Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader

Abstract Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer. However, continual evolution during prostate cancer progression can result in AR alterations (e.g., mutation, amplification, and splicing) that can cause tumors to become resistant to these therapies. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC) protein degrader that recruits the cereblon-containing E3 ubiquitin ligase to direct the polyubiquitination and subsequent proteasomal degradation of AR. Bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. The advantages of the degradation mechanism of action are demonstrated by the higher activity of bavdegalutamide relative to the AR antagonist enzalutamide in cell-based systems that assess effects on PSA synthesis, proliferation of prostate cancer cells, and induction of apoptosis. In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide showed substantial AR degradation and greater tumor growth inhibition compared with enzalutamide. Bavdegalutamide also showed robust tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer animal models and enhanced activity in combination with abiraterone. These promising preclinical data supported 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, specifically in patients with metastatic castration-resistant prostate cancer in a phase I/II study (NCT03888612).