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Estrogen Receptor

ARV-471: an ER-targeting protein degrader for breast cancer

Arvinas is developing ARV-471, an oral estrogen receptor (ER)-targeting PROTAC® protein degrader for the potential treatment of patients with locally advanced or metastatic ER positive / HER2 negative breast cancer.

This program is currently in a Phase 1 clinical study and is wholly owned by Arvinas.

Breast Cancer 80% of newly diagnosed cases of breast cancer are ER+

Approximately 80% of all newly diagnosed cases of breast cancer are ER alpha-positive (ER+). While approved treatments have produced some success in this patient population, many ER+ breast cancers become resistant to therapy. Today, fulvestrant (Faslodex®)—a selective estrogen receptor degrader (SERD)—is the standard of care for ER+ metastatic breast cancer after anti-estrogen therapy. While fulvestrant has validated the importance of ER degradation as a therapeutic intervention, up to 50% of ER can remain when compared to baseline levels after six months of treatment with fulvestrant. Unlike fulvestrant, which is administered via intramuscular injection, Arvinas’ ER-directed PROTAC protein degrader, ARV-471, is an oral therapy under development for the treatment of women with ER+ metastatic breast cancer.

Preclinical studies

In preclinical studies ARV-471 has shown promising activity as an ER degrader, demonstrating superior tumor growth inhibition compared to fulvestrant. ARV-471 has demonstrated potency as both a single agent and as a combination therapy with CDK4/6 inhibitors.

Select in vivo data

In a patient-derived xenograft (PDX) model from an ESR1 mutant patient, an oral dose of ARV-471 inhibited tumor growth by 99% at 10 milligrams per kilogram (mpk) and 106% at 30 mpk (below). This suggests ARV-471’s potential as a superior inhibitor of tumor growth compared to fulvestrant.

Chart ER 1

CDK4/6 inhibitors, such as palbociclib (Ibrance®), are often used in combination with fulvestrant. In the study shown, comparing ARV-471 in combination with palbociclib versus fulvestrant in combination with palbociclib, ARV-471/palbociclib demonstrated superior tumor shrinkage (tumor growth inhibition: 131%) in comparison to fulvestrant/palbociclib (tumor growth inhibition: 108%).

Chart ER 2

Arvinas is currently evaluating ARV-471 in a Phase 1 study for patients with locally advanced or metastatic ER+ positive / HER2- negative breast cancer. In future studies, Arvinas intends to study ARV-471 as both a single agent and in combination with other therapies, such as CDK4/6 inhibitors.