UPDATE: MRT-2359 in Metastatic Castration-Resistant Prostate Cancer

MRT‑2359 is an investigational, orally bioavailable molecular‑glue degrader targeting GSPT1, a protein involved in translation termination.

We talked about this new molecule in this article just one month ago, we already have some good news.

In prostate cancer it is being studied in combination with androgen‑receptor (AR)‑axis inhibitors, particularly in metastatic castration‑resistant prostate cancer (mCRPC), where early‑phase data show encouraging activity in heavily pretreated patients, especially those with AR‑mutant disease. MRT‑2359 induces degradation of GSPT1 by hijacking the cereblon‑E3 ubiquitin ligase complex, disrupting protein synthesis in tumor cells that are addicted to MYC‑driven translational demand.

The drug is currently being evaluated in a Phase 1/2 trial in mCRPC in combination with enzalutamide, a second‑generation AR inhibitor. Interim and updated data from late 2025 and early 2026 highlight a particularly strong signal in AR‑mutant patients.
In a small AR‑mutant subgroup of heavily pretreated mCRPC patients, updated reads show a 100% PSA response rate (5 of 5 patients), with two PSA90 responses and three PSA50 responses. All five patients also achieved disease control by RECIST, including two partial responses and three patients with stable disease and measurable lesion shrinkage. Across 14 evaluable non‑neuroendocrine mCRPC patients, disease control was around 64%, with declines in both PSA and tumor burden observed in several patients. The population was heavily pretreated, with most having prior exposure to second‑generation AR inhibitors, taxane chemotherapy, and/or radioligand therapy.

Translational analyses indicate that MRT‑2359 plus enzalutamide leads to robust GSPT1 degradation and downregulation of AR, MYC, and associated cell‑cycle drivers in both preclinical and patient‑derived models. RNA‑sequencing and circulating‑tumor‑DNA profiling suggest that the strongest responses cluster in tumors with AR mutations or AR‑driven transcriptional signatures, providing a plausible biomarker framework for future development. The combination appears capable of overcoming some mechanisms of resistance to AR‑axis inhibitors, including AR‑ligand‑binding‑domain mutations and altered AR‑signaling pathways that are common in late‑line mCRPC.

Building on these early results, the development program is being expanded to test MRT‑2359 in combination with another next‑generation AR inhibitor, apalutamide. A planned signal‑confirming Phase 2 trial will evaluate MRT‑2359 plus apalutamide in up to 25 mCRPC patients with AR mutations, with the study expected to initiate in the third quarter of 2026. The trial is designed to efficiently assess the efficacy and safety of the combination, with primary endpoints including PSA response, RECIST response, duration of response, progression‑free survival, radiographic progression‑free survival, and overall safety.

Source.