idetrexed + olaparib (The Institute of Cancer Research)

The combination of idetrexed and olaparib is an experimental therapy being evaluated in the Phase I/Ib IDOL Study for the treatment of high-grade serous ovarian cancer (HGSOC). Idetrexed is a small-molecule thymidylate synthase (TS) inhibitor that selectively targets cells overexpressing the alpha-folate receptor (FRα), which is prevalent in over 90% of ovarian cancers. By blocking TS, idetrexed inhibits DNA synthesis and induces DNA damage. Olaparib is a potent PARP inhibitor that prevents the repair of single-strand DNA breaks, leading to the accumulation of double-strand breaks and subsequent cell death, particularly in cells with existing DNA repair deficiencies. The combination is designed to act synergistically: idetrexed increases DNA damage while olaparib prevents its repair, specifically targeting FRα-overexpressing tumor cells to enhance efficacy while potentially reducing systemic toxicity. At Dose Level 3 of the IDOL trial, patients receive 12 mg/m² of idetrexed intravenously on days 1 and 15, combined with 200 mg of olaparib orally twice daily on days 1-7 and 15-21.

Other names

IDOL Study combination