ONCT-534 Reduces PSA Levels, Is Tolerable in Relapsed/Refractory mCRPC

James Breitmeyer, MD, PhD

ONCT-534, an investigational, dual-action androgen receptor (AR) inhibitor, reduced prostate-specific antigen (PSA) levels in patients with relapsed/refractory metastatic castration-resistant prostate cancer (mCRPC), according to updated findings from the phase 1/2 ONCT-534-101 trial (NCT05917470).¹

Initial pharmacokinetic results from the trial led to the incorporation of 2 additional cohorts with twice-daily dosing of ONCT-534. In total, 15 patients received the agent once daily across 6 dosing cohorts, and 6 patients received the agent twice daily across 2 dosing cohorts. At a data cutoff of September 30, 2024, the twice-daily dosing schedule was deemed well tolerated, and no treatment-related grade 3 or higher adverse effects were reported.

One patient had a rising PSA level during treatment with ONCT-534 at 160 mg twice daily and experienced a subsequent 50% reduction in PSA levels after receiving the agent at 300 mg twice daily for 4 weeks. At the same time, a CAT scan in this patient demonstrated a 16% reduction in target lesions compared with baseline.

Biomarker and enumeration analyses of circulating tumor cells demonstrated that ONCT-534 had efficacy on expression of AR-regulated genes and AR nuclear translocation. The circulating tumor cell analysis also showed that among nonresponders, some had prostate cancer that developed neuroendocrine features, which are associated with AR-independent disease.

Notably, on September 12, 2024, Oncternal Therapeutics, the developer of ONCT-534, announced its decision to terminate the ONCT-534-101 trial after interim phase 1 findings failed to demonstrate clinically meaningful improvements in outcomes, including PSA levels, in 20 patients treated across 8 dose levels with varying doses and administration schedules.² The news release announcing the termination noted that ONT-534 was perceived to be generally well tolerated, and that dose-limiting toxicities occurred in 2 of the 3 patients treated at the highest dose level tested, which was 1200 mg orally once daily.

“While we still believe the decision to discontinue the ONCT-534-101 clinical trial remains the correct one in the current biotechnology environment, the updated clinical results highlight the potential of ONCT-534 in prostate cancer. We believe there is value in exploring [twice-daily] dosing further, as well as studying ONCT-534 in earlier lines of therapy for advanced prostate cancer,” James Breitmeyer, MD, PhD, president and chief executive officer of Oncternal Therapeutics, stated in a news release.¹ “We continue to explore strategic alternatives for our product candidates, including ONCT-534, ONCT-808, zilovertamab [formerly cirmtuzumab; formerly UC-961], and ONCT-216 in an ongoing effort to maximize value to our shareholders.”

ONCT-534-101 enrolled patients at least 18 years of age with mCRPC without small cell features or neuroendocrine differentiation.³ Eligible patients included those with relapsed/refractory disease following treatment with 1 or more next-generation AR-signaling inhibitors; at least 1 measurable lesion per RECIST 1.1 criteria; an ECOG performance status of 0 to 2; and a life expectancy of at least 6 months.

Patients received oral ONCT-534 monotherapy at once-daily dose levels of 40 mg, 80 mg, 160 mg, 300 mg, 600 mg, or 1200 mg; or twice-daily doses of 160 mg or 300 mg. The study’s primary outcomes included maximum tolerated dose, safety and tolerability, PSA reduction, time to PSA reduction, objective response rate, complete response rate, duration of response, and progression-free survival. Secondary outcomes included pharmacokinetic results.

Notably, in October 2023, ONCT-534 received fast track designation from the FDA for the treatment of patients with relapsed/refractory mCRPC that is resistant to approved AR pathway inhibitors.⁴

References

1. Oncternal Therapeutics announces updated safety and efficacy data for phase 1/2 study of ONCT-534 for the treatment of R/R metastatic castration-resistant prostate cancer. News Release. Oncternal Therapeutics. October 22, 2024. Accessed October 22, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-announces-updated-safety-and-efficacy
2. Oncternal Therapeutics announces termination of its clinical studies and exploration of strategic alternatives. News Release. Oncternal Therapeutics. September 12, 2024. Accessed October 22, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-announces-termination-its-clinical
3. A clinical study of ONCT-534 in subjects with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated September 23, 2024. Accessed October 22, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05917470
5. 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 22, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-announces-fda-granted-fast-track