Monte Rosa Reports Encouraging Phase 1/2 Data For MRT-2359 Plus Enzalutamide In Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Monte Rosa Therapeutics announced encouraging interim results from an ongoing Phase 1/2 clinical study evaluating MRT-2359, its investigational GSPT1-directed molecular glue degrader, in combination with enzalutamide in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). The oral regimen demonstrated early clinical activity and a manageable safety profile in a population with significant prior treatment exposure, including second-generation androgen receptor (AR) inhibitors, taxane chemotherapy, and radioligand therapy.

“We continue to be highly encouraged by the clinical activity observed with MRT-2359 in combination with enzalutamide in heavily pretreated mCRPC patients, a population with limited therapeutic options, with an overall disease control rate (DCR) of 64%. The responses seen in the subset of patients harboring AR mutations were particularly compelling, with 4 of 4 patients demonstrating a PSA response, including 2 PSA90 responses and 2 PSA50 responses. Two of the 4 patients with AR mutations showed a RECIST response, and the DCR in the AR mutant population was 100%. We believe these results are especially promising given that most of the patients with AR mutations, even more so than in the overall mCRPC trial population, received prior chemotherapy as well as radioligand therapy, or even experimental bispecific antibodies,” said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics.

He also commented, “We were also pleased to see through our biomarker work that MRT-2359 significantly impacted both the MYC and the E2F signaling pathways, suggesting a mechanism of action that is at least in part independent of inhibiting AR signaling, and confirming our preclinical studies. Given these findings and the favorable safety profile observed to date, we believe there is a significant opportunity for MRT-2359 in the rapidly evolving treatment landscape of prostate cancer.”

The study evaluated two dose levels of MRT-2359 (0.5 mg and 0.75 mg) administered on a 21-days-on, 7-days-off schedule alongside enzalutamide. As of the December 3, 2025 data cutoff, 20 patients were enrolled and evaluable for safety. Treatment-related adverse events were primarily gastrointestinal, mild to moderate in severity, and considered manageable, supporting continued clinical development of the combination.

Among 14 patients evaluable for efficacy and confirmed to have non-neuroendocrine mCRPC, meaningful anti-tumor activity was observed, particularly in those with AR mutations. All four patients with AR-mutant disease achieved PSA responses, including two with PSA90 reductions, and two partial responses were observed by RECIST criteria. Disease control was achieved in 100% of AR-mutant patients and 64% of the overall evaluable population, with durable responses noted especially in AR-mutant and AR inhibitor–naïve patients.

“While the data from the ongoing trial continue to mature, we plan to initiate a new, signal-confirming Phase 2 study, evaluating MRT-2359 in combination with a second-generation AR inhibitor in mCRPC patients with AR mutations,” said Filip Janku, M.D., Ph.D., Chief Medical Officer of Monte Rosa Therapeutics. “Data from this study have the potential to confirm MRT-2359’s clinical activity and may position the program for advancement into registrational studies. We also look forward to presenting updated data from the ongoing Phase 1/2 study at the ASCO Genitourinary Cancers Symposium conference in February.”

Molecular analyses demonstrated that clinical benefit correlated with MYC and AR pathway activity, with evidence of pathway modulation in paired tumor biopsies. Based on these findings, Monte Rosa plans to present updated data at the 2026 ASCO Genitourinary Cancers Symposium and initiate a Phase 2 study focused on mCRPC patients with AR mutations. While the study also included a small cohort of hormone receptor–positive breast cancer patients, limited activity in this group does not support further development in that indication.