(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a trial in progress presentation by Dr. Neal Shore discussing a phase 1b study of bavdegalutamide, an androgen receptor PROTAC degrader, combined with abiraterone in patients with metastatic prostate cancer. Bavdegalutamide (ARV-110) is a novel, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that targets wild-type androgen receptor and clinically relevant mutants. Of note, bavdegalutamide demonstrated tumor growth inhibition in multiple xenograft models (eg. androgen receptor gene amplification, androgen receptor mutation, enzalutamide resistance, and enzalutamide insensitivity):
In a phase 1/2 study (NCT03888612), bavdegalutamide showed clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received 1–2 prior novel hormonal agents (eg. abiraterone and/or enzalutamide), including heavily pretreated patients. Among 28 evaluable patients with tumors harboring AR T878X/H875Y mutations, 46% had best PSA declines of >= 50%. The RP2D of 420 mg once daily was tolerable with manageable side effects. Abiraterone is approved, in combination with a corticosteroid, to treat patients with mCRPC or with high-risk castration-sensitive prostate cancer (CSPC). Up to a third of patients treated with abiraterone develop primary resistance to this drug and nearly all patients experience disease progression. At the 2022 ASCO meeting, Dr. Shore and colleagues describe a phase 1b study that will evaluate the combination of bavdegalutamide with abiraterone at the initiation of progression on abiraterone (PSA progression without radiographic progression) to test if the addition of bavdegalutamide will overcome resistance to abiraterone and re-establish the androgen receptor pathway blockade in patients with prostate cancer.
Eligible patients are men ≥18 years of age with histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients must be receiving ongoing treatment with stable doses of abiraterone and a concomitant corticosteroid for mCRPC or CSPC and have PSA progression ≥16 weeks after initiation of abiraterone, ≥2 rising PSA values measured ≥1 week apart, and no radiographic evidence of disease progression while receiving abiraterone. Ongoing ADT with a gonadotropin-releasing hormone analogue or inhibitor or orchiectomy is required. Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental androgen receptor-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. The trial schema, by phase of the study, is as follows:
Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities). Patients in this trial will be enrolled in the United States, Canada, France, and the United Kingdom.
Presented by: Neal D. Shore, MD, FACS, Carolina Urologic Research Center, Myrtle Beach, SC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.