FDA Grants Fast Track Designation to ONCT-534 for Relapsed/Refractory mCRPC

US FDA

The FDA has granted fast track designation to the dual-acting androgen receptor inhibitor ONCT-534 for the treatment of patients with relapsed/refractory, metastatic castration-resistant prostate cancer (mCRPC) that is resistant to approved androgen receptor pathway inhibitors (ARPIs).¹

The single-arm, open-label, multicenter phase 1/2 ONCT-534-101 trial (NCT05917470) is investigating the safety and tolerability, pharmacokinetics, and preliminary antitumor activity of ONCT-534 in patients with mCRPC who are refractory to or have relapsed on FDA-approved ARPIs, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), darolutamide (Nubeqa), and apalutamide (Erleada).

ONCT-534 interacts with the ligand-binding domain (LBD) and N-terminal domain of the AR, inducing AR degradation and inhibiting cell growth. Preclinical studies have demonstrated the activity of ONCT-534 in prostate cancer models. In these models, the agent is active against unmuted AR and several mutations, such as those in the AR ligand-binding domain (LBD), splice variants with AR LBD loss, and AR amplifications.

“The receipt of fast track designation for ONCT-534 supports our belief that patients with mCRPC who relapse after treatment with ARPIs, such as enzalutamide or abiraterone, represent an important unmet medical need,” James Breitmeyer, MD, PhD, president and chief executive officer of Oncternal, stated in a press release. “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.”

Phase 1 of the first-in-human ONCT-534-101 trial is a dose-escalation study that will enroll approximately 27 patients.² At the end of phase 1, investigators will choose 2 dose levels of ONCT-534 to test in the phase 2 dose-expansion portion, in which approximately 16 patients will be randomly assigned to each dose level group. Dose escalation will evaluate daily oral doses of the agent at 40 mg, 80 mg, 160 mg, 300 mg, and 600 mg.

Male patients 18 years of age or older are eligible for this trial if they have histologically documented prostate adenocarcinoma without small cell features or neuroendocrine differentiation, as confirmed by biopsy; a history of mCRPC; relapsed/refractory disease following treatment with at least 1 next-generation ARPI; at least 1 measurable lesion per RECIST v1.1 criteria or evaluable bony disease; an ECOG performance status of 0 to 2; a life expectancy of at least 6 months; evidence of disease progression on or after their most recent systemic treatment; a prostate-specific antigen (PSA) level of at least 10 ng/mL (or ≥2 ng/mL and a ≥50% increase from nadir on prior therapy, whichever is lowest); serum testosterone levels of less than 50 ng/dL; and adequate renal, hepatic, and pulmonary function.

Patients must also agree to begin or continue taking luteinizing hormone-releasing hormone agonist or antagonist therapy if they have not undergone bilateral orchiectomy. At least 2 weeks or 5 half-lives must have elapsed since patients’ last systemic therapy, including taxanes or other chemotherapy. At least 1 month must have elapsed since systemic therapy with radionuclide pharmaceutical agents.

Key exclusion criteria include small cell prostate cancer or neuroendocrine disease histology, including mixed histology; brain or central nervous system metastases; a history of a major surgery within 30 days before starting the study drug; current, untreated, pathologic long-bone fractures or a risk of imminent pathologic fractures; and any other serious illness or medical condition that would interfere with study participation. Patients will also be excluded if they are receiving concurrent anticancer therapy, except for ongoing aromatase inhibitor therapy. Supportive non-cancer–directed therapies are permitted. Additionally, patients taking a strong CYP3A4 inhibitor or a substrate of CYP2C9 or CYP2C19 are not allowed.

The primary end points of ONCT-534-101 are determination of the maximum tolerated dose; safety and tolerability; reduction of PSA by more than 50%; time to reduction of PSA by more than 50%; PSA reduction by more than 90%; time to PSA reduction by more than 90%; overall response rate; complete response rate; duration of response; and progression-free survival. Key secondary end points include an assessment of the maximum plasma concentration of ONCT-534, area under the curve of ONCT-534, and the correlation of ONCT-534 with AR phenotype.

“We look forward to working with FDA, investigators, and industry collaborators to bring ONCT-534 to patients as quickly as possible,” Breitmeyer concluded.¹

References

1. Oncternal Therapeutics announces FDA granted fast track designation for ONCT-534 for the treatment for metastatic castration-resistant prostate cancer. News Release. Oncternal Therapeutics. October 26, 2023. Accessed October 27, 2023. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-announces-fda-granted-fast-track
2. A clinical study of ONCT-534 in subjects with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated October 23, 2023. Accessed October 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05917470