Therapeutic Programs

therapeutic programs

Androgen Receptor

Targeting Androgen Receptor to Improve Treatment of Prostate Cancer

Arvinas is developing an androgen receptor (AR) degrader, which employs our proprietary protein degradation technology PROTACTM (Proteolysis-Targeting Chimera) 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®) & abirateron (Zytiga®), the standard of care treatments for metastatic castration-resistant prostate cancer (mCRPC), have shown limited efficacy due to increased levels of androgen production, increased AR expression and/or specific AR mutations.

AR PROTAC stops growth of enzalutamide resistant prostate tumors: 1.) VCaP tumors grown in castrated mice were treated with 30 mpk enzalutamide for 60 days; 2.) Then the animals were either continued on enzalutamide or switched to AR PROTAC; 3.) AR PROTAC degraded AR in treated tumors

AR PROTAC stops growth of enzalutamide resistant prostate tumors: 1.) VCaP tumors grown in castrated mice were treated with 30 mpk enzalutamide for 60 days; 2.) Then the animals were either continued on enzalutamide or switched to AR PROTAC; 3.) AR PROTAC degraded AR in treated tumors.

 

To overcome these challenges and improve upon current treatment options, our novel AR PROTAC degrader works by hijacking the E3 ubiquitin ligase to efficiently target AR. It is designed to result in elimination—not simply inhibition—of the AR protein from cancer cells. In contrast to traditional target inhibition, which is a competitive process, degradation is progressive and therefore less susceptible to increases in endogenous ligand, target expression, or mutations in the target.

In the preclinical setting, AR PROTACs have shown promise in addressing the many mechanisms of AR resistance in patients with prostate cancer. Results demonstrate that AR PROTACs are rapid and potent degraders of AR, and that degradation is specific and extensive. The results also demonstrate superior tumor growth inhibition versus enzalutamide, including in the setting of the clinically relevant F876L enzalutamide resistance mutation. AR PROTACs also degraded all clinically relevant AR mutations and are especially effective when AR is overexpressed. This targeted degradation may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed.

AR PROTAC potently degrades AR mutations that arise in 15% of patients who become resistant to current therapies (enzalutamide and abiraterone)* Source: *Clin Cancer Res May 15, 2015 21:2315; Sci Trans Med 7:1-8, 2015

AR PROTAC potently degrades AR mutations that arise in 15% of patients who become resistant to current therapies (enzalutamide and abiraterone)*.
Source: *Clin Cancer Res May 15, 2015 21:2315; Sci Trans Med 7:1-8, 2015