Midgut Neuroendocrine Tumors , 2017, The New England journal of medicine.

[13]  P. Bernhardt,et al.  A novel planar image-based method for bone marrow dosimetry in 177Lu-DOTATATE treatment correlates with haematological toxicity , 2016, EJNMMI Physics.

[14]  Iain J Hyndman,et al.  An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma , 2016, BMC Cancer.

[15]  C. V. van Eijck,et al.  Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib , 2016, Theranostics.

[16]  G. ClaringboldPhillip,et al.  NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study , 2015 .

[17]  J. Turner,et al.  Pancreatic Neuroendocrine Tumor Control: Durable Objective Response to Combination 177Lu-Octreotate-Capecitabine-Temozolomide Radiopeptide Chemotherapy , 2015, Neuroendocrinology.

[18]  Eva Forssell-Aronsson,et al.  Renal function affects absorbed dose to the kidneys and haematological toxicity during 177Lu-DOTATATE treatment , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[19]  J. Turner,et al.  Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. , 2012, Cancer biotherapy & radiopharmaceuticals.

[20]  J. Turner,et al.  Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[21]  E. Krenning,et al.  Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[22]  Eva Forssell-Aronsson,et al.  Dosimetric comparison of radionuclides for therapy of somatostatin receptor-expressing tumors. , 2001, International journal of radiation oncology, biology, physics.

[23]  R. Herrmann,et al.  Yttrium-90 DOTATOC: first clinical results , 1999, European Journal of Nuclear Medicine.

[24]  M. Williams,et al.  Basic clinical radiobiology , 1994, British Journal of Cancer.