Trial launches of molecular glue degrader plus apalutamide in mCRPC

The first patient has been dosed in the phase 2 MODeFIRe-1 trial of MRT-2359, an investigational GSPT1-directed molecular glue degrader, in combination with apalutamide (Erleada) in patients with androgen receptor (AR) mutation positive metastatic castration-resistant prostate cancer (mCRPC), Monte Rosa Therapeutics announced in a news release.¹

“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,” said Filip Janku, MD, PhD, Chief Medical Officer of Monte Rosa Therapeutics, in a news release from the company.¹

About the MODeFIRe-1 trial

MODeFIRe-1 (NCT07745361) is an open-label, multicenter phase 2 study that plans to enroll up to 25 patients with mCRPC and AR mutations. Patients must have previously received a second-generation ARPI and have prostate-specific antigen (PSA) disease, with or without measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).

Participants will receive MRT-2359 at 0.5 mg orally once daily for 21 days followed by 7 days off in 28-day cycles, in combination with apalutamide. Planned efficacy assessments include PSA response, RECIST response, duration of response, radiographic progression-free survival, PSA progression-free survival, and safety.

Previous data on MRT-2359

The trial is intended to build on findings from an ongoing phase 1/2 study of MRT-2359 plus enzalutamide (Xtandi). In an abstract presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, 23 heavily pretreated patients with advanced CRPC had received the combination as of January 30, 2026.^2,3

Across the full efficacy-evaluable population, the reported RECIST disease control rate was 67% (10 of 15 patients), and 10 patients had reductions in target lesion size.

In the subset of participants with AR mutations, 5 of 5 patients had PSA responses, including 2 patients with a PSA decline of at least 90%. All 5 patients with AR mutations had reductions in target lesion size. Additionally, 5 patients with wild-type AR or AR-V7 transcripts had stable disease by RECIST, several of whom had reductions in tumor size.

The combination was reported to be generally well tolerated, with the most common treatment-related adverse events being fatigue, diarrhea, nausea, and decreased appetite. These events were characterized as mild or moderate, and no patient discontinued treatment because of an adverse event.

“[MODeFIRe-1] builds on the encouraging results we observed in our phase 1/2 study of MRT-2359 in combination with enzalutamide. As we disclosed previously, in that study of heavily pretreated, advanced CRPC patients—including those who had progressed on prior second-generation AR inhibitors, chemotherapy, and radioligand therapy—5 of 5 patients with AR mutations demonstrated a PSA response, with a 100% disease control rate and 2 RECIST responses,” Janku added in the news release.¹ “MODeFIRe-1 pairs MRT-2359 with apalutamide using a design intended to efficiently further evaluate and potentially confirm clinical activity in this population. We believe this study can position MRT-2359 for advancement into registrational development if the data continue to support our earlier results, with the potential to also extend clinical benefit to additional AR-driven patient populations including patients without prior second-generation AR inhibitors, as well as into combinations with radioligand therapies independent of AR status.”

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