Phase 2 MRT-2359 GSPT1 molecular glue degrader + apalutamide AR inhibitor in AR-mutant mCRPC.

This Phase 2 open-label, multicenter study (MODeFIRe-1) from Monte Rosa Therapeutics tests oral MRT-2359 plus apalutamide in patients with castration-resistant prostate adenocarcinoma whose tumors harbor androgen receptor (AR) mutations (often AR ligand-binding-domain mutations, which can drive resistance to AR-pathway inhibitors). MRT-2359 is a selective GSPT1 (eRF3a) molecular glue degrader that recruits an E3 ubiquitin ligase to degrade GSPT1, broadly reducing translation of short-lived oncogenic proteins and showing AR-pathway suppression in combination datasets; apalutamide (from Janssen/Johnson & Johnson) is a second-generation androgen receptor inhibitor that blocks AR signaling. The primary aim is PSA decline, with additional endpoints covering safety/tolerability and other anti-tumor activity measures, supported by PK/PD and biopsy-based biomarker work. Commercially, this is positioned as a “signal-confirming” Phase 2 leveraging earlier combination experience with another AR inhibitor (enzalutamide) that suggested activity in AR-mutant mCRPC. Today’s care for ARPI-resistant mCRPC typically sequences additional AR-pathway therapy when feasible, taxane chemotherapy (docetaxel/cabazitaxel), PARP inhibitors for HRR-altered disease, and radioligand therapy (Lu-177–PSMA) for eligible patients—so this study targets a resistance-enriched subset with a non-AR-directed degrader mechanism layered onto AR blockade.