First Patient Dosed in Molecular Glue Degrader Trial for mCRPC

The first patient has been dosed in MODeFIRe-1 (NCT07745361), a phase 2 study evaluating MRT-2359 in combination with apalutamide (Erleada) in patients with androgen receptor (AR) mutation-positive metastatic castration-resistant prostate cancer (mCRPC), according to a news release.¹

MRT-2359 is an investigational, orally bioavailable molecular glue degrader (MGD) directed against GSPT1. The study follows previously reported clinical data from a phase 1/2 study (NCT05546268) of MRT-2359 in combination with enzalutamide (Xtandi) in heavily pretreated patients with advanced mCRPC.²

“Dosing the first patient in MODeFIRe-1 is an important step in advancing MRT-2359 as a potential therapy for patients with mCRPC with AR mutations, a population with limited therapeutic options,” Filip Janku, MD, PhD, chief medical officer of Monte Rosa Therapeutics, stated in a news release. “This study builds on the encouraging results we observed in our phase 1/2 study of MRT-2359 in combination with enzalutamide.”¹

Trial Design

MODeFIRe-1 is an open-label, multicenter trial that will evaluate MRT-2359 at a dose of 0.5 mg orally on a 21-days-on, 7-days-off schedule over 28-day cycles, in combination with apalutamide. The study is designed to enroll up to 25 patients using a Simon 2-stage design. Eligible patients must have AR mutations, prostate-specific antigen (PSA) with or without RECIST-measurable disease, and have received at least 1 prior second-generation AR inhibitor. The primary end point is PSA response, with secondary end points including RECIST response, duration of response, radiographic progression-free survival (rPFS), PSA progression-free survival, and safety.¹

Rationale From Phase 1/2 Combination Data

According to the release, enrollment in the expansion arm of the earlier phase 1/2 study evaluating MRT-2359 plus enzalutamide in patients with advanced mCRPC has been completed, with a total of 6 patients with AR mutations enrolled and treated. Among these patients, the company reported that 5 of 5 with AR mutations achieved a PSA response, along with a 100% disease control rate and 2 RECIST responses, in a population that included patients who had progression on prior second-generation AR inhibitors, chemotherapy, and radioligand therapy.

Interim data from this cohort were presented at the ASCO Genitourinary Cancers Symposium in February 2026.² As of September 22, 2025, 18 heavily pretreated patients including 3 with AR ligand binding domain mutations received MRT-2359 plus enzalutamide, establishing the 0.5 mg dose. The regimen showed strong PSA response and antitumor activity in the 3 patients with AR mutations, including over 60% tumor reduction in 2 with AR H875Y mutations and durable stable disease in 1 with AR L702H mutation; these patients had received prior taxane chemotherapy and radioligand therapy as well as AR inhibitor therapy. Stable disease was the best response in 5 of the 15 other patients.

The continued enrollment of 29 more patients in this trial had a focus on those with AR-mutated disease; the sponsor stated that it plans to provide an updated analysis of this patient subset by the end of the year.^1,2

Mechanism of Action and Safety

MRT-2359 is designed to selectively degrade GSPT1, a translation termination factor, thereby disrupting enhanced oncoprotein translation that MYC-driven cancers, including prostate cancer, rely on for growth. In preclinical models of mCRPC, MRT-2359 reduced cellular abundance of several prostate cancer–relevant oncoproteins, including AR, MYC, and cyclin D1-E2F, according to the sponsor.¹

In the phase 1/2 trial, 1 dose-limiting toxicity consisting of grade 3 stomatitis associated with pain was observed during dose escalation; other adverse events were largely grade 1 or 2 and included fatigue, diarrhea, and nausea.²

Janku said in the news release that the MODeFIRe-1 design is intended to build efficiently on the earlier combination data and can position MRT-2359 for advancement into registrational development and could potentially be used in patients previously untreated with AR inhibitors or in combination with radioligand therapies regardless of AR status.¹

REFERENCES

1. Monte Rosa Therapeutics Announces First Patient Dosed in MODeFIRe-1, a Phase 2 Study of MRT-2359 in Combination with Apalutamide in Patients with AR Mutation-Positive Metastatic Castration-Resistant Prostate Cancer. News release. Monte Rosa Therapeutics, Inc. August 24, 2026. Accessed August 25, 2026. https://tinyurl.com/54x4jch5

2. Parikh RA, Herzberg B Stein MN, et al. A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations. J Clin Oncol. 2026;44(suppl 7):161. doi:10.1200/JCO.2026.44.7_suppl.161