Phase 1 Trial: EZH2 Degrader AXT-1003 With Enzalutamide in Metastatic Prostate Cancer

A new phase 1a/1b clinical trial is investigating AXT-1003, an experimental oral EZH2 degrader, in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). The approach aims to interfere with epigenetic mechanisms that may contribute to resistance to androgen receptor (AR)-targeted therapies.

EZH2 is a key component of the Polycomb Repressive Complex 2 (PRC2), which regulates gene expression through histone modifications. In prostate cancer, abnormal EZH2 activity has been associated with treatment resistance and lineage plasticity, a process through which tumor cells can become less dependent on androgen signaling. Unlike conventional EZH2 inhibitors, AXT-1003 both inhibits EZH2 enzymatic activity and promotes degradation of the EZH2 protein through the ubiquitin–proteasome pathway. This dual action could potentially disrupt functions that remain active when EZH2’s enzymatic activity alone is inhibited.

Preclinical findings presented at AACR 2026 demonstrated dose-dependent EZH2 degradation, reduced H3K27me3 levels, and antitumor activity across several experimental models. Importantly, AXT-1003 combined with enzalutamide demonstrated synergistic antitumor activity in mice bearing LNCaP prostate cancer xenografts, providing a rationale for investigating the combination in patients.

AXT-1003 has also undergone preliminary clinical evaluation as monotherapy in patients with various advanced malignancies. Early phase 1 findings presented at ESMO 2026 reported pharmacodynamic evidence of target engagement, including mean H3K27me3 inhibition exceeding 80% across evaluated dose levels on day 8. However, these observations come from a heterogeneous patient population and do not establish clinical efficacy in prostate cancer or demonstrate reversal of resistance to hormonal therapy.

The new trial is an open-label, nonrandomized phase 1a/1b study planning to enroll approximately 105 patients with mCRPC. Participants will receive oral AXT-1003 alongside enzalutamide, initially through dose escalation followed by expansion at selected dose levels. The study will assess safety, dose-limiting toxicities, pharmacokinetics, and preliminary antitumor activity, including PSA-related and radiographic outcomes.

Clinical trial.