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.
Authors: Daniel P. Petrylak, Meredith McKean, Joshua Michael Lang, Xin Gao, Robert Dreicer, Daniel M. Geynisman, Tyler F. Stewart, Mitul Gandhi, Leonard Joseph Appleman, Tanya B. Dorff, Gurkamal S. Chatta, Ronald Tutrone, Jose De La Cerda, Elmer Berghorn, Jiachang Gong, Tinghui Yu, Erin Dominy, Edward Chan, Neal D. Shore
Journal: Journal of Clinical Oncology (2024)

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 .