Researchers Optimistic After Dose-Determining Trial of Compound Against Metastatic Castration-Resistant Prostate Cancer

A new multi-institution, dose-determining clinical trial of a compound against metastatic, castration-resistant prostate cancer showed promising results, researchers reported in Clinical Cancer Research.

The phase 1b/2a 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, the University of California, San Francisco, and Memorial Sloan Kettering Cancer Center, and was sponsored by Zenith Epigenetics.

“Resistance to androgen receptor-targeting agents is inevitable in metastatic, castration-resistant prostate cancer,” says co-senior study author Joshi Alumkal, M.D., who leads the Prostate and Genitourinary Medical Oncology Section at the U-M Rogel Cancer Center. “This study provides evidence that inhibition of BET bromodomain proteins that facilitate gene activation may be able to overcome resistance mechanisms and re-sensitize patients to androgen receptor-targeting agents.”

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

The results were encouraging, Alumkal says, including a median progression-free survival of 9 months in those who had prior progression on enzalutamide or the related drug abiraterone.

“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 adds.

Fourteen patients (19%) reported severe adverse reactions, including three patients (4%) who developed thrombocytopenia, or low blood platelet count.

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 frontline 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,” Alumkal says

Zenith Epigenetics provided financial support for the current study and also supplied the study compound.

Paper cited: “A Phase 1b/2a Study of the Pan-BET Bromodomain Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration Resistant Prostate Cancer,” Cancer Clinical Research. DOI: 10.1158/1078-0432.CCR-20-1707

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