Androgen receptor (AR) signaling remains a primary driver of prostate cancer progression, even with the use of AR-targeting drugs like abiraterone and enzalutamide. Resistance often develops through AR alterations such as mutation, amplification, and splicing. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to address this resistance by inducing the degradation of AR.
Preclinical Efficacy
Bavdegalutamide works by recruiting the cereblon-containing E3 ubiquitin ligase to ubiquitinate AR, leading to its proteasomal degradation. Preclinical studies demonstrate that bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. In cell-based assays, bavdegalutamide showed higher activity than the AR antagonist enzalutamide in suppressing prostate-specific antigen (PSA) synthesis, inhibiting prostate cancer cell proliferation, and inducing apoptosis.
Superior Tumor Growth Inhibition
In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide significantly degraded AR and inhibited tumor growth more effectively than enzalutamide. Notably, bavdegalutamide also demonstrated robust tumor growth inhibition in animal models of enzalutamide- and abiraterone-resistant prostate cancer. Furthermore, combining bavdegalutamide with abiraterone enhanced its activity.
Clinical Development
These promising preclinical results led to the clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials and is currently being evaluated in a phase 1/2 study (NCT03888612) in patients with metastatic castration-resistant prostate cancer (mCRPC).
