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

Area of Science:

• Nuclear Medicine
• Radiopharmaceutical Therapy
• Oncology

Background:

• ¹⁷⁷Lu-DOTATATE is a low-toxicity radiopharmaceutical for neuroendocrine tumours (NETs).
• Combining ¹⁷⁷Lu-DOTATATE with poly-[ADP-ribose]-polymerase (PARP) inhibitors may improve efficacy by hindering tumour DNA repair.
• Optimizing treatment sequencing is crucial to enhance the tumour-to-normal tissue enhanced dose ratio (TNED) and minimize side effects.

Purpose of the Study:

• To determine the optimal timing for administering a PARP inhibitor in combination with ¹⁷⁷Lu-DOTATATE therapy.
• To investigate methods for enhancing the therapeutic ratio of ¹⁷⁷Lu-DOTATATE treatment through combination with PARP inhibitors.

Main Methods:

• Biokinetic modeling based on SPECT/CT and planar imaging data from 17 patients treated with ¹⁷⁷Lu-DOTATATE.
• Calculation of absorbed doses to bone marrow, kidneys, and tumour.
• Simulation of PARP inhibitor administration over various time intervals using relative biological effectiveness (RBE) to assess enhanced biological effect.

Main Results:

• Tumour absorbed dose rate peaked at 12 hours post-infusion, while bone marrow dose rate rapidly decreased.
• Full absorbed dose to bone marrow and kidneys was reached 28 days post-infusion.
• Modeling indicated that introducing a PARP inhibitor approximately 24 hours after ¹⁷⁷Lu-DOTATATE infusion and continuing for four weeks optimizes the TNED, especially with an RBE of 2.

Conclusions:

• Optimal sequencing involves introducing PARP inhibitors around 24 hours post-¹⁷⁷Lu-DOTATATE administration.
• This combination strategy has the potential to increase the therapeutic efficacy of ¹⁷⁷Lu-DOTATATE in NETs.
• A Phase I clinical trial (NCT04375267) evaluating olaparib and ¹⁷⁷Lu-DOTATATE in NETs has been initiated based on these findings.