The U.S. Food and Drug Administration has cleared the way for the first clinical trial of an NSD2 inhibitor in metastatic castration-resistant prostate cancer, approving the Investigational New Drug application for KTX-2001. The oral, selective therapy will be tested in a Phase 1 study known as STRIKE-001, which will enroll patients whose cancer has progressed despite at least one androgen receptor–targeted treatment. The trial will explore KTX-2001 both as a single agent and in combination with the androgen receptor blocker darolutamide, with enrollment expected to begin in the third quarter of 2025.

NSD2, a histone methyltransferase that chemically modifies DNA packaging proteins to control gene activity, has emerged as a powerful driver of aggressive prostate cancer.
While its expression is minimal in healthy prostate tissue, NSD2 is markedly elevated in advanced and treatment-resistant forms of the disease, including neuroendocrine variants.  Research shows that the enzyme helps build the enhancer landscape that allows the androgen receptor to control tumor-specific genes, amplifies cancer-promoting signaling loops such as AKT/mTORC2, and contributes to an immune-suppressive tumor microenvironment.

In preclinical models, silencing or inhibiting NSD2 disrupts these programs, sharply reducing tumor growth and preventing metastases. KTX-2001 is designed to selectively block NSD2’s methyltransferase activity, removing a critical epigenetic mark and collapsing the chromatin state that sustains tumor progression.

Combining the drug with darolutamide is expected to strike at two interdependent pillars of mCRPC biology: the androgen receptor axis and the epigenetic machinery that enables it to remain active despite hormonal therapy.

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