Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Abstract

Purpose: Estrogen receptor-positive (ER þ ) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER þ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER þ breast cancer models, including several patientderived xenograft models.

Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor–Positive Breast Cancer Models with a Distinct Mechanism of Action

“…S3D). This observation is consistent with previous clinical experience with anastrozole-fulvestrant combination and preclinical data of fulvestrant-RAD1901 combination, both of which showed such intense ER blockade failed to yield additional benefit (35,36). Together, these results indicated that RAD140 as a single agent is effective in inhibiting the growth of AR/ER þ breast cancer xenografts.…”

“…In the HBCx-22 model, fulvestrant, a selective ER downregulator (SERD) and standard of care for ER þ breast cancer dosed at 1 mg weekly, exhibited a statistically significant antitumor activity, as judged by a TGI of 59%, comparable with a previous report of this model and indicative of its dependency on ER (31). It has been previously determined that the 1 mg weekly administration of fulvestrant achieves exposure equivalent to the 500 mg monthly dose in human (35). The changes in tumor volume of the RAD140-or fulvestrant-treated HBCx-22 xenografts appeared to be lower compared with those treated with vehicle (Fig.…”

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

“…IGF, Insulin Growth Factor; FGFR, Fibroblast Growth Factor Receptor) [23], and other immunotherapy inhibitors [58]. Additionally, more potent and bioavailable selective estrogen receptor degraders (SERD) are being tested to overcome resistance induced by ESR1 mutations [10]. Advances in genomic and other technologies that allow deeper understanding of individual tumors and further investigation into the cross-talk between these signaling pathways have provided a plethora of data that require continued mining, both in the preclinical and clinical settings, to personalize therapeutic regimens for each patient.…”

ESR1 mutations in breast cancer

“…Preclinical studies have shown the effectiveness of the newer SERDs AZD9496, GDC-0810, and elacestrant (RAD1901) in reducing tumor growth of ESR1 WT and mutant tumors. [51][52][53][54] AZD9496 exhibited higher activity against ESR1 mutant cells than fulvestrant, as demonstrated through transcriptional and growth assays and in xenograft growth models. However, the short half-life of AZD9496 and reduced efficacy of GDC0810 are significant limitations for clinical development of these agents.…”