Research and Development | Oncology
Bavdegalutamide (ARV-110) and ARV-766: PROTAC® AR-Targeting Protein Degraders for mCRPC
Arvinas is developing bavdegalutamide and ARV-766, investigational, oral PROTAC® androgen receptor (AR) degraders for the potential treatment of men with metastatic prostate cancer. Preclinically, both investigational agents have demonstrated activity in models of wild type tumors in addition to tumors with AR mutations or amplifications, both potential mechanisms of resistance to currently available AR-targeted therapies.
Bavdegalutamide and ARV-766 are currently in Phase 1/2 clinical studies.
About the Androgen Receptor
What is androgen receptor?
Androgen receptor (AR) is a nuclear hormone receptor. The AR is part of a normal cellular pathway in which androgen (a hormone) binds to the AR, leading to its movement to the cell’s nucleus and interaction with other signaling proteins.
How does AR relate to prostate cancer?
Signaling via the AR has been implicated in prostate cancer. AR can remain a principal driver of castration-resistant prostate cancer during its transition from localized to metastatic disease. Changes to AR in prostate cancer can take multiple forms: AR gene amplification occurs in 40% to 60% of patients, amplification of a transcription regulatory region upstream of the AR gene occurs in 70% to 87% of patients, and AR point mutations occur in approximately 15% of patients.
Why is AR an important target?
In the United States, prostate cancer is the most prevalent cancer in men and the second leading cause of cancer death in men. 1 in 8 men will be diagnosed with prostate cancer during his lifetime, and the average age of diagnosis is 66. There remains meaningful unmet medical need in the treatment paradigm of mCRPC, including a significant underserved set of patients who are or become resistant to current therapies. AR degradation has been a long-term therapeutic focus for Arvinas due to the well-documented biology of AR signaling as a principal driver of this cancer.
Prostate Cancer and the Need for Novel AR Therapies
Around the world, prostate cancer is the most prevalent cancer in men.
Novel hormonal agents have become standard of care in castration-sensitive prostate cancer, and there is a need for novel AR therapies with the potential to provide benefit for patients with mCRPC and tumors that have developed resistance.
Bavdegalutamide harnesses 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—bavdegalutamide may 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 therefore may 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, bavdegalutamide has shown promising activity as a targeted degrader of AR. In enzalutamide-sensitive models, bavdegalutamide demonstrates similar prostate-specific antigen (PSA) reduction to enzalutamide but at lower doses. In in vivo models of both acquired and intrinsic resistance to enzalutamide, bavdegalutamide has been shown to inhibit tumor growth by 70% and 100%, respectively.
Our scientists have led many of the significant breakthroughs in the field.
Patient resources for men with prostate cancer.
- American Cancer Society. Cancer Facts for Men. https://www.cancer.org/healthy/cancer-facts/cancer-facts-for-men.html. August 27, 2021. Accessed July 19, 2022.
- Neklesa et al. An oral androgen receptor PROTAC degrader for prostate cancer. Poster presented at: ASCO Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA.