Early Results From a Phase 1 Trial for MRT-2359 Plus Enzalutamide in mCRPC

MRT-2359 is a daily pill that destroys certain cancer-driving proteins, including the androgen receptor (AR), MYC, and Cyclin D1, by blocking a key step in how cells read genetic instructions. This approach targets metastatic castration-resistant prostate cancer (mCRPC), where AR mutations in the ligand-binding domain (LBD) allow tumors to grow despite hormone-blocking drugs like enzalutamide.

As of September 2025, 18 heavily treated mCRPC patients with tumors that could be measured on scans received MRT-2359 (low dose, 21 days on then 7 days off) plus full-dose enzalutamide. These patients had already failed hormone therapies, chemotherapy like docetaxel, and often lutetium-177 PSMA therapy.

Side effects were mostly mild: tiredness (in 1/3 of patients), diarrhea (about 1/4), and nausea (about 1/4). Only one serious mouth inflammation case stopped dosing.

Results stood out in three patients with confirmed AR LBD mutations: all had their PSA drop by at least half (two by 90%), two saw tumors shrink significantly (one by 62% for 10 treatment cycles, one by 61% ongoing), and the third had stable disease with 20% shrinkage for 8+ cycles. Of the other 15 without these mutations, five had stable disease for 2 to 8+ cycles, but no major PSA drops.

For men with advanced prostate cancer resistant to standard treatments, MRT-2359 offers hope by directly breaking down mutated AR proteins instead of just blocking them. The strong responses after lutetium and enzalutamide failure highlight its promise for hard-to-treat cases, where gene tests could identify who benefits most.

Clinical trial.