Few targeted therapies are approved for recurrent endometrial cancer (EC); and aggressive histologic subtypes such as serous EC (SEC, also known as uterine serous carcinoma) and serous-like EC remain clinically challenging. Serous-like and SECs share molecular characteristics with high grade serous ovarian cancer (OC), raising the possibility that therapeutic approaches in OC might also be effective in these ECs. Our preliminary data show that most SEC patient-derived xenograft (PDX) tumors with a high genomic instability score (GIS) still have a functional homologous recombination (HR) DNA repair pathway as manifested by formation of RAD51 foci after DNA damage. In addition, monotherapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib failed to induce tumor regression in 5 of 5 SEC and serous-like EC PDXs, arguing against clinical development of PARPi monotherapy for SEC. In contrast, treatment with rucaparib in combination with the TOP1 inhibitor SN-38 demonstrated strong synergy in SEC cell lines in vitro; and PDX studies demonstrated significantly greater efficacy of rucaparib + PLX038A (a novel pegylated formulation of SN-38) over monotherapy in 3 of the same 5 EC PDXs in vivo. Although the combination appears promising, several unanswered questions remain: i) Do SECs and serous-like ECs have the same responses to the PARPi/PLX038 combination, which would impact the design of future trials? ii) Because patients may experience increased toxicity from combination therapy despite the excellent tolerability in mice, can the schedule of PLX038A + rucaparib be modified without losing efficacy? iii) Because GIS and DNA damage-induced RAD51 foci have not correlated with response in preliminary studies, is it possible to identify an alternative predictor of response to PLX038A/rucaparib therapy? To address these knowledge gaps, we will test the hypothesis that PLX038A + rucaparib will be more efficacious in SEC and serous-like ECs than either monotherapy and that tumors with the greatest response will demonstrate prolonged TOP1-DNA covalent complexes (TOP1ccs), which can serve as a biomarker of response to PLX038-containing combinations.