5011 Background: Patients with mCRPC inevitably develop resistance to available therapies, eg, novel hormonal agents (NHAs), and experience disease progression. Certain mutations that can develop in the ligand-binding domain (LBD; amino acids 671–920) of the AR gene during mCRPC treatment have been associated with poor outcomes. ARV-766 is a novel, potent, orally administered PROTAC AR degrader that targets wild-type AR and clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. We report initial results from a phase 1/2 study (NCT05067140) of ARV-766 in men with mCRPC and disease progression on prior NHA therapy. Methods: Eligible patients had progressive mCRPC and ongoing androgen deprivation therapy. The phase 1 dose escalation portion evaluated the safety and tolerability of escalating doses of ARV-766 (20–500 mg once daily [QD]) in patients who had progressed on ≥2 prior systemic therapies (including ≥1 NHA). The phase 2 cohort expansion portion is evaluating the clinical activity and safety of 2 doses of ARV-766 (100 or 300 mg QD) in patients who had received 1–3 prior NHAs and ≤2 prior chemotherapy regimens. Here we report safety in all patients treated with ARV-766 across the phase 1/2 study and clinical activity (proportion of patients with best prostate-specific antigen [PSA] declines of ≥50% [PSA 50 ] after ≥1 month of PSA follow-up) in the subgroup of patients with AR LBD mutations. Results: As of December 15, 2023, 103 patients received ARV-766 (34 in phase 1 and 69 in phase 2). Patients had received a median of 4 prior therapies (range: 1–9), including 56% with ≥1 prior taxane and 46% with ≥2 prior NHAs. Patients with AR LBD mutations (n=30) had received a median of 4 prior therapies (range: 1–9), including 60% with ≥1 prior taxane and 57% with ≥2 prior NHAs. In phase 1, there were no dose-limiting toxicities, and a maximum tolerated dose was not reached. Across 103 phase 1/2 patients, treatment-emergent adverse events led to dose reduction and treatment discontinuation, respectively, in 7 (7%) and 10 (10%). Any grade treatment-related adverse events (TRAEs) reported in ≥10% of patients were fatigue (36%; 3% grade 3), nausea (19%; 1% grade 3), diarrhea (15%; 1% grade 3), alopecia (14%), increased blood creatinine (13%; 0 grade 3), and decreased appetite (11%; 0 grade 3); there were no grade 4 TRAEs. In 28 PSA-evaluable patients with AR LBD mutations, PSA 50 was 50.0%. Preliminary pharmacokinetics indicated dose-dependent increases in ARV-766 exposure up to 320 mg QD, with exposure accumulation ranging from ≈5- to 8-fold at steady state. Conclusions: In this phase 1/2 study of pretreated patients with mCRPC, ARV-766 was well tolerated and showed promising clinical activity in those with tumors harboring AR LBD mutations. ARV-766 warrants further development in advanced prostate cancer. Clinical trial information: NCT05067140 .

ARV-766, a proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC): Initial results of a phase 1/2 study.