A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations.

161 Background: Progression to mCRPC is driven by numerous mechanisms including emergence of AR LBD mutations that reactivate the AR pathway and blunt response to hormone therapies including novel hormonal agents (NHA). MRT-2359, an orally bioavailable MGD that selectively degrades the translation termination factor GSPT1, reduces cellular abundance of many oncogenic proteins including AR, MYC and Cyclin D1. This reduction is associated with robust anti-tumor activity across multiple preclinical models of mCRPC both as a monotherapy or in combination with enzalutamide. Methods: MRT-2359 has been tested in an open-label study to evaluate safety, dose-limiting toxicities (DLTs), pharmacokinetic and pharmacodynamic, and early signals of clinical efficacy (RECIST 1.1, PCWG3). In the monotherapy dose escalation portion of the study, 59 patients with selected tumor types (NSCLC, SCLC, NE tumors) received MRT-2359 orally once daily at doses from 0.5 mg to 2 mg per day in a 5 days on/9 days off (5/9) or a 21 days on/7 days off (21/7) schedule. Once the recommended phase 2 dose of 0.5 mg 21/7 was established, evaluation of MRT-2359 in combination with oral enzalutamide at 160 mg daily was initiated in heavily pretreated mCRPC with RECIST 1.1 measurable disease. Results: As of 22 SEP 25, 18 heavily pretreated patients have been treated with MRT-2359 and enzalutamide including three patients with AR LBD mutations. One (6%) patient had a DLT (grade 3 stomatitis associated with pain). Most frequent adverse events were manageable, grade 1 or 2, and included fatigue (6, 33%), diarrhea (5, 28%) and nausea (5, 28%). Preliminary signals of anticancer activity have been observed, including in all 3 patients with AR LBD mutations, who demonstrated 2 (67%) partial responses (PRs; -62% tumor reduction maintained for 10 cycles in a patient with AR H875Y post NHA, docetaxel and lutetium-177 PSMA; -61% ongoing for 3+ cycles in a patient with AR H875Y post NHA including enzalutamide, docetaxel and lutetium-177 PSMA ) and 1 durable stable disease (SD; -20% ongoing for 8+ cycles in a patient with AR L702H post NHA including enzalutamide, docetaxel and PSMA T-cell engager). Also, all 3 (100%) patients had ≥ PSA50 response (PSA90 in 2 patients with PRs and PSA50 in the patient with SD). Remaining 15 patients without AR LBD mutations had 5 SDs (maintained for 2, 5, 6, 6+, and 8+ cycles, respectively, and no PSA50 responses). The study continues to enroll up to 29 patients with a focus on enrichment for patients with AR LBD mutations, and updated data will be presented at the meeting. Conclusions: MRT-2359, an orally bioavailable, highly selective GSPT1 MGD was safe with encouraging preliminary activity (PR rate 67%, ≥ PSA50 rate 100%) in mCRPC with AR LBD mutations. Clinical trial information: NCT05546268 .