Abstract PS12-23: Development of H3B-6545, a first-in-class oral selective ER covalent antagonist (SERCA), for the treatment of ERaWT and ERaMUT breast cancer
Authors: Korpal Manav , Furman Craig , Puyang Xiaoling , Zhang Zhaojie , Wu Zhenhua , Banka Deepti , Das Subhasree , Destenaves Benoit , Gao Lei , Hamilton Erika , Hao Ming-Hong , Irwin Sean , Johnston Stephen , Joshi Jaya J , Juric Dejan , Kim Amy , Nguyen Tuong-Vi , Pipas Marc , Pluard Timothy , Rimkunas Victoria , Rioux Nathalie , Schindler Joanne , Smith Peter , Thomas Michael , Wang John , Wang Judy S , Warmuth Markus , Yao Huilan , Yao Shihua , Yu Lihua , Vaillancourt Frédéric H , Bolduc David M , Larsen Nicholas A , Zheng GuoZhu , Prajapati Sudeep , Sahmoud Tarek , Gualberto Antonio , Zhu Ping 
Published: February 2021

Abstract
Mutations in the ligand-binding domain of estrogen receptor alpha (ERα) are detected in up to 30% of patients (pts) who have relapsed or progressed during endocrine therapy. By favoring the agonistic conformation in ERα, these hotspot mutations promote ligand-independent activation of ERα and confer partial resistance to ER-directed therapies. Of the various hotspot mutations, Y537S is the most constitutively active, promotes the greatest resistance phenotype to current endocrine therapies, and is associated with the worst prognosis relative to other ERα mutations. The fact that current ER-directed therapies have limited activity in the ERα mutant setting emphasizes the critical need to develop the next generation of high affinity ER antagonists that can overcome the aberrant activity of mutant ERα.
H3B-6545 is a first-in-class selective ERα covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα by irreversibly engaging cysteine-530. Biophysical and biochemical analyses confirm the long residence time achieved by covalent binding, and cellular analyses confirm the selectivity and single-digit nanomolar potency of H3B-6545 across a panel of ERαWT and ERαMUT breast cancer cell lines. H3B-6545 as a monotherapy demonstrates superior anti-tumor activity relative to fulvestrant across a set of CDK4/6 inhibitor naïve ERαWT and ERαY537S cell line-derived xenograft (CDX)/patient-derived xenograft (PDX) models, with regressions being noted in both the ERαWT and ERαMUT settings. Furthermore, H3B-6545 continues to demonstrate single agent activity in CDK4/6 inhibitor-resistant ERαWT and ERαY537S PDX models, in which fulvestrant fails to demonstrate significant anti-tumor activity. Lastly, improved activity and duration of response are noted when H3B-6545 is combined with several targeted therapies, including CDK4/6 inhibitors palbociclib and abemaciclib across a range of ERαWT and ERαY537S CDX/PDX models.
The phase I-II trial (NCT03250676) enrolled 130 heavily pretreated pts with ER+, HER2- metastatic breast cancer, including 12 pts harboring high allele frequency clonal ESR1 Y537S circulating tumor DNA (ctDNA). Median number of prior therapy in the metastatic setting was 3 (range: 1-10). Consistent with the preclinical data, H3B-6545 demonstrated promising clinical activity among these pts with clonal Y537S mutations, with a median progression free survival of 7.3 months and an overall response rate of 25% (3 confirmed partial responses).
In summary, these compelling preclinical data coupled with emerging clinical activity in heavily pretreated poor prognosis pts support further development of H3B-6545 as monotherapy or combination treatment.
Citation Format: Manav Korpal, Craig Furman, Xiaoling Puyang, Zhaojie Zhang, Zhenhua Wu, Deepti Banka, Subhasree Das, Benoit Destenaves, Lei Gao, Erika Hamilton, Ming-Hong Hao, Sean Irwin, Stephen Johnston, Jaya J Joshi, Dejan Juric, Amy Kim, Tuong-Vi Nguyen, Marc Pipas, Timothy Pluard, Victoria Rimkunas, Nathalie Rioux, Joanne Schindler, Peter Smith, Michael Thomas, John Wang, Judy S Wang, Markus Warmuth, Huilan Yao, Shihua Yao, Lihua Yu, Frédéric H Vaillancourt, David M Bolduc, Nicholas A Larsen, GuoZhu Zheng, Sudeep Prajapati, Tarek Sahmoud, Antonio Gualberto, Ping Zhu. Development of H3B-6545, a first-in-class oral selective ER covalent antagonist (SERCA), for the treatment of ERaWT and ERaMUT breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-23.