FDA Allows Continuation of Phase 1/2 Trial of ONCT-534 in mCRPC


The FDA has approved a study may proceed letter in advance of its 30-day review period to Oncternal Therapeutics for its phase 1/2 study evaluating ONCT-534, a novel dual-action AR inhibitor in patients with mCRPC who have relapsed or are refractory to approved AR signaling inhibitors.

James Breitmeyer, MD, PhD

James Breitmeyer, MD, PhD

The FDA has approved a study may proceed letter in advance of its 30-day review period to Oncternal Therapeutics for its phase 1/2 dose-escalation study (NCT05917470) evaluating ONCT-534, a novel dual-action androgen receptor inhibitor (DAARI) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have relapsed or are refractory to approved androgen receptor signaling inhibitors (ARSIs).1

The announcement follows the submission of an investigational new drug application for the agent.

“We are very pleased with the FDA’s authorization to proceed with our phase 1/2 clinical trial of ONCT-534,” James Breitmeyer, MD, PhD, president and chief executive officer of Oncternal, said in a news release. “Many men suffering from prostate cancer that has relapsed or is refractory after treatment with standard-of-care ARSI therapy, such as enzalutamide [Xtandi] or abiraterone [acetate (Zytiga)], need additional treatment alternatives. We believe that ONCT-534’s novel mechanism of action may help address key tumor escape mechanisms that cause such resistance.”

Patients with mCRPC who develop resistance to androgen receptor (AR) inhibitors, including those with AR amplification, mutations in the AR ligand binding domain (LBD), or splice variants with loss of the AR LBD, represent a population with high unmet clinical need.

ONCT-534 is a DAARI with preclinical activity2,3 in prostate cancer models against unmutated and aberrant forms of AR and represents a potential treatment for patients with relapsed/refractory mCRPC.

“Preclinical studies suggest that ONCT-534 binds to both the LBD and N-terminal domain of the AR, inhibiting AR function and triggering AR protein degradation, even in the presence of LBD alterations including mutations and splice variants such as AR-V7. Clinical sites that will conduct the initial dose finding study for ONCT-534 have been selected and we expect to report preliminary data in the first half of 2024,” Breitmeyer said.

The first-in-human, phase 1/2 trial will evaluate escalating daily doses of ONCT-534 (40 mg, 80 mg, 160 mg, 300 mg, and 600 mg) to establish the safety and maximum tolerated dose of the agent.4 Efficacy of the 2 selected dose levels from dose escalation will be evaluated in dose expansion by way of prostate-specific antigen (PSA) response (≥50% and ≥90%), time to reduction of PSA, objective response rate, complete response rate, duration of response, and progression-free survival.

To be eligible for enrollment, patients must be at least 18 years of age and have histologically documented metastatic adenocarcinoma of the prostate confirmed by biopsy without neuroendocrine differentiation or small cell features; a history of mCRPC; relapsed or refractory disease following treatment with at least 1 next-generation ARSI; at least 1 measurable lesion per RECIST v1.1 criteria; an ECOG performance status of 0 or 1; and life expectancy of at least 6 months. Regarding prior therapy, at least 2 weeks or 5 half-lives must have passed since last systemic therapy, and at least 1 month must have passed since treatment with radionuclide pharmaceutical agents.

Additional eligibility criteria state that patients should be willing to take or continue luteinizing hormone-releasing hormone agonist or antagonist therapy or have undergone bilateral orchiectomy; have a PSA level of at least 10 ng/mL or at least 2 ng/mL and at least 50% increase from nadir on prior therapy; serum testosterone below 50 ng/dL; and adequate renal, hepatic, and pulmonary function. 


  1. Oncternal Therapeutics receives FDA study may proceed letter for ONCT-534, its novel dual-action androgen receptor inhibitor, for the treatment of patients with advanced prostate cancer. News release. Oncternal Therapeutics, Inc. August 3, 2023. Accessed August 10, 2023. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-receives-fda-study-may-proceed-letter
  2. Narayanan R. Androgen receptor (AR) N-terminus domain-binding small molecule degraders for the treatment of AR splice variant-positive castration-resistant prostate cancer. Mol Cancer Ther. 2021;20(suppl 12):LBA016. doi:10.1158/1535-7163.TARG-21-LBA016
  3. ONCT-534. Oncternal Therapeutics. Accessed August 10, 2023. https://www.oncternal.com/pipeline/onct-534/
  4. A clinical study of ONCT-534 in subjects with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated July 11, 2023. Accessed August 10, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05917470
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