Therapeutic Programs

therapeutic programs

Androgen Receptor

ARV-110: TARGETING THE ANDROGEN RECEPTOR

Developing an Oral PROTACTM Protein Degrader to Improve Treatment of mCRPC

Arvinas is developing an androgen receptor (AR) degrader that employs our proprietary PROTACTM (Proteolysis-Targeting Chimera) protein degradation technology to potently and specifically degrade AR and AR mutations, which play a role in the development of prostate cancer. The ability to regulate androgen receptor signaling is an important factor in controlling disease progression and could potentially change the treatment paradigm for prostate cancer.

Enzalutamide (Xtandi®) and abiraterone (Zytiga®), the standard of care treatments for metastatic castration-resistant prostate cancer (mCRPC), are reduced in efficacy by resistance mechanisms including increased levels of androgen production, increased AR gene and enhancer expression, and/or specific AR point mutations.

To overcome these challenges and improve upon current treatment options, our lead AR PROTAC protein degrader, ARV-110, works by harnessing the ubiquitin-proteasome system (UPS) to efficiently degrade AR. It is in development for the treatment of men with mCRPC who have progressed on abiraterone and/or enzalutamide and is designed to result in the destruction—not simply inhibition—of the AR protein from cancer cells. In contrast to traditional target inhibition, which is a competitive- and occupancy-driven process, degradation is iterative and therefore less susceptible to increases in target expression and mutations in the target protein, enabling ARV-110 to overcome known mechanisms of resistance to current standards of care.

This program is wholly owned by Arvinas.

Preclinical Studies

In preclinical studies, ARV-110 has shown promising activity as a degrader of AR. In enzalutamide-sensitive models, ARV-110 demonstrates similar prostate-specific antigen (PSA) reduction to enzalutamide but at lower doses. In in vivo models of acquired and intrinsic resistance to enzalutamide, ARV-110 has been shown to inhibit tumor growth by 70% and 100%, respectively.

Select In Vitro Data


1Tubulin is a protein ARV-110 is not targeted to degrade and is included as a loading control to ensure total protein is equivalent in each lane.

ARV-110 degraded 95% to 98% of AR in multiple cell lines typically used in prostate cancer research. We tested ARV-110 in vertebral cancer of the prostate (VCaP) and demonstrated that ARV-110 decreased the presence of AR (diminished shading, below) over time with near-maximal degradation of AR within four hours of administration.


Select In Vivo Data

In a VCaP xenograft mouse model, plasma PSA reduction by ARV-110 was comparable to enzalutamide but at lower dose (below). PSA is often used an indicator of the effectiveness of treatment in clinical trials and acts as a guide for physicians when making treatment decisions.

 


We developed an in vivo model of acquired enzalutamide resistance by dosing VCaP xenograft mice with enzalutamide, daily for 3 years. In this model, daily and orally delivered ARV-110 inhibited tumor growth by up to 70% in enzalutamide-resistant VCaP tumors (below).


In a PDX model derived from a patient not treated with, but insensitive to enzalutamide, orally delivered ARV-110 significantly inhibited the growth of enzalutamide-insensitive tumors (TGI: 100%; below).


ARV-110 is currently in IND-enabling studies.