Rinzimetostat May Limit Prostate Cancer Lineage Plasticity and Restore Therapeutic Targets

New preclinical and translational findings presented at ESMO 2026 suggest that rinzimetostat (ORIC-944), an experimental epigenetic therapy, may help prevent prostate cancer cells from changing their identity to escape androgen receptor (AR)-targeted treatments.

Rinzimetostat inhibits the PRC2 complex through its EED subunit. PRC2 regulates gene expression and contributes to lineage plasticity, a process through which prostate cancer cells can become less dependent on androgen signalling and more resistant to hormonal therapies.

In preclinical models, rinzimetostat reinforced the tumour cells’ original AR-dependent characteristics and increased their sensitivity to AR inhibitors. Interestingly, it also maintained activity against prostate cancer cells carrying an EZH2 mutation associated with resistance to another experimental epigenetic inhibitor, mevrometostat.

The findings were supported by analyses of samples from patients with metastatic castration-resistant prostate cancer (mCRPC) receiving rinzimetostat. Changes in circulating tumour DNA methylation suggested increased AR signalling, while paired tumour biopsies showed increased expression of PSMA and KLK2, two important therapeutic targets in prostate cancer.

These observations raise the possibility that epigenetic treatment could help preserve tumour sensitivity to hormonal therapies and potentially influence the effectiveness of PSMA- or KLK2-targeted treatments. However, increased target expression does not necessarily translate into improved radioligand uptake or therapeutic response.

The findings remain exploratory, combining laboratory experiments with early translational observations. They do not demonstrate clinical reversal of treatment resistance, prevention of neuroendocrine transformation or improved survival.

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