Therapeutic Programs

therapeutic programs

Estrogen Receptor

ARV-471: TARGETING THE ESTROGEN RECEPTOR

Developing an Oral PROTACTM Protein Degrader for ER+ Metastatic Breast Cancer

Arvinas is developing a novel ER (estrogen receptor) PROTACTM (proteolysis-targeting chimera) protein degrader for the targeted degradation of ER alpha with the goal of reducing its levels in cancer cells and providing greater clinical benefits to patients. 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 post-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’ lead ER PROTAC protein degrader, ARV-471, is being developed for the treatment of women with ER+ metastatic breast cancer as an oral therapy.

This program is wholly owned by Arvinas.

Preclinical Studies

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

Select In Vitro Data

ARV-471 induced ER degradation in multiple cell lines typically used in breast cancer research.

 


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.

 


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

 


ARV-471 is currently in IND-enabling studies.