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 prognosis and limited response to current therapies.

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

• Cancer cells with SMARCA4 mutations become highly dependent on SMARCA2, making selective SMARCA2 degradation a synthetic lethality strategy and a potential new precision medicine option.

• The study aims to establish safety, pharmacokinetics, pharmacodynamics, and early clinical activity of PRT3789 as monotherapy and in combination.

Study design and patient population

• Phase 1 open-label, dose-escalation study enrolled 65 patients with advanced solid tumors harboring SMARCA4 mutations, primarily NSCLC and esophageal cancer, including heavily pretreated patients.

• Patients received weekly intravenous PRT3789 at escalating doses (24–376 mg), with ongoing escalation to 500 mg and backfill cohorts enriched for Class 1 mutations.

• 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.

• Both Class 1 and Class 2 SMARCA4 mutations were included to further characterize response profiles.

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%), with most events mild to moderate.

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

• Dose holds occurred in about 30% of patients, but only a few were drug-related and not consistent in type.