Bavdegalutamide (ARV-110), belongs to the class of PROteolysis TArgeting Chimeras (PROTAC). It effectively degrades the androgen receptor (AR) by forming a trimer complex with AR and the cereblon E3 ubiquitin ligase. This interaction triggers ubiquitination, leading to the degradation of AR by the proteasome. In preclinical studies, ARV-110 has shown efficacy against both wild type androgen receptor tumors as well as tumors with AR mutations. Preclinically, the drug has demonstrated activity in models of wild type androgen receptor tumors in addition to tumors with AR mutations.

Interim analysis data from the Phase I/II clinical trial for bavdegalutamide was presented in a poster session at ESMO on 22^nd October 2023. As of August 11, 2023, 153 patients across the Phase I/II study received bavdegalutamide 420 mg daily, including 45 patients with AR ligand binding domain mutations excluding L702H alone, 26 of whom had AR 878/875 without L702H. 

The study results revealed a radiographic progression-free survival (rPFS) of 11.1 months in a subgroup of patients with metastatic castration-resistant prostate cancer (mCRPC) who had tumors with AR T878X/H878Y mutations (AR 878/875; T878X=T878A or T878S) without the presence of co-occurring AR L702H mutations. AR L702H is a common AR ligand-binding domain (LBD) mutation that is not potently degraded by bavdegalutamide. In patients with tumors harboring any AR LBD mutation except L702H alone, bavdegalutamide showed an rPFS of 8.2 months. 

Notably, 56% of patients with tumors harboring AR 878/875 mutations and lacking co-occurring AR L702H mutations experienced a prostate-specific antigen (PSA) decline of ≥50%, compared to 37.2% in patients with tumors harboring any AR LBD mutation except L702H alone. Among response-evaluable patients with measurable disease at baseline, the overall response rate was 10.0% in patients with AR ligand-binding domain mutations and 9.1% in patients with AR 878/875 mutations. Additionally, 55% and 54.5%, respectively, showed stable disease in response to bavdegalutamide treatment.

The presence of AR L702H mutations greatly diminished the efficacy of bavdegalutamide. However, the drug demonstrated manageable tolerability with no severe (Grade ≥ 4) treatment-related adverse events (TRAEs). The most frequently reported TRAEs were mild to moderate, including Grade 1 and 2 nausea (56%), fatigue (35%), vomiting (33%), decreased appetite (25%), and diarrhea (24%). About 10% of patients discontinued treatment due to these adverse events.

KOL insights

“Looking at both the trials for bavdegalutamide and ARV-766, it’s gratifying to see these innovative therapies developed in advanced prostate cancer where there remains a significant need for better treatments. In my experience, these novel therapies have the potential to be an important treatment choice for patients whose tumors harbor androgen receptor LBD mutations. The improvement in tolerability that ARV-766 has shown in clinical trials compared to bavdegalutamide is also a big advantage for patients with prostate cancer. “─ MD, United States

Conclusion 

Bavdegalutamide, developed by Arvinas, is a once-daily, oral, first-in-class PROTAC AR degrader that degrades wild type and all clinically relevant AR LBD mutations except AR L702H. Extended follow-up of data from the Phase I/II trial with bavdegalutamide presented at the ESMO 2023, showed that bavdegalutamide had encouraging efficacy in patients with mCRPC and AR 878/875 or any AR missense LBD mutation (excluding AR L702H alone) with improved median rPFS of 11.1 months. The daily administration of 420 mg bavdegalutamide remains well-tolerated with manageable side effects. These promising results in patients with AR ligand binding domain mutated mCRPC warrant further research and exploration. 

While bavdegalutamide’s efficacy is very exciting, its breadth of activity could be limited to a small patient population in a late-line setting. Arvinas is also developing another second generation PROTAC AR degrader, ARV-766, that has demonstrated a broader efficacy profile and even better tolerability compared to bavdegalutamide in clinical settings. The prevalence of mutations in the androgen receptor's ligand-binding domain (LBD), especially the L702H mutation, has increased over time, with around 25% of tumors developing these mutations after initial treatment with a novel hormonal agent (NHA) such as enzalutamide or abiraterone. The broader degradation profile of ARV-766 represents a potential addressable patient population for the drug that is approximately three times as many patients compared to bavdegalutamide in the post-novel hormonal agent treatment population.

Recent findings from the Phase I/II clinical trial of ARV-766 demonstrate strong effectiveness in tumors carrying all types of ligand-binding domain (LBD) mutations (with a 41% PSA50 response rate) and in patients with tumors possessing the specific AR L702H mutation (with a 50% PSA50 response rate). Notably, ARV-766 exhibits a superior tolerability profile compared to bavdegalutamide. Progression-free survival (PFS) data are anticipated in 2024.

Based on ARV-766’s superior tolerability profile and encouraging efficacy data to date, Arvinas believes that ARV-766 will be a superior PROTAC AR degrader compared to bavdegalutamide for both mCSPC and mCRPC, and hence, are prioritizing the initiation of a Phase III clinical trial in mCRPC with ARV-766.

For more insight into the Prostate cancer types including metastatic CRPC, metastatic CSPC, non-metastatic CRPC and non-metastatic CSPC, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Metastatic Prostate Cancer - Market Insight, Epidemiology And Market Forecast - 2032 report
• Metastatic Castration-Sensitive Prostate Cancer (mCSPC) - Market Insight, Epidemiology And Market Forecast - 2032
• Non-metastatic Prostate Cancer (nmPC) - Market Insight, Epidemiology and Market Forecast -2032
• Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Market Insight, Epidemiology And Market Forecast - 2032