Rinzimetostat Inhibits PRC2 in Over 1,100 Samples, Enhances CSPC/CRPC Response
ORIC Pharmaceuticals showed that rinzimetostat inhibited PRC2 activity in over 1,100 prostate cancer samples, with elevated PRC2 in >50% of localized tumors linked to poor survival. In vivo, rinzimetostat boosted darolutamide efficacy in CSPC and CRPC models and maintained activity against EZH1-driven resistance, outperforming other PRC2 inhibitors on solubility.
1. Preclinical Transcriptomics Findings
ORIC’s transcriptomics analysis of over 1,100 prostate tissue samples spanning normal, primary, and metastatic disease stages revealed PRC2 activation early in tumorigenesis and persistent elevated activity in metastatic CSPC and CRPC. More than 50% of localized primary tumors showed heightened PRC2 activity versus normal tissue, correlating with poorer survival outcomes.
2. In Vivo Combination Studies
In a range of in vivo prostate cancer models, rinzimetostat combined with darolutamide produced robust antitumor responses in both CSPC and CRPC settings, indicating synergy with androgen receptor pathway inhibition and sustained efficacy across disease stages.
3. Resistance and Drug Properties
Preclinical studies demonstrated that rinzimetostat retains antitumor potency in EZH1-overexpressing cells where competitor PRC2 inhibitors lose effectiveness, while also exhibiting enhanced solubility, oral bioavailability, favorable CYP profile, and extended clinical half-life.