ONCT-534 Earns FDA Fast Track Designation in R/R Metastatic CRPC

Investigators will evaluate the preliminary anti-tumor activity, safety, and pharmacokinetics of ONCT-534 among those with metastatic CRPC that is relapsed or refractory to approved ARPIs as part of the single-arm, open-label, multi-center phase 1/2 Study ONCT-534-101 (NCT05917470).

The FDA has granted fast track designation to the investigational, dual-acting androgen receptor inhibitor (DAARI) ONCT-534 as a treatment for patients with relapsed/refractory metastatic castration-resistant prostate cancer (CRPC), according to a press release from Oncternal Therapeutics, Inc.¹

Developers designed ONCT-534 to interact with the AR’s N-terminal domain and ligand-binding domain, thereby impeding cell growth and enabling AR degradation. According to findings from preclinical studies, the agent has demonstrated activity in prostate cancer models with and without AR mutations.

“The receipt of fast track designation for ONCT-534 supports our belief that patients with [metastatic] CRPC who relapse after treatment with androgen receptor pathway inhibitors [ARPIs] such as enzalutamide [Xtandi] or abiraterone [Zytiga], represent an important unmet medical need,” James Breitmeyer, MD, PhD, president and chief executive officer at Oncternal Therapeutics, said in the press release.¹

“We believe that due to ONCT-534’s novel mechanism of action, it may address important AR escape mechanisms that result in resistance to currently approved ARPIs. We look forward to working with FDA, investigators, and industry collaborators to bring ONCT-534 to patients as quickly as possible.”

Investigators will evaluate the preliminary anti-tumor activity, safety, and pharmacokinetics of ONCT-534 among those with metastatic CRPC that is relapsed or refractory to approved ARPIs as part of the single-arm, open-label, multi-center phase 1/2 Study ONCT-534-101 (NCT05917470). In the dose escalation portion of the study, patients will receive 40 mg to 600 mg of ONCT-534 orally once a day. Investigators will choose 2 of these dose levels for testing in the study’s second phase.

The study’s primary end points include maximum tolerated dose, safety, prostate-specific antigen reduction, objective response rate, complete response rate, duration of response, and progression-free survival. Secondary end points include the maximum plasma concentration of ONCT-534 and the associations between objective responses and changes in AR levels or phenotype.

Patients 18 years and older with histologically documented metastatic adenocarcinoma of the prostate and a history of CRPC are able to enroll on the study. Additional eligibility criteria include having relapsed/refractory disease following treatment with at least 1 next-generation AR-signaling inhibitor (ARSI), and least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and a life expectancy of at least 6 months. Patients must also have adequate renal, hepatic, and pulmonary function to enroll.

Those with small cell prostate cancer or neuroendocrine disease histology are unable to enroll on the trial. Patients are also unsuitable for enrollment if they have central nervous system metastases, major surgery within 30 days of beginning study treatment, current or imminent spinal cord compression, an active seizure disorder, or any serious illness or medical condition that would interfere with study participation.

Developers of ONCT-534 received a Study May Proceed letter from the FDA permitting their dose escalation study of the agent in August 2023.²

“We are very pleased with the FDA’s authorization to proceed with our phase 1/2 clinical trial of ONCT-534,” Breitmeyer said in a press release at the time developers received the letter.² “Many [patients with] prostate cancer that has relapsed or is refractory after treatment with standard of care ARSI therapy, such as enzalutamide or abiraterone, 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.”

References

1. Oncternal Therapeutics announces FDA granted fast track designation for ONCT-534 for the treatment of metastatic castration-resistant prostate cancer. News release. Oncternal Therapeutics. October 26, 2023. Accessed October 27, 2023. https://shorturl.at/kpt24
2. 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. August 3, 2023. Accessed October 27, 2023. https://shorturl.at/dDEH7