ARV-110: an AR-targeting protein degrader for mCRPC
Arvinas is developing ARV-110, a PROTAC® protein degrader that targets the androgen receptor (AR), for the potential treatment of men with metastatic castration resistant prostate cancer (mCRPC) and who have progressed on existing therapies. AR activity is a key driver of prostate cancer and the ability to regulate AR signaling is an important factor in controlling disease progression. We believe that by destroying AR—not simply inhibiting it— ARV-110 can potentially change the treatment paradigm for prostate cancer.
This program is currently in a Phase 1 clinical study and is wholly owned by Arvinas.
For men in the United States, prostate cancer is the second most prevalent cancer and the second leading cause of cancer death. Current standard of care treatments for mCRPC, enzalutamide and abiraterone, have been beneficial to some patients, but their efficacy is reduced by resistance mechanisms including increased levels of androgen production, increased AR gene and enhancer expression, and/or AR point mutations. Up to 25% of patients do not respond to these treatments, and the vast majority of responsive patients will ultimately become resistant, resulting in poor prognosis for men diagnosed with this devastating condition.
To overcome these challenges and improve upon current treatment options, ARV-110 works by harnessing the body’s natural mechanism for the degradation of the AR protein that plays a key role in the development of prostate cancer. We believe that by destroying AR—not simply inhibiting it—ARV-110 can have advantages over existing inhibitors, which rely on their ability to “occupy” cellular receptors to reduce functioning. PROTAC protein degraders also work iteratively, degrading many copies of the target protein, and can therefore overcome increases in target expression and mutations in the target protein, which are both common mechanisms of resistance to current standards of care.
In preclinical studies, ARV-110 has shown promising activity as a targeted 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 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, every day, for 3 years. In this model, daily and orally delivered ARV-110 inhibited tumor growth by up to 70% in enzalutamide-resistant VCaP tumors.
In a patient-derived xenograft (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 (tumor growth inhibition: 100%).
Arvinas is currently evaluating ARV-110 in a Phase 1 study for men with castration-resistant metastatic prostate cancer (mCRPC) who have progressed on standards of care.