Prelude Therapeutics (PRLD) Study Update summary

Study background and rationale

• PRT3789 is a first-in-class, highly selective SMARCA2 degrader developed for SMARCA4-deficient cancers, which represent about 5% of all cancers and are associated with poor outcomes on current therapies.

• SMARCA4 mutations are prevalent in NSCLC, esophageal, gastric, and endometrial cancers, with patients often ineligible for other targeted therapies and facing poor prognosis.

• Cancer cells with SMARCA4 mutations become highly dependent on SMARCA2, making selective SMARCA2 degradation a synthetic lethality strategy.

• The study aims to establish safety, pharmacokinetics, pharmacodynamics, and early efficacy of PRT3789 in this population.

Study design and patient population

• Phase 1 dose escalation study enrolled 65 patients with advanced solid tumors and SMARCA4 mutations, primarily NSCLC, including heavily pretreated individuals.

• Patients received PRT3789 IV weekly at doses from 24 to 376 mg, with enrollment ongoing into higher dose cohorts and backfill cohorts enriched for NSCLC and esophageal cancer.

• Median age was 62, with a median of 3 prior systemic therapies; 52% had NSCLC and 52% had Class 1 (loss-of-function) SMARCA4 mutations.

• 52.3% had Class 1 (loss of function) SMARCA4 mutations, 36.9% had Class 2 (missense, VUS), and 10.8% had SMARCA4 protein loss.

Safety and tolerability

• PRT3789 was generally well tolerated, with no dose-limiting toxicities or drug-related serious adverse events reported.

• Most common adverse events were nausea (24.6%), decreased appetite (18.5%), and fatigue (18.5%).

• Most adverse events were mild to moderate, including abdominal pain (16.9%), anemia (16.9%), and constipation (15.4%).

• Only one patient discontinued due to an adverse event, which was unrelated to the study drug.

• About 30% of patients had dose holds, but only a few were considered drug-related and were not consistent in type.