Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA₃₀) and 50% (PSA₅₀). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140.