Abstract P6-20-08: Anti-tumor activity of elacestrant (RAD1901) in models harboring ESR1 mutations resistant to standard of care therapies

Abstract

Abstract Background: Estrogen receptor positive (ER+) breast cancers make up approximately 75% of all breast cancers diagnosed and ER, a protein encoded by the ESR1 gene, plays a major role in the initiation, growth and survival of these cancers. Current targeted therapies inhibit the ER pathway by either blocking the synthesis of the natural ligand of ER, estradiol, (aromatase inhibitors (AI)), or by antagonizing and/or degrading the receptor (selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs)). AIs are used in both the adjuvant and metastatic setting and recent clinical reports have shown that 20-50% of patients that had received AI therapy had detectable mutations in the ER ligand binding domain (ER-LBD). Two frequently found point mutations in the ER-LBD, Y537S and D538G, have been shown to result in estradiol-independence and constitutive activation of ER, consistent with their ability to cause resistance to AIs. While the selection of ESR1 mutations post-AI has been demonstrated clinically, the clinical response of ESR1 mutant tumors to fulvestrant, an approved SERD, is not fully understood. Preclinical studies have suggested that ESR1 mutations can cause decreased binding and a corresponding decrease in potency of ER antagonists, including fulvestrant (SERD) and tamoxifen (SERM). Conversely, clinical data from the SoFEA, PALOMA-3, and FERGI trials suggested the presence of ESR1 mutations did not alter fulvestrant activity. The limited clinical data that exists, however, is based on retrospective study designs with relatively small data sets, making it difficult to accurately predict fulvestrant activity against specific mutations and the activity of fulvestrant against tumors that harbor multiple mutations. In fact, recent additional data from the PALOMA-3 trial suggests that the Y537S mutation, specifically, was selected out in clinical samples from patients treated with fulvestrant, more closely matching preclinical results. This suggests there may be certain contexts of ESR1 mutations where fulvestrant may have limited activity. It will be important to further understand the consequence of specific mutations and to utilize therapies that have activity against all ESR1 mutations. We have previously described elacestrant (RAD1901), a novel orally bioavailable SERD, that exhibited activity in multiple ER+ breast cancer models. Interestingly, elacestrant exhibited similar effects to fulvestrant in in vitro ESR1 mutant models, however, in some in vivo PDX models harboring the Y537S mutation elacestrant inhibited growth, while fulvestrant had limited activity. Here, we describe a more complete in vivo dataset describing elacestrant activity versus fulvestrant in multiple patient-derived xenograft (PDX) models harboring ESR1 mutations. Methods: Multiple PDX models harboring natural mutations in ESR1 or genetically-engineered CRISPR models were used to assess the anti-tumor efficacy and the pharmacokinetic/pharmacodynamic properties of elacestrant and fulvestrant. Results: Elacestrant significantly inhibited the growth of xenograft models harboring ESR1 mutations, including those harboring Y537S or D538G mutations and models that were insensitive to fulvestrant and tamoxifen. Citation Format: Patel H, Tao N, Arlt H, Bihani T. Anti-tumor activity of elacestrant (RAD1901) in models harboring ESR1 mutations resistant to standard of care therapies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-08.