A Phase 2 clinical trial, dubbed the COSMYC Trial (COmbined Suppression of MYC), is set to investigate a novel sequential treatment strategy for men with metastatic castration-resistant prostate cancer (mCRPC).
This open-label study, led by Dr Samuel Denmeade at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, aims to determine whether combining ZEN-3694, a BET inhibitor, with high-dose testosterone followed by enzalutamide can shrink tumors and delay disease progression in patients whose cancer has become resistant to standard therapies.

The COSMYC Trial leverages Bipolar Androgen Therapy (BAT), which involves cycling high-dose testosterone to disrupt cancer cell growth, combined with ZEN-3694, which targets MYC-driven pathways implicated in prostate cancer progression. Researchers hypothesize that this combination may sensitize tumors to subsequent treatment with enzalutamide, a potent AR inhibitor, potentially overcoming resistance and improving outcomes.

The trial, expected to begin in June 2025, will enroll approximately 50 asymptomatic men with mCRPC and is projected to conclude by June 2031.

The COSMYC Trial focuses on patients with mCRPC who have progressed after treatment with second-generation androgen receptor (AR)-axis inhibitors, such as abiraterone, enzalutamide, darolutamide, or apalutamide. The study tests two sequential treatment regimens:

BATZEN (Bipolar Androgen Therapy + ZEN-3694): Patients receive ZEN-3694 (48 mg daily) and testosterone cypionate (400 mg injection on day 1 of each 28-day cycle) while continuing androgen deprivation therapy (ADT) to suppress natural testosterone production.

ZENZA (ZEN-3694 + Enzalutamide): Upon disease progression, patients transition to ZEN-3694 (increased to 72 mg daily) and enzalutamide (160 mg daily), alongside ongoing ADT.

The primary goals are to assess whether BATZEN improves clinical or radiographic progression-free survival (PFS) compared to historical controls and whether ZENZA, following BATZEN, enhances PSA-progression-free survival. Secondary objectives include evaluating PSA response rates (≥50% reduction), objective tumor responses, overall survival, quality of life, and treatment-related adverse events.

Clinical trials.