Pan-BET Bromodomain Inhibitor Plus Enzalutamide in Advanced Prostate Cancer

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A new multi-institution, dose-determining clinical trial of a compound for patients with metastatic, castration-resistant prostate cancer showed the combination “demonstrated acceptable tolerability and potential efficacy,” reported Aggarwal et al in Clinical Cancer Research.

The phase Ib/IIa study of the pan-BET bromodomain inhibitor ZEN-3694 in combination with enzalutamide was led by researchers at the University of Michigan Rogel Cancer Center, Ann Arbor; the University of California, San Francisco; and Memorial Sloan Kettering Cancer Center, New York.

“Resistance to androgen receptor–targeting agents is inevitable in [patients with] metastatic, castration-resistant prostate cancer,” said co–senior study author Joshi Alumkal, MD, in a statement. “This study provides evidence that inhibition of BET bromodomain proteins that facilitate gene activation may be able to overcome resistance mechanisms and resensitize patients to androgen receptor–targeting agents.”

Study Findings

The trial recruited 75 patients with abiraterone- and/or enzalutamide-resistant metastatic, castration-resistant prostate cancer.

The results were encouraging, according to Dr. Alumkal, including a median progression-free survival of 9 months in those whose disease had progressed on enzalutamide or the related drug abiraterone in the past.

“We saw particular benefit in patients who were in high-risk subgroups, including those with more aggressive disease with lower androgen receptor activity in their tumors,” he added.

Fourteen patients (19%) reported severe adverse reactions, including three patients (4%) who developed thrombocytopenia.

Dr. Alumkal recently led a separate trial, published in the Proceedings of the National Academy of Sciences, that found that a gene program associated with lower androgen receptor activity contributes to upfront resistance in the one-third of cancers that don’t respond at all to enzalutamide treatment.

“That subset of patients with front-line resistance to enzalutamide or abiraterone and low androgen receptor activity are the ones who appeared to respond best to ZEN-3694—suggesting a promising treatment approach for this group of patients whose cancers behave quite poorly with currently approved treatments,” concluded Dr. Alumkal.

Disclosure: Zenith Epigenetics provided financial support for the current study and also supplied the study compound. For full disclosures of the study authors, visit

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