Monte Rosa Therapeutic (GLUE) Study Result summary

Key clinical results and efficacy

• MRT-2359 combined with enzalutamide achieved a 100% PSA response and 100% disease control rate in AR mutant metastatic CRPC patients, with two achieving PSA90 and two PSA50 responses; RECIST partial responses and durable disease control were observed, with three of four AR mutant patients remaining on therapy at data cutoff.

• Overall disease control rate was 64% across all evaluable patients, including several non-AR mutant patients with stable disease and tumor size reductions.

• Durable responses were seen, with some patients on treatment for 10 cycles or longer.

• The combination was well tolerated, with mild or moderate gastrointestinal adverse events as the most frequent toxicity, and no therapy-limiting toxicities observed.

• The study population was heavily pretreated, with high prior exposure to AR inhibitors, chemotherapy, and radioligand therapy.

Mechanism of action, biomarker, and preclinical rationale

• MRT-2359 is a GSPT1-directed molecular glue degrader that reduces MYC and AR pathway activity, leading to tumor growth inhibition and cell death.

• Preclinical studies showed that prostate cancer cell lines with high MYC and AR expression were highly sensitive to MRT-2359, and combination with enzalutamide or radioligand therapy led to significant tumor regressions.

• RNA-Seq and proteomics confirmed modulation of MYC, E2F, and AR pathways, correlating with tumor shrinkage.

• Biomarker profiling identified AR mutations and AR-V7 transcripts in tumor and liquid biopsies, with significant decreases in ctDNA mutant allele frequency and circulating tumor cell counts in AR mutant patients.

• Tumor size reductions correlated with high baseline MYC, E2F, and AR signaling, and post-treatment biopsies showed decreased pathway activity.

Study design and patient characteristics

• Phase I/II study enrolled 20 heavily pretreated mCRPC patients, with 14 evaluable for efficacy; molecular profiling characterized AR alterations and excluded neuroendocrine tumors.

• Most patients had received multiple prior therapies, including AR inhibitors, chemotherapy, and Pluvicto.

• The study required RECIST-measurable disease, enrolling a more severe and heavily-pretreated population.