Selinexor Maintenance Misses Mark in TP53 Wild-Type Endometrial Cancer

Maintenance selinexor did not improve progression-free survival (PFS) when used following either chemotherapy alone or chemotherapy plus a checkpoint inhibitor in patients with TP53 wild-type (TP53wt) advanced or recurrent endometrial cancer, according to results from the phase 3 XPORT-EC-042 trial (NCT05611931) announced by Karyopharm Therapeutics.¹

In the trial's modified intent-to-treat (mITT) population, which enrolled 236 patients, the median PFS was 12.75 months with selinexor compared with 7.43 months with placebo (HR, 0.76; 95% CI, 0.51-1.12; one-sided P = .0791). Although the difference numerically favored selinexor, it did not cross the threshold for statistical significance, and the trial's primary endpoint of PFS was not met.

The safety and tolerability profile observed in the trial was consistent with the established safety profile of selinexor, with no new safety signals identified.

"Delaying the progression of cancer by five months at the median is a meaningful and encouraging outcome," Robert Coleman, MD, FACOG, FACS, of Texas Oncology and the Gynecologic Oncology Group (GOG), lead XPORT-EC-042 principal investigator in the United States stated in a news release. "Although I am disappointed that the PFS improvement was not statistically significant, I look forward to continuing to follow these results over time and presenting the data from this important trial at an upcoming medical meeting. This patient population who have TP53 wild-type/pMMR advanced or recurrent endometrial cancer remains in need of new treatment options."

XPORT-EC-042 Rationale and Design

The rationale for launching XPORT-EC-042 stems from an exploratory subgroup analysis of the earlier phase 3 SIENDO trial (ENGOT-EN5/GOG-3055), in which long-term follow-up data for a prespecified TP53wt subgroup showed a median PFS of 27.4 months with selinexor versus 5.2 months with placebo (HR, 0.42; 95% CI, 0.25-0.70; one-sided nominal P = .0003).^3,4

XPORT-EC-042 randomized 257 patients 1:1 to receive oral selinexor at a fixed 60 mg once-weekly dose or placebo until disease progression. Eligible patients had histologically confirmed disease, TP53wt status confirmed by next-generation sequencing, and had completed at least 12 weeks of platinum-based therapy with a confirmed partial or complete response per RECIST v1.1, with either primary stage IV disease or first relapse.²

The trial tested its primary end point sequentially across two populations: the mITT group, comprising patients with TP53wt tumors that are either mismatch repair-proficient (pMMR) or mismatch repair-deficient but medically ineligible for checkpoint inhibitor therapy, and the broader original ITT population, which included all enrolled patients with TP53wt tumors regardless of mismatch repair status.

"These results are meaningful for a patient population lacking effective maintenance therapies that can delay disease progression," Ignace Vergote, MD, gynecologic oncologist at the Catholic University Leuven in Belgium, ENGOT, and global lead principal investigator for the trial, stated in the news release.¹ "The trend for a longer progression-free survival observed in the mITT population of the selinexor arm continues to highlight the potential of XPO1 inhibition in patients with TP53 wild-type/pMMR endometrial cancer."

Reshma Rangwala, MD, PhD, chief medical officer and head of research at Karyopharm, added, “While disappointed by these unexpected results, we believe they advance the scientific understanding of XPO1 inhibition for tens of thousands of endometrial cancer patients worldwide. We are deeply committed to further investigating these data. I would like to thank all of the patients, their families and the clinical trial investigators and their staff, as well as ENGOT and GOG, for participating in this trial.”

REFERENCES

1. Karyopharm Therapeutics Inc. Karyopharm announces topline results from phase 3 XPORT-EC-042 trial in endometrial cancer. News release. July 30, 2026. Accessed July 31, 2026. https://tinyurl.com/2faxrr6f

2. Vergote I, Perez Fidalgo A, Valabrega G, et al. ENGOT-EN20/GOG-3083/XPORT-EC-042, a phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design. Int J Gynecol Cancer. 2024;34(8):1283-1289.

3. Vergote I, Perez-Fidalgo JA, Hamilton EP, et al. Oral selinexor as maintenance therapy after first-line chemotherapy for advanced or recurrent endometrial cancer. J Clin Oncol. 2023;41(35):5400-5410. doi: 10.1200/JCO.22.02906

4. Slomovitz B, Perez-Fidalgo JA, Hamilton E, et al. Long-term follow-up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: a pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study. J Clin Oncol. 2023;41(suppl 36):427956.