Background: Endometrial cancers (ECs) are stratified into four molecular categories: wild type TP53 with non-specific molecular profile typically with microsatellite stability (NSMP, p53wt/MSS), DNA polymerase ε exonuclease domain-mutated (POLEmut), microsatellite instability high (MSI) and TP53 abnormal (p53abn). These are associated with specific prognoses. Selinexor (SEL) is a specific XPO1 inhibitor that leads to the nuclear retention and activation of tumor suppressor proteins (TSP) including p53. SEL showed improved progression-free survival (PFS) over placebo (PLB) in the stratification adjusted results of the ENGOT-EN5/GOG-3055/SIENDO study (NCT03555422; ESMO 2022). Methods: The SIENDO study is a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of SEL (80 mg once weekly) vs. PLB (2:1 randomization) as maintenance therapy in 263 patients (pts) with advanced or recurrent EC after one line of taxane-platinum therapy with partial or complete remission. TP53 mutations and MSI were assessed by centralized targeted sequencing and local immunohistochemistry. Classification was based on sequencing 648 genes on tumor samples from 172 pts (107 on SEL), assigned first by POLEmut, then MSI, then p53abn or p53wt (NSMP). Preliminary exploratory analyses based on molecular classification were prespecified in the trial. Results: The SIENDO study resulted in a median progression-free survival (PFS) of 5.7 months (SEL) vs. 3.8 months (PLB), with a stratification adjusted (eCRF) hazard ratio (HR) of 0.70 (p =.024; and a stratification non-adjusted (IRT) HR of 0.76 (p=0.063). Among the 172 patients who underwent molecular classification, those on SEL (107 pts) were classified as follows: 37 (35%) NSMP, 2 (2%) POLEmut, 18 (17%) MSI, and 50 (46%) p53abn. A similar distribution was seen in those on PLB (65 pts): 20 (31%) NSMP; 4 (6%) POLEmut; 8 (12%) MSI; 33 (51%) p53abn. Subgroup analysis of pts with TP53wt showed a PFS of 13.7 mo with SEL vs. 3.7 mo with PLB (HR 0.375; 95% CI, 0.210-0.670; nominal p =.0003) and pts with MSS/pMMR disease had a PFS of 6.9 mo with SEL vs. 5.4 with PLB (HR 0.593; 95% CI, 0.388-0.905, nominal p =.007). An analysis of patients with NSMP (p53wt, MSS) showed a substantial difference in PFS for SEL vs. PLB: medians NR and 3.71 months, respectively (HR 0.163; 95% CI, 0.060-0.444; nominal p <.0001). Analyses of the other 3 molecular categories did not show significant differences in PFS between SEL and PLB. Additional biomarker identification studies assessing tumor genetics and epigenetics are ongoing. Conclusions: SEL showed improved PFS over PLB in the SIENDO study based on the stratification adjusted analysis. As an indirect p53 activator, preliminary exploratory subgroup analyses of SEL showed improvement over PLB amongst the patients with TP53wt, MSS, and the NSMP EC comprising approximately 50% of patients with advanced/recurrent EC. Clinical trial information: NCT03555422.