First Patient Dosed in Molecular Glue Degrader Trial for mCRPC

The first patient has been dosed in the phase 2 MODeFIRe-1 trial (NCT07745361) evaluating MRT-2359 in combination with apalutamide (Erleada) in patients with AR mutation–positive metastatic castration-resistant prostate cancer (mCRPC), according to a news release from the agent’s developer, Monte Rosa Therapeutics, Inc.¹

MRT-2359 is an investigational, orally bioavailable molecular glue degrader 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, said.¹ “This study builds on the encouraging results we observed in our phase 1/2 study of MRT-2359 in combination with enzalutamide.”

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-day-on, 7-day-off schedule over 28-day cycles in combination with apalutamide. The study is designed to enroll up to 25 patients using the Simon 2-stage design. Eligible patients must have AR mutations, a prostate-specific antigen (PSA) with or without RECIST-measurable disease, and received treatment with 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, PSA progression-free survival, and safety.¹

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.

Rationale From Phase 1/2 Combination Data

All 5 of 5 patients with AR mutations in the previous study 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.¹

Interim data from this cohort were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in February 2026. 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 more than 60% tumor reduction in 2 with AR H875Y mutations, and durable stable disease in 1 with an 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.²

The continued enrollment of 29 more patients in this trial focused on those with AR-mutant 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 PC–relevant oncoproteins, including AR, MYC, and cyclin D1-E2F.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, 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