Study launched exploring novel BET inhibitor plus pembrolizumab and enzalutamide in mCRPC


The first patient has been treated in a phase 2 trial examining a triplet regimen combining the investigational BET inhibitor ZEN-3694 plus pembrolizumab (Keytruda) and enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have become resistant to first-line treatment with an androgen receptor signaling inhibitor (ARSI).1

The patient was dosed at the University of California, San Francisco (UCSF), where the study is being led by principal investigator Rahul Aggarwal, MD, a medical oncologist and associate professor of Hematology/Oncology at UCSF. Aggarwal is also associate director for Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center.

“ZEN-3694 has been shown to mitigate resistance to immune-checkpoint and ARSI therapies in pre-clinical models. Significantly, this combination will simultaneously target multiple pathways to suppress tumor growth. Also, epigenetic and immune-checkpoint based therapies have a potential to significantly increase the duration of response,” Donald McCaffrey, president and CEO of Zenith, the manufacturer of ZEN-3694, stated in a press release.

ZEN-3694 works by inhibiting expression of the MYC gene, which blocks cellular growth in prostate cancer tumors.

The open-label, nonrandomized phase 2 trial (NCT04471974)2 is accruing patients with prostate adenocarcinoma that is histologically confirmed at diagnosis, with ensuing development of mCRPC. At the time of enrollment, there must be evidence of progressive disease as shown by PSA and/or radiographic progression (PCWG3 criteria).

Regarding previous treatments, all patients must have received and progressed on 1 or more ARSI, such as abiraterone acetate (Zytiga), enzalutamide, apalutamide (Erleada), or darolutamide (Nubeqa). Chemotherapy in the mCRPC setting is not allowed; however, patients are still eligible if they received chemotherapy in the castration-sensitive setting and their final chemotherapy dose was received at least 6 months prior to initiation of study treatment. Previous sipuleucel-T (Provenge) treatment is allowed.

Patients are not eligible to enroll if they had de novo small cell prostate cancer at their initial diagnosis; received radiotherapy ≤2 weeks from starting study treatment; received prior therapy with an immune checkpoint inhibitor, including pembrolizumab; or received a radiopharmaceutical, such as radium-223 (Xofigo) or 177Lu-PSMA-617 ≤6 months from beginning study treatment.

The target enrollment for the trial is 54 patients. The primary end point of the trial is composite response rate. Secondary end points include objective response rate, duration of response, progression-free survival, overall survival, PSA50 response proportion, and safety. The estimated primary completion date for the trial is December 31, 2025.

“Our therapy has proven to be safe and effective in treating multiple solid tumors and is combinable with multiple targeted agents. This is the first immune-oncology combination with ZEN-3694 and we will be announcing other immune-checkpoint based combination therapy clinical trials in other tumor types in the near future,” stated McCaffrey.


1. Zenith epigenetics announces dosing of first mCRPC patient with a combination of ZEN-3694 + Merck’s immune check point inhibitor Keytruda. Published online March 15, 2021. Accessed March 17, 2021.

2. NIH US National Library of Medicine Clinical ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer. Last updated December 22, 2020. Accessed March 17, 2021.

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