[VIRTUAL] Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD (AACR 2021)
Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties...Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 mutant-Y537S mouse tumors and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. Importantly, in these mutant ESR1 models, we demonstrate that the efficacy of SAR439859 was increased when coadministered with palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6. In the clinical setting, SAR439859 also demonstrated a high level of target engagement, ER degradation and inhibition of ER signaling as well as encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER-positive breast cancer. These findings indicate that SAR439859 would provide therapeutic benefit to patients with ER+ breast cancer, including those who are resistant to endocrine therapy with both wild-type and mutant ER.