Monte Rosa doses first patient in Phase 2 MRT-2359 prostate cancer study
Monte Rosa Therapeutics has dosed the first patient in MODeFIRe-1 (NCT07745361), a Phase 2 study evaluating MRT-2359 in combination with apalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring androgen receptor (AR) mutations. The milestone, announced on 24 August 2026, marks the programme's transition from early-phase signal-finding into a dedicated expansion study designed to position MRT-2359 for registrational development.
MRT-2359 is an orally bioavailable molecular glue degrader (MGD) that selectively targets GSPT1, a translation termination factor on which MYC-driven cancers, including prostate cancer, are thought to depend. By degrading GSPT1, the compound is intended to reduce levels of multiple oncoproteins simultaneously, including AR itself, MYC, and Cyclin D1-E2F, offering a mechanism distinct from direct AR antagonism.
Trial design and prior signals
MODeFIRe-1 will enrol up to 25 patients using a Simon's two-stage design. Participants must have confirmed AR mutations, prior treatment with a second-generation AR inhibitor, and measurable or PSA-evaluable disease. MRT-2359 will be administered orally at 0.5 mg on a 21-days-on, 7-days-off schedule within 28-day cycles, alongside continuous apalutamide. Primary and secondary endpoints include PSA response rate, RECIST response, duration of response, radiographic progression-free survival, and safety.
The study builds on data from an earlier Phase 1/2 expansion arm in which MRT-2359 was combined with enzalutamide in heavily pre-treated mCRPC patients. Chief Medical Officer Filip Janku described the prior results: "5 of 5 patients with AR mutations demonstrated a PSA response, with a 100% disease control rate and two RECIST responses." Enrolment in that arm, which ultimately treated six AR-mutation patients, has now closed. Monte Rosa said it plans to share updated data on the full six-patient cohort before the end of 2026.
The decision to pair MRT-2359 with apalutamide rather than enzalutamide in MODeFIRe-1 allows the company to enrol patients without prior second-generation AR inhibitor exposure, potentially broadening the eventual addressable population. Janku also noted ambitions to explore combinations with radioligand therapies independent of AR status, signalling an intent to pursue MRT-2359 beyond the narrow AR-mutation niche.
Market and competitive context
CRPC with AR mutations represents a clinically meaningful but underserved segment. AR mutations, particularly at the ligand-binding domain, are a well-characterised resistance mechanism to approved AR pathway inhibitors such as enzalutamide and apalutamide. Few approved agents specifically address this population, and the market need has attracted investment from both large pharma and emerging biotechs developing next-generation AR degraders and protein degrader platforms.
Monte Rosa sits within a competitive landscape of targeted protein degradation that includes companies pursuing PROTACs as well as MGDs. The MGD modality, which repurposes the CRL4-CRBN E3 ligase machinery rather than bifunctional linker chemistry, has attracted particular interest for intractable oncology targets. The company's QuEEN discovery engine, combining structural biology, AI-guided chemistry and proteomics, is central to its selectivity claims. Investors will scrutinise whether the Phase 2 dataset can translate the early 5-of-5 PSA response signal into a robust, reproducible readout across a larger and more heterogeneous patient cohort.
Updated enzalutamide-combination data expected by year-end will serve as an important interim read before the full MODeFIRe-1 dataset matures, giving the market a near-term catalyst ahead of any registrational decision.