Selinexor Maintenance Improves PFS in TP53 Wild-Type Endometrial Cancer

The median PFS in patients with pMMR TP53 wild-type endometrial cancer was 39.5 months with selinexor and 4.9 months with placebo.

Selinexor (Xpovio) maintenance therapy demonstrated positive efficacy emphasizing a progression-free survival (PFS) benefit in patients with TP53 wild-type advanced or recurrent endometrial cancer, according to results from the phase 3 SIENDO trial (NCT03555422) presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).

At a data cutoff of April 1, 2024, with a median follow-up of 36.8 months, the median PFS with selinexor was 28.4 months (95% CI, 13.1-not reached [NR]) vs 5.2 months (95% CI, 2.0-13.1) with placebo in the TP53 wild-type subgroup (HR, 0.44; 95% CI, 0.27-0.73; P = .0005).

Furthermore, in the TP53 wild-type subgroup, patients who were proficient mismatch repair (pMMR) demonstrated a median PFS of 39.5 months (95% CI, 19.3-NR) with selinexor vs 4.9 months (95% CI, 2.0-NR) with placebo (HR, 0.36; 95% CI, 0.19-0.71; P = .0011). For those in the TP53 wild-type subgroup who had TP53 wild-type deficient MMR (dMMR) disease, the median PFS was 13.1 months (95% CI, 3.6-NR) with selinexor vs 3.7 months (95% CI, 1.9-NR) with placebo (HR, 0.49; 95% CI, 0.18-1.34; P = .0825).

At 33.1 months of follow-up, the median time to second disease progression (PFS2) in the overall TP53 wild-type subgroup was NR (95% CI, 41.1-NR) in the selinexor group vs 35.2 months (95% CI, 17.3-NR) with placebo (HR, 0.62; 95% CI, 0.33-1.36; P = .0581).

In all patients with TP53 wild-type disease, the median time to first subsequent therapy (TFST) was 31.7 months (95% CI, 18.7-NR) with selinexor vs 10.6 months (95% CI, 4.8-15.1) with placebo (HR, 0.41; 95% CI, 0.25-0.68; P = .0002); 50% of patients in the selinexor group and 83% of the placebo group discontinued study treatment and initiated a new therapy.

The median time to second subsequent therapy (TSST), at 35.8 months of follow-up, was NR (95% CI, 43.9-NR) with selinexor vs 22.1 months (95% CI, 13.1-NR) with placebo (HR, 0.47; 95% CI, 0.26-0.83; P = .0041).

“While there are multiple mechanisms by which selinexor induces cancer cell death, in [endometrial cancer], the primary mechanism is believed to be through nuclear retention and reactivation of [tumor suppression proteins] such as wild-type p53,” presenting author Debra L. Richardson, MD, associate professor and chief of the Section of Gynecologic Oncology in the Oklahoma TSET Phase I Program at the University of Oklahoma, stated in the presentation. “Consistent improvements in PFS2, TFST, and TSST provide supportive evidence for the substantial signal of PFS improvement with selinexor in [TP53 wild-type].”

The randomized, double-blind ENGOT-EN5/GOG-3055/SIENDO trial evaluated the efficacy and safety of selinexor maintenance compared with placebo maintenance after combination chemotherapy in patients with endometrial cancer. A total of 263 patients were randomly assigned, in a 2:1 ratio, to receive either 80 mg of oral selinexor once daily or placebo. If patients weighed less than 20 kg/m², they were to receive 60 mg of selinexor.

Eligible patients were female adults with stage IV or first relapse of endometrial cancer who received 12 or more weeks of taxane/carboplatin chemotherapy. Prior surgery, radiotherapy, and hormonal therapy were permitted, and patients were required to have a partial response (PR) or complete response after prior chemotherapy.

In the TP53 wild-type subgroup, 77 patients received selinexor and 36 received placebo. The median age of patients was 64.0 years (range, 40-81) and 61.5 (range, 33-74), respectively; 55.8% and 61.1% had an ECOG performance status of 0; 84.4% and 80.6% had endometrioid histology; 53.2% and 50.0% had recurrent disease at the time of chemotherapy; 59.7% and 52.8% achieved a PR due to chemotherapy; and 61.0% and 63.9% had pMMR disease.

The trial’s primary end point was PFS per RECIST v1.1. Key secondary end points include overall survival (OS), TFST, PFS2, and TSST. The histological subtype and molecular subclassification such as TP53 mutation status and MMR status were exploratory end points.

At the data cutoff, OS data was at 29.2% maturity; 24.7% of patients who received selinexor experienced an OS event and 38.9% of patients who received placebo experienced an OS event. The median OS was NR (95% CI, 45.4-NR) with selinexor and NR (95% CI, 35.2-NR) with placebo (HR, 0.65; 95% CI, 0.32-1.29).

Treatment-emergent adverse events (TEAEs) were mostly low-grade and manageable; the most common TEAEs of any grade with selinexor and placebo were nausea (90% vs 40%, respectively), vomiting (60% vs 14%), diarrhea (45% vs 37%), and constipation (33% vs 40%). Of grade 3 or higher, the most common TEAEs were neutropenia (20% vs 0%), nausea (13% vs 0%), thrombocytopenia (10% vs 0%), vomiting (3% vs 3%), constipation (0% vs 6%), and abdominal pain (0% vs 6%).

The study authors highlighted the randomized, phase 3 ENGOT-EN20/GOG-3083/XPORT-EC-042 trial (NCT05611931) is currently enrolling patients to evaluate selinexor maintenance therapy after systemic therapy in patients with advanced or recurrent P53 wild-type endometrial carcinoma as an important next step.

References

Richardson DL, Makker V, Gaba L, et al. Long-term safety and efficacy of selinexor maintenance treatment in patients with TP53 wild-type advanced or recurrent endometrial cancer: follow-up subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO); March 14-17, 2025; Seattle, WA.