(UroToday.com) The 2025 ASCO annual meeting featured a prostate cancer trials in progress session and a presentation by Dr. Rahul Aggarwal discussing a randomized, open-label, phase 2b study of the bromodomain inhibitor ZEN-3694 + enzalutamide versus enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). Androgen receptor signaling inhibitors, such as enzalutamide and abiraterone, are standard therapies for metastatic hormone-sensitive prostate cancer (mHSPC) and mCRPC. Patients who respond to the initial androgen receptor signaling inhibitor are frequently prescribed a second androgen receptor signaling inhibitor upon progression. A suboptimal response to first line androgen receptor signaling inhibitor, including the ~ 20% treated with an androgen receptor signaling inhibitor for mHSPC who progress within 12 months of treatment initiation, may enrich for cancers harboring AR-independent mechanisms of resistance, including treatment-emergent neuroendocrine prostate cancer.
Bromodomain inhibitors have been shown pre-clinically to block the neuroendocrine prostate cancer lineage plasticity program through modulating E2F1, a transcription factor involved in stemness and cell differentiation. Prior results from a mCRPC phase 1b/2a trial of ZEN-3694 + enzalutamide support this notion, as lower AR transcriptional activity in baseline tumor biopsies was associated with longer radiographic progression-free survival. Additionally, mCRPC patients who were primarily refractory to first line abiraterone had prolonged radiographic progression-free survival with ZEN-3694 + enzalutamide, suggesting that the patients with primary resistance may benefit from the combination. The mechanism of action for ZEN+3694 + enzalutamide is highlighted in the following figure:
To test this hypothesis, a phase 2b randomized trial was initiated, enriching for mCRPC with suboptimal response to first line androgen receptor signaling inhibitor.
This is a multi-national (USA and China), open-label, randomized, two cohort, phase 2b study of ZEN-3694 + enzalutamide versus enzalutamide in mCRPC patients who have progressed on abiraterone (NCT04986423). Cohort A (n = 150) includes patients with poor response to abiraterone defined either as progression in < 12 months or failure to achieve PSA nadir of 0.2 ng/mL while taking abiraterone in the HSPC setting, or progression in < 6 months and/or failure to achieve a PSA50 response while taking abiraterone in the CRPC setting. Cohort B (n = 50) includes patients who responded to abiraterone, defined as > 12 months duration without progression while on abiraterone in the HSPC setting and achieving a nadir PSA < 0.2 ng/mL, or > 6 months duration without progression while on abiraterone in the CRPC setting and confirmed PSA50 response:
The primary endpoint is radiographic progression-free survival by blinded independent central review (BICR) in Cohort A evaluated by PCWG3. Key secondary endpoints include:
- Radiographic progression-free survival by BICR for Cohorts A + B
- Progression free survival by investigator assessment
- Overall survival
- PSA50 response rate
- Objective response rate by RECIST 1.1
- Efficacy endpoints for only USA patients
- Patient-reported health status and quality of life, evaluated in Cohorts A, and Cohorts A + B together
There is also an aggressive translational plan for this trial, as highlighted in the following schema:
The trial has dosed approximately 150 of 200 patients to date, with the following recruiting states/provinces:
Presented by: Rahul R. Aggarwal, MD, UCSF, San Francisco, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.