Karyopharm’s Phase 3 XPORT-EC-042 trial of selinexor maintenance therapy missed its primary PFS endpoint in TP53 wild-type advanced or recurrent endometrial cancer despite a 5.3-month improvement in median progression-free survival and no new safety signals.
Written By: Mayuresh Salvi, PharmD
Reviewed By: Pharmacally Editorial Team
Karyopharm Therapeutics has reported topline results from the Phase 3 XPORT-EC-042 trial evaluating selinexor as maintenance therapy for adults with TP53 wild-type advanced or recurrent endometrial cancer. The study failed to meet its primary endpoint of progression-free survival (PFS), although the data showed a numerical improvement favoring selinexor over placebo. The company plans to continue monitoring patients for longer-term outcomes while reducing future investment in its endometrial cancer program.
Selinexor Targets Nuclear Export Pathway in Endometrial Cancer
Selinexor (XPOVIO®) is an oral first-in-class inhibitor of exportin 1 (XPO1), a nuclear export protein involved in transporting tumor suppressor proteins out of the cell nucleus. By blocking XPO1, selinexor promotes the retention of tumor suppressor proteins within the nucleus, potentially slowing cancer growth.
Endometrial cancer is the most common gynecologic malignancy in the United States. Patients with TP53 wild-type and mismatch repair-proficient (pMMR) tumors have limited maintenance treatment options after first-line chemotherapy, highlighting an ongoing need for effective targeted therapies.
Phase 3 Trial Shows Numerical PFS Improvement but Misses Statistical Significance
The global, randomized, double-blind, placebo-controlled Phase 3 XPORT-EC-042 trial (NCT05611931) enrolled 257 patients with TP53 wild-type advanced or recurrent endometrial cancer. Patients received either oral selinexor 60 mg once weekly or placebo as maintenance therapy following chemotherapy or chemotherapy combined with an immune checkpoint inhibitor.
The primary analysis focused on the modified intent-to-treat (mITT) population of 236 patients. Selinexor achieved a median progression-free survival of 12.75 months compared with 7.43 months for placebo, representing a 5.32-month improvement. However, the result did not reach statistical significance (HR 0.76; 95% CI: 0.51-1.12; one-sided p=0.0791).
At the time of analysis, investigators had recorded 106 progression-free survival events in the mITT population. Overall survival remains a key secondary endpoint, and patient follow-up will continue.
Safety Profile Remained Consistent
The safety and tolerability findings matched the established safety profile of selinexor. Investigators reported no new safety signals, supporting previous clinical experience with the drug across approved multiple myeloma indications.
Investigators Highlight Persistent Unmet Need
Global principal investigator Professor Ignace Vergote said the observed trend toward longer progression-free survival continues to support investigation of XPO1 inhibition in TP53 wild-type endometrial cancer despite the study missing its primary endpoint.
U.S. principal investigator Dr. Robert Coleman noted that delaying disease progression by more than five months is clinically meaningful, although the improvement was not statistically significant. He added that longer follow-up may provide additional insights into the treatment’s benefit.
Karyopharm Chief Medical Officer Reshma Rangwala said the findings contribute to the scientific understanding of XPO1 inhibition in endometrial cancer and thanked patients and investigators participating in the study.
Company Prioritizes Myelofibrosis and Multiple Myeloma Programs
Following the trial outcome, Karyopharm said it will reduce planned investment in endometrial cancer while concentrating resources on its myelofibrosis and multiple myeloma portfolio.
The company expects several important milestones during the second half of 2026, including submission of a supplemental New Drug Application (sNDA) for selinexor in myelofibrosis, potential inclusion in relevant treatment compendia, and topline results from the 60 mg cohort of the Phase 2 SENTRY-2 myelofibrosis trial.
Karyopharm plans to complete a comprehensive analysis of the XPORT-EC-042 data and present the full results at a future medical meeting.
Reference
About the Writer
Mayuresh Sunil Salvi (Linkedin) is a PharmD professional and healthcare writer with a strong interest in pharmacovigilance, drug safety, and emerging medical research. He is passionate about exploring new drug discoveries, clinical research, and advances in evidence-based medicine. His interests also include ward rounds, prescription audits, and treatment analysis to support rational pharmacotherapy and improved patient care.