(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on prostate cancer trials in progress, and a presentation by Dr. Evan Y. Yu discussing the trial design of a phase 1/2 study of ONCT-534, a dual-action androgen receptor inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC). Current therapeutic strategies for mCRPC include treatment with next-generation androgen receptor pathway inhibitors, which target the ligand-binding domain of the androgen receptor. Approximately 5% to 10% of patients will have primary resistance to androgen receptor pathway inhibitors and most initial responders will develop resistance within 1 to 3 years. Eventually, nearly all men with prostate cancer treated with androgen receptor pathway inhibitors develop resistance via several mechanisms including androgen receptor genomic alterations, epigenetic alterations, and expression of truncated constitutively active androgen receptor splice variants. Thus, there is substantial unmet need for treatment of men with mCRPC resistant to at least one next-generation androgen receptor pathway inhibitors. ONCT-534 is a dual-action androgen receptor inhibitor with a novel mechanism of action that combines inhibition of androgen receptor function with degradation of the androgen receptor protein:
Importantly, this activity includes interaction with both ligand-binding domain and the N-terminal domain of the androgen receptor, rendering it effective against splice variants and ligand-binding domain mutants, unlike existing androgen receptor pathway inhibitors. ONCT-534 has demonstrated preclinical activity in prostate cancer models against unmutated androgen receptor and multiple forms of androgen receptor alteration, including amplification, mutations in the ligand-binding domain, and splice variants with loss of ligand-binding domain.
ONCT-534-101 is a phase 1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of ONCT-534 in subjects with histologically confirmed mCRPC without neuroendocrine differentiation or small cell features who have relapsed or are refractory to at least one next-generation androgen receptor pathway inhibitors. The study is separated into phase 1 dose escalation and a phase 2 dose expansion portions. The complete trial design is as follows:
The phase 1 portion will evaluate approximately 27 subjects in 5 dose levels using an adaptive Bayesian Optimal Interval design to assess safety, tolerability, and dose limiting toxicities at escalating doses and to determine the maximum tolerated dose and inform the two dose levels or schedules to be tested in Phase 2. Dose limiting toxicities will be assessed during the first 28 days of treatment. Androgen receptor phenotype and androgen receptor levels will be evaluated for each subject pre- and post-treatment.
The phase 2 portion will evaluate approximately 32 subjects in two randomized cohorts to assess the safety and tolerability of ONCT-534, compare the two different dose levels or schedules to select the optimal dose for further study and assess the preliminary antitumor activity of ONCT-534. In both phases, after a screening period, eligible subjects with mCRPC will receive their assigned dose regimen of ONCT-534, which will be administered orally daily for 2 years or until disease progression and no longer clinically benefiting from treatment or development of unacceptable toxicity. In a planned exploratory biomarker analysis, the AR phenotype and AR levels of each subject’s disease will be evaluated post-treatment based on (i) circulating tumor cells, (ii) ctDNA, and (iii) tumor biopsies:
ONCT-534-101 is currently active and enrolling patients in the phase 1 dose escalation portion of the study. At the time of submission, 9 patients have been enrolled across four dose levels, and no dose limiting toxicities have been reported.
Clinical trial information: NCT05917470.
Presented by: Evan Y. Yu, MD, Fred Hutchinson Cancer Research Center, Seattle, WA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, May 31st – June 4th, 2024