Dual AR blockade shows promise for treatment-naïve mHSPC

The combination of masofaniten (EPI-7386) and enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) demonstrated early efficacy with an acceptable safety profile in patients with treatment-naïve metastatic hormone-sensitive prostate cancer (mHSPC), according to findings from the phase 2 EXTRA-PC trial (NCT06312670) published in Oncologist.¹

“The EXTRA-PC trial was designed to explore whether targeting the androgen receptor N-terminal domain with masofaniten, in combination with enzalutamide and ADT, could deepen [androgen receptor] (AR) pathway suppression in treatment-naïve mHSPC,” explained senior author Pedro C. Barata, MD, of University Hospitals Seidman Cancer Center, Cleveland, Ohio, in correspondence with Urology Times^®. “Although the study closed early due to discontinuation of masofaniten development, the results provide important proof-of-concept insights into AR-targeting strategies beyond ligand-binding domain inhibition.”

The single-arm, single-institution study planned to enroll a total of 35 patients with previously untreated de novo or recurrent mHSPC. Patients were eligible for enrollment if they were older than 18 years, had an ECOG performance status of 0 to 2, and had no prior exposure to second-generation antiandrogen therapies for this disease.

The first stage of the study was designed to enroll 13 patients, with a requirement of 9 or more patients achieving a biochemical response (prostate-specific antigen [PSA] less than 0.2 ng/mL) in order for the study to proceed to stage 2, which would include an additional 22 patients.

For the study, participants received the combination of masofaniten 600 mg twice daily and enzalutamide 160 mg daily with ADT. The primary outcome measures included the biochemical response rate at 6 months following treatment plus progression-free survival (PFS), radiographic PFS, and objective response rate.²

In total, the study enrolled 13 patients, of whom 5 were African American and 8 were Caucasian. The median age was 68 years (range, 52 to 75) at the time of enrollment, and the median follow-up time was 9.9 months (range, 7.7 to 13.6).

At 6-month follow-up, 10 of 13 patients (77%; 95% CI, 50 to 92) achieved a PSA level less than 0.2 ng/mL. Although the study closed early, the response threshold to move on to stage 2 of the study was met. The median time to a PSA level less than 0.2 ng/mL was 1.9 months (range, 0.5 to 3.7).

Adverse events were primarily grade 1 to 2. One patient in the study experienced disease progression to metastatic castration-resistant prostate cancer and subsequently died of disease.

Despite early termination of the trial, the authors say these findings support further investigation into dual AR blockade in patients with mHSPC.

“More broadly, EXTRA-PC reflects the ongoing effort to intensify therapy in metastatic hormone-sensitive prostate cancer through biologically rational combinations,” Barata concluded. “While this specific agent will not move forward, the scientific rationale of targeting alternative AR domains remains compelling and continues to inform future drug development in this space.”

REFERENCES

1. Jang A, Fowler P, Helminiak K, et al. EXTRA-PC: a phase II trial of masofaniten (EPI-7386) and enzalutamide for patients with treatment-naïve metastatic hormone-sensitive prostate cancer. Oncologist. 2026;31(2):oyaf434. doi:10.1093/oncolo/oyaf434

2. Combining EPI-7386 with enzalutamide and androgen deprivation therapy for metastatic hormone-sensitive prostate cancer. ClinicalTrials.gov. Last updated May 29, 2025. Accessed February 13, 2026. https://clinicaltrials.gov/study/NCT06312670