Oral CYP11A1 inhibitor shows promise in mCRPC

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Article

The phase 1/2a CYPIDES trial assessed the safety and preliminary efficacy of ODM-208 in heavily pretreated patients with metastatic castration-resistant prostate cancer.

Data from the first part of the phase 1/2a CYPIDES trial (NCT03436485) showed that the investigational, oral CYP11A1 inhibitor ODM-208 potently inhibits steroid-hormone biosynthesis with demonstrated evidence of antitumor activity in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC).1,2

“These results support the continued importance of hormone-based treatments and potential of ODM-208 in prostate cancer, even in heavily treated patients with advanced disease," said Outi Vaarala, MD, PhD.

“These results support the continued importance of hormone-based treatments and potential of ODM-208 in prostate cancer, even in heavily treated patients with advanced disease," said Outi Vaarala, MD, PhD.

In phase 1 of the study, 73.7% (14 of 19) of patients with an androgen receptor gene ligand-binding domain mutation (ARmut, AR LBD) experienced a decrease in prostate-specific antigen (PSA) of at least 50%. Further, 8.7% (2 of 23) of patients with AR wild type experienced a PSA decrease of at least 50%. In phase 2a of the trial, 53.3% (24 or 45) of patients with an AR LBD mutation experienced a PSA decrease of at least 50%.

Further, 87% (46 of 53) of patients experienced a decline in median circulating testosterone levels from 3.0 ng/dL (IQR, 1.3-6.2 ng/dL) at baseline to undetectable levels within the first week of treatment with ODM-208.

Overall, the treatment was well tolerated by patients. The most common treatment-related adverse event was adrenal insufficiency, which was experienced by 36.2% of patients in phase 1 and 13.3% of patients in phase 2a. These patients received an adjustment of hormone replacement therapy and/or additional supplementation, after which study treatment was commonly continued. The toxicity led to treatment discontinuation in 1 patient in phase 1 of the trial.

In total, the CYPIDES trial included 92 previously treated patients with mCRPC. Each participant received at least 1 dose of 5 mg ODM-208, given twice daily, in addition to 1 mg dexamethasone/0.1 mg fludrocortisone to provide a balance between decreased steroidogenesis and toxicity. Patients also received ongoing androgen deprivation therapy. Phase 1 of the study included 47 patients, of which 20 had ARmut, and phase 2a included 45 patients, all of which harbored ARmut.

Patients were excluded from the study if they had a history of pituitary or adrenal dysfunction, known brain metastases or active leptomeningeal disease, active infection or any other medical condition that would contraindicate corticosteroid, poorly controlled diabetes, hypotension or uncontrolled hypertension, clinically significant abnormal levels of serum potassium or sodium, active or unstable cardio-cerebro vascular disease including thromboembolic events, or prolonged QTcF interval.3

The primary outcome measures for the study were safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy.

Senior vice president of innovative medicines and research and development at Orion, Outi Vaarala, MD, PhD, concluded in the news release, “These results support the continued importance of hormone-based treatments and potential of ODM-208 in prostate cancer, even in heavily treated patients with advanced disease. Additional data also shows promising improvement in managing the treatment-related adrenal insufficiency. We look forward to having further data from the latter part of the study both in AR LBD positive and negative patients.”2

References

1. Fizazi K, Bernard-Tessier A, Roubaud G, et al. Targeted inhibition of CYP11A1 in castration-resistant prostate cancer. NEJM Evid. 2024;3(1). doi:10.1056/EVIDoa2300171

2. NEJM Evidence publishes results from phase I/IIa CYPIDES trial with ODM-208. News release. Orion. December 27, 2024. Accessed January 5, 2024. https://www.biospace.com/article/releases/nejm-evidence-publishes-results-from-phase-i-iia-cypides-trial-with-odm-208/?keywords=prostate

3. Safety and Pharmacokinetics of ODM-208 in patients with metastatic castration-resistant prostate cancer (CYPIDES). ClinicalTrials.gov. Last updated December 14, 2023. Accessed January 5, 2024. https://clinicaltrials.gov/study/NCT03436485

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