Enrollment begins in phase 2 trial of opaganib plus darolutamide in mCRPC

Patient recruitment has begun in a phase 2 trial (NCT04207255) of opaganib plus darolutamide (Nubeqa) in patients with metastatic castration-resistant prostate cancer (mCRPC), RedHill Biopharma announced in a news release.¹

The study plans to enroll approximately 60 patients with mCRPC.

The study is sponsored by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd. (ANZUP) in Australia, and will be led by Lisa Horvath, MBBS, FRACP, PhD, of Chris O’Brien Lifehouse and ANZUP. Overall, the study is assessing the efficacy of opaganib in overcoming resistance to standard of care treatment with androgen receptor pathway inhibitors.

According to the RedHill, “Prior research shows that opaganib enhances androgen receptor signaling inhibitor efficacy in vitro, through simultaneous inhibition of 3 sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS), and may potentially provide the key to overcoming darolutamide resistance in men with mCRPC.”

In total, the placebo-controlled, randomized trial plans to enroll approximately 60 patients through at least 10 clinical trial sites in Australia and New Zealand.

The target population is patients who have not received prior treatment with a newer, potent androgen receptor signaling inhibitor, including darolutamide, enzalutamide (Xtandi), apalutamide (Erleada), or abiraterone acetate (Zytiga).

The study will utilize the companion lipid biomarker test, PCPro, to identify patients who have a poor prognosis to standard of care treatment and who may therefore benefit from the addition of opaganib to darolutamide. The investigators will initially identify 200 potentially eligible patients to undergo PCPro testing using a 5-mL plasma sample.

Patients who are PCPro-positive (an estimated 40% of patients) and agree to enter the study will then be randomly assigned 1:1 to receive either 600 mg darolutamide plus 500 mg opaganib twice daily (n = 30) or to 600 mg darolutamide plus placebo twice daily (n = 30).

The primary end point for the study is radiographic progression-free survival (rPFS) at 12 months. According to RedHill Biopharma, the trial will also assess several secondary and exploratory end points.

"The approach of developing therapeutic combinations and the companion lipid biomarker, PCPro, in parallel is unique in metabolic targeting in metastatic prostate cancer, and this exciting study will test the ability of sphingosine kinase-2 (SPHK2) inhibitors, such as opaganib, to overcome resistance to ARPI treatment," said Horvath, chief clinical officer and director of research at Chris O'Brien Lifehouse, in a prior news release on the study.²

Additional evaluation of opaganib

The phase 2 trial initially explored opaganib in combination with the androgen agonists enzalutamide and abiraterone.³ In total, the study enrolled 69 patients with mCRPC whose tumors progressed while receiving abiraterone or enzalutamide. Participants were enrolled in the study through clinical trial sites in the US.

For the trial, patients received either 250 mg or 500 mg opaganib in combination with abiraterone or enzalutamide. The primary end point was disease control status (stable disease or better) per PCWG3 criteria following 4 cycles of treatment. Secondary end points included overall survival, rPFS, and prostate-specific antigen progression-free survival.³

REFERENCES
1. RedHill Biopharma announces recruitment initiated into expanded phase 2 opaganib/darolutamide combination study in advanced prostate cancer. News release. RedHill Biopharma Ltd. July 1, 2025. Accessed July 2, 2025. https://www.redhillbio.com/news/news-details/2025/RedHill-Biopharma-Announces-Recruitment-Initiated-into-Expanded-Phase-2-OpaganibDarolutamide-Combination-Study-in-Advanced-Prostate-Cancer/default.aspx

2. RedHill Announces Initiation of Phase 2 Study of Opaganib and Darolutamide in Advanced Prostate Cancer. News release. RedHill Biopharma. February 4, 2025. Accessed July 2, 2025. https://www.redhillbio.com/news/news-details/2025/RedHill-Announces-Initiation-of-Phase-2-Study-of-Opaganib-and-Darolutamide-in-Advanced-Prostate-Cancer/default.aspx

3. Addition of opaganib to androgen antagonists in patients with mCRPC. ClinicalTrials.gov. Last updated September 25, 2024. Accessed July 2, 2025. https://clinicaltrials.gov/study/NCT04207255

4. Kucuk O, Smith C, Plasse T, et al. Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255). J Clin Oncol. 2021;39(suppl 6). doi:10.1200/JCO.2021.39.6_suppl.TPS19