Endometrial Cancer Maintenance Therapy Setback: Phase 3 Selinexor Trial Misses Primary Endpoint

The treatment landscape for endometrial cancer has been rapidly reshaped in recent years by immune checkpoint inhibitors, creating a higher and continually shifting bar for new drug trials. Karyopharm Therapeutics announced that XPORT-EC-042, a phase 3 trial of the nuclear export protein inhibitor selinexor as maintenance therapy for advanced or recurrent endometrial cancer, failed to meet its primary efficacy endpoint.

In the modified intent-to-treat population, median progression-free survival was 12.75 months in the selinexor group and 7.43 months in the placebo group. Although the numerical difference exceeded five months, statistical testing could not rule out the possibility that the result was caused by random variation, so it cannot be concluded from these findings that the treatment definitively delayed disease progression. The company has not yet fully presented data such as the hazard ratio and confidence interval in these topline results, and the magnitude of efficacy and outcomes in different patient subgroups remain subject to complete analysis.

XPORT-EC-042, registered as NCT05611931, was a randomized, double-blind, placebo-controlled trial that enrolled 257 patients with TP53 wild-type advanced or recurrent endometrial cancer. Participants had previously received platinum-containing systemic therapy and achieved a complete or partial response. They were then assigned in a one-to-one ratio to receive oral selinexor 60 mg once weekly or placebo until disease progression.

The trial’s statistical design also reflected the challenges created by changing standards of care. Karyopharm previously disclosed to the U.S. Securities and Exchange Commission that the U.S. Food and Drug Administration believed the original placebo-controlled design, which did not include immune checkpoint inhibitors that had become a new standard of care, might be insufficient to support a marketing application. The company subsequently adopted sequential testing, first analyzing a modified population of approximately 220 patients and then evaluating the full intent-to-treat population. The former included patients with TP53 wild-type, mismatch repair-proficient disease, as well as patients with mismatch repair-deficient disease who were unsuitable for checkpoint inhibitors for medical reasons.

This adjustment attempted to incorporate eligibility for immunotherapy into the trial framework but failed to eliminate the risk of missing the primary endpoint. Even though the median values showed a numerical difference, the lack of statistical significance still means that selinexor has not demonstrated a reliable progression-free survival benefit in the predefined primary analysis population. Overall survival, a key secondary endpoint in the full population, was also insufficient to change the current conclusion that the trial did not achieve its primary objective.

Karyopharm said it will reduce investment in the endometrial cancer indication and prioritize resources for its myelofibrosis and multiple myeloma programs. The announcement remains limited to topline data provided by the company, without complete statistical results, subgroup analyses, or detailed safety information. Until these data are released, it is not yet possible to determine whether a specific beneficiary population exists that could be identified in subsequent research.