Tumors characterized by homologous recombination deficiency, including BRCA1/2-mutated cancers, are sensitive to inhibition of poly (ADP-ribose) polymerases (PARPs), enzymes that regulate DNA repair. 1, 2 In tumor cells with mutated homologous recombination repair (HRR) genes, PARP inhibition synergizes with homologous recombination deficiency leading to synthetic lethality because of accumulated DNA damage. 2, 3

Rational combinations designed to increase DNA damage and reliance on HRR are promising strategies for increasing sensitivity to PARP inhibitors, although overlapping toxicities, such as myelosuppression, suggest a need for more selective and rational targeted agents. 2, 4-6 In human tumor cell lines, topoisomerase 1 (Topo1) inhibitors, including irinotecan and topotecan, have demonstrated synergy with PARP inhibitors. 4, 5 Since PARP1 is required for the clearance of Topo1-DNA cleavable complexes, PARP inhibition may augment Topo1-mediated DNA damage or delay repair. 7, 8 PARP inhibition has been shown to potentiate the cytotoxicity of SN-38, the active metabolite in irinotecan and topotecan, in mismatch repair-deficient and repair-proficient cell lines. 9 Furthermore, combination of a PARP inhibitor with topotecan or irinotecan in early clinical studies delayed repair of Topo1-mediated DNA damage, but also demonstrated challenges with overlapping hematologic and/or gastrointestinal toxicities. 10, 11