Biochemical assays demonstrated that rinzimetostat, a selective allosteric EED inhibitor, retained potent inhibition of PRC2 complexes containing EZH1 or EZH2, while EZH2 or dual EZH1/2 inhibitors showed reduced activity in EZH1-containing complexes. In cell-based studies, rinzimetostat preserved antitumor activity in prostate cancer lines overexpressing EZH1 and in cells bearing the EZH2 Y666N or EED-H213R resistance mutations, suggesting superiority in key resistance contexts.

Integrated transcriptome analyses of over 1,000 patient samples spanning primary, metastatic castration-resistant and neuroendocrine prostate cancer revealed increasing PRC2 activity signatures during disease progression. In multiple in vivo models—including castration-sensitive, castration-resistant, AR inhibitor–sensitive and AR inhibitor–resistant tumors with both AR-mutant and AR wild-type backgrounds—rinzimetostat plus the AR inhibitor darolutamide demonstrated broad antitumor efficacy and re-sensitization of resistant tumors.

A global Phase 1b trial (NCT05413421) is underway evaluating rinzimetostat in combination with androgen receptor inhibitors in patients with metastatic prostate cancer. The study will assess safety, tolerability and preliminary efficacy across a spectrum of AR pathway inhibitor–treated and treatment-naive cohorts.