Potential of Arvinas’ PROTAC AR Degraders Reinforced by 11.1 months rPFS with Bavdegalutamide and Updated Positive Interim Data from Second Generation ARV-766 in mCRPC - Seite 2

Bavdegalutamide 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. ARV-766 was designed to improve upon the degradation profile of bavdegalutamide by also degrading AR L702H. The prevalence of all AR LBD mutations, especially AR L702H, has increased over time, and these mutations are present in approximately 25% of tumors after initial treatment with a novel hormonal agent (NHA) such as enzalutamide or abiraterone. This represents a potential addressable patient population for ARV-766 that is approximately three times that of bavdegalutamide in the post-NHA population due to its broader degradation profile.

New data from the ongoing Phase 1/2 clinical trial of ARV-766 continues to show robust efficacy in tumors with all LBD mutations (41% PSA₅₀) and in patients with tumors harboring AR L702H mutations (50% PSA₅₀). In addition to a tolerability profile that is superior to bavdegalutamide, early durability data for ARV-766 are encouraging and provide additional support for prioritizing ARV-766 over bavdegalutamide, with PFS data anticipated in 2024.

"I’ve been involved in trials with both 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,” said Daniel Petrylak, M.D., Professor of Medicine and Urology at Yale School of Medicine and investigator in the Phase 1/2 studies with bavdegalutamide and ARV-766. “In my experience, these novel therapies have the potential to be an important treatment choice for patients whose tumors harbor androgen receptor LBD mutations, which may be present in up to 25% of metastatic castration resistant prostate cancer. The increasing prevalence of the L702H mutation means that more patients could potentially benefit from the broader efficacy profile offered with ARV-766. 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.”

Highlights from the Phase 1/2 trial with bavdegalutamide (data cut-off date Aug. 11, 2023):
In a post-NHA (median prior therapies = 4) mCRPC population, bavdegalutamide at the recommend Phase 2 dose (420 mg, oral, once daily) demonstrated:

• Median rPFS of 11.1 months in patients harboring AR 878/875 mutations and without co-occurring AR L702H mutations (n=26), and median rPFS of 8.2 months in patients with tumors harboring any AR LBD mutation except L702H alone (n=45)
• PSA50 rates of 54% in patients with tumors harboring AR 878/875 mutations and without co-occurring AR L702H, and 36% in patients with tumors harboring any AR LBD mutation except L702H alone
• The presence of AR L702H mutations greatly diminished the efficacy of bavdegalutamide
  • In patients with any tumor harboring an AR L702H mutation, the PSA50 was 8%
• Bavdegalutamide had a manageable tolerability profile with no grade ≥ 4 treatment-related adverse events (TRAEs). The most common TRAEs were grade 1 and 2 and included nausea (56%), fatigue (35%), vomiting (33%), decreased appetite (25%) and diarrhea (24%). The discontinuation rate due to TRAEs was 10%.