Abstract P2-13-18: Activity and tolerability of combination of trastuzumab deruxtecan with olaparib in preclinical HER2+ and HER2-low breast cancer models
Authors: Proia Theresa , Wallez Yann , Bashi Azadeh Cheraghchi , Wilson Zena , Randle Suzanne , Anderton Mark , Carroll Danielle , Rasheed Zeshaan , Pease J. Elizabeth , Leo Elisabetta , Mettetal Jerome 
Published: March 2022

Abstract
Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor approved for HER2+ metastatic breast and gastric cancer. Clinically, T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low cancers. PARP performs a key role as a mediator in the resolution of topoisomerase1 cleavage complexes (TOP1cc) through recruitment of tyrosyl-DNA phosphodiesterase 1 (TDP1). We hypothesized that combination of T-DXd with the PARP1/2 inhibitor olaparib, will halt the resolution of TOP1cc and enhance the activity of T-DXd. Methods: To test the hypothesis, we evaluated the antiproliferative ability of the combination of T-DXd with olaparib in a panel of 27 breast cancer cell lines in an in vitro 7-day viability assay. The combination was also evaluated in vivo in two non-HRD models, a HER2+ (KPL4) and HER2-low (JIMT1) cell line xenograft at 3mg/kg and 10mg/kg Q3W for T-DXd, as well as 100mg/kg BID of olaparib. To evaluate the specificity of the combination activity in tumor cells (vs normal tissue), we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: We found that the combination had enhanced in vitro cell killing activity over single agents in 8/27 of the models tested. The benefit was present in both Homologous Repair Deficient (HRD) as well as wild-type models, suggesting it does not depend on HRD (as defined by mutations in DNA damage repair genes). In vivo, the combination was more active than monotherapy of either compound in both KPL4 (28d TGI of 76% with T-DXd, olaparib 17% TGI, and T-DXd + olaparib 94.4% TGI; p=0.009) and JIMT1 (28d TGI of 80.8% with T-DXd, olaparib 52%, and T-DXd + Olaparib 88.1%; p=0.03). In the in vitro human bone marrow assay, the combination demonstrated modest enhancement over monotherapy activity (average Loewe Synergy Score of 2.5). To explore the ability to optimize therapeutic index, we tested alternative doses and schedules of the combination in vivo. Specifically, we tested whether lower doses of T-DXd or delayed administration of olaparib would provide greater activity. We found that combination of 3mg/kg of T-DXd with olaparib provided greater activity in KPL4 xenograft model than 3mg/kg T-DXd alone (69% TGI for combination vs. 35% TGI for monotherapy on d28), but this was no greater than high dose 10mg/kg monotherapy T-DXd (76% TGI on d28; p=0.19). Interestingly, 7-day delay of olaparib in combination with 10mg/kg T-DXd provided greater activity (91% TGI on d28) than monotherapy T-DXd or olaparib alone (76% TGI and 17% TGI on d28, respectively). Conclusions: These results suggest that T-DXd combined with olaparib is a potentially active combination in breast cancer, with preclinical activity demonstrated in HRD and non-HRD models.
Citation Format: Theresa Proia, Yann Wallez, Azadeh Cheraghchi Bashi, Zena Wilson, Suzanne Randle, Mark Anderton, Danielle Carroll, Zeshaan Rasheed, J. Elizabeth Pease, Elisabetta Leo, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with olaparib in preclinical HER2+ and HER2-low breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-18.