Introduction Serous endometrial cancer (EC) is the deadliest subtype because of high recurrence rates and few proven targeted therapies in this setting. Leveraging a tendency to have homologous recombination deficiency (HRD) and the development of novel topoisomerase inhibitor-based antibody drug conjugates, this study aimed to test synergy between poly (ADP-ribose) polymerase inhibitor, rucaparib, and SN38, an active metabolite of DNA topoisomerase I inhibitor, irinotecan.

Methods A genomic instability score (GIS) was derived from low-pass whole genome sequencing-based bioinformatics analysis and calculated for 34 patient derived xenograft (PDX) tumors, of which eight had serous histology. EC PDX tumors were treated with rucaparib and SN38 in ex vivo 3D cell culture experiments using RealTime Glo to assess viability after 4–5 days. Synergy was assessed by calculating the combination index (CI) using Chou-Talalay method. Clinical information was extracted for correlation.

Results 62.5% (5/8) of serous EC PDX tumors had GIS≥42 while only 19.2% (5/26) of non-serous ones did. Synergy (CI<1.0) between rucaparib and SN38 was demonstrated in 85.7% (6/7) of serous EC PDX ex vivo 3D cell culture experiments, but only 62.5% (10/16) of non-serous ones. 66.7% (6/9) of serous EC primary patient 3D cell culture experiments also showed synergy.

Conclusion/Implications Most serous EC PDX tumors had high GIS, consistent with HRD, compared to a minority of non-serous histologies. Combination therapy demonstrated synergy in almost all serous and most non-serous EC PDX models. Additional studies including more tumors and in vivo correlation are needed to assess the predictive value of GIS on synergy between rucaparib and SN38.