UPDATE: MRT-2359 Plus Apalutamide Combination Enters Phase 2 Trial for AR-Mutated Advanced Prostate Cancer

A new phase 2 trial is evaluating MRT-2359 in combination with apalutamide for patients with androgen receptor (AR) mutation-positive metastatic castration-resistant prostate cancer, an advanced disease that may become resistant to standard hormone-directed treatments.

The first patient has been dosed in the MODeFIRe-1 study, which plans to enroll up to 25 patients. Participants must have previously received a second-generation androgen receptor inhibitor and show evidence of disease progression through rising prostate-specific antigen levels. The trial will assess PSA responses, tumor responses, response duration, progression-free survival, and safety.

MRT-2359 is an investigational molecular glue degrader that targets GSPT1, a protein involved in protein translation. By promoting GSPT1 degradation, the drug is intended to disrupt the production of proteins needed for cancer-cell growth. Apalutamide blocks androgen receptor signaling, providing a complementary treatment strategy.

The study builds on early results from a phase 1/2 trial of MRT-2359 combined with enzalutamide in heavily pretreated patients (we talked about it in a previous article you can find here.). Among 15 patients evaluable for radiographic efficacy, 10 achieved disease control and 10 experienced reductions in target-lesion size. In the subgroup of five patients with AR mutations, all had PSA responses, including two with declines of at least 90%.

The combination was generally well tolerated in the earlier study. The most common treatment-related adverse events were fatigue, diarrhea, nausea, and decreased appetite, typically described as mild or moderate.

These findings are encouraging but preliminary because the AR-mutated subgroup included only five patients and the earlier study was nonrandomized. MODeFIRe-1 will help determine whether the responses can be reproduced in a larger group and whether they are durable enough to support further clinical development.

Clinical trial.