MON-318 Lasofoxifene acts as a selective agonist in the bone microenvironment

Abstract Disclosure: E.K. Zboril: None. D. Boyd: None. N. Dashti-Gibson: None. R. Myrick: None. A. Olex: None. J. Harrell: None. Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means, therefore inhibition of ER signaling has been a mainstay of treatment for decades. While primary ER+ breast cancer has a relatively good initial prognosis, ∼30% of patients will develop treatment-refractory recurrence or metastasis within their lifetime, with bone metastasis being twice as likely for patients with hormone positive disease. Breast to bone metastasis of ER+ breast cancer remains an incurable condition. Treatment includes administration of ER antagonists like Fulvestrant or aromatase inhibitors. ELAINE-III [NCT05696626] is a clinical trial currently investigating the efficacy of lasofoxifene and abemaciclib compared to fulvestrant abemaciclib combination therapy for advanced or metastatic ER+ breast cancer with an ESR1-mutation. Interestingly, this compound shows selective protective effects in the bone microenvironment. The purpose of this study is to characterize the physiological relevance of lasofoxifene selective agonist activity in the context of the bone, and to determine what effect this has on breast cancer metastasis progression. In this study, animal models were treated with endocrine therapies, including lasofoxifene, or subjected to estrogen withdrawal, and femurs were interrogated by histology and histomorphometric analysis by micro-CT. Anti-tumor effects of Lasofoxifene were evaluated in vitro and in vivo in clinically relevant endocrine therapy-sensitive and -resistant primary and metastatic PDX models, and ongoing studies will utilize selected models to determine if lasofoxifene will prolong progression free survival in the bone metastatic setting when compared to standard of care. Additionally, drug synergism studies with lasofoxifene and the NCI NExT Oncology Interrogation Tools Set of 555 drugs were performed to identify pathways which were vulnerable in Elacestrant-treated cells. This data will translate into novel treatment combinations which are targeted to bone metastasis in pre-clinical models. This study has determined that lasofoxifene is protective in the bone microenvironment, unlike other new-generation endocrine therapies, and future directions include evaluating the ramifications of this activity on bone metastasis progression. Presentation: Monday, July 14, 2025