Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931.