Phase 1/2 Trial: Epigenetic KAT6 Inhibitor Plus Darolutamide in mCRPC

A Phase 1b/2 trial is planned to test an investigational KAT6 inhibitor combined with darolutamide in metastatic castration-resistant prostate cancer (mCRPC). About 36 patients will be enrolled, with the study expected to start in the second half of 2026. The focus is on safety, tolerability, and early signs of anti-tumor activity.

The KAT6 inhibitor blocks KAT6A/B, epigenetic enzymes that acetylate histones and keep oncogenic transcription programs turned on. By reducing this acetylation, the drug downregulates key drivers like MYC and impairs cell-cycle progression. In androgen receptor, positive prostate cancer models, it shows nanomolar potency and shrinks tumors in an enzalutamide-resistant line. It also enhances the effect of docetaxel in the same resistant model, showing that epigenetic inhibition can synergize with standard therapy.

Darolutamide directly blocks androgen receptor signaling, the main driver of prostate cancer even in the castration-resistant setting. Resistance to AR-targeted therapy often involves epigenetic reprogramming and AR variants that keep the tumor growing. KAT6 inhibition disrupts chromatin accessibility at AR target genes and dampens AR signaling output, which complements darolutamide’s direct receptor blockade. This creates a two-pronged approach: stop the receptor and disable the epigenetic machinery that supports it.

The combination is mechanistically sound and has preclinical support in AR-positive, treatment-resistant prostate cancer. The trial will test whether this rationale translates into a safe, active regimen in patients.

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