Selinexor Misses PFS End Point in TP53 Wild-Type Endometrial Cancer

The phase 3 XPORT-EC-042/ENGOT-EN20/GOG-3083 trial (NCT05611931) evaluating selinexor (Xpovio) as a maintenance-only therapy did not meet its primary end point of progression-free survival (PFS) in patients with TP53 wild-type advanced or recurrent endometrial cancer, according to a news release from Karyopharm Therapeutics Inc.¹

What were the topline results of the XPORT-EC-042 trial?

In the modified intent-to-treat (mITT) population (n = 236), 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; 1-sided P = .0791). As of the data cutoff, 106 investigator-assessed PFS events had occurred in the mITT population. Although the difference did not reach statistical significance, investigators characterized the 5.3-month improvement in median PFS as clinically meaningful for a population with few maintenance options. The developer plans to continue to follow up with patients for longer-term outcomes.

“Delaying the progression of cancer by 5 months at the median is a meaningful and encouraging outcome,” said Robert Coleman, MD, FACOG, FACS, a gynecologic oncologist at Texas Oncology, special advisor to the president of the Gynecologic Oncology Group, and lead principal investigator in the US, in the press release.¹ “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/mismatch repair proficient [pMMR] advanced or recurrent endometrial cancer remains in need of new treatment options.”

Overall survival, a key secondary endpoint, will continue to be followed; results in the trial's original ITT population were not detailed in the release. The safety profile remained consistent with the known profile of selinexor, with no new safety signals reported. Karyopharm plans to present full data from the trial at a future medical meeting.

What is the design of the XPORT-EC-042 trial?

XPORT-EC-042 is a global, randomized, double-blind, placebo-controlled trial that enrolled 257 patients with TP53 wild-type advanced or recurrent endometrial cancer following chemotherapy or chemotherapy plus a checkpoint inhibitor. Patients were randomly assigned 1:1 to 60 mg of oral selinexor once weekly or placebo until disease progression. The trial’s ITT population included all patients in the trial whose tumors were TP53 wild-type, regardless of MMR status. The mITT population included patients with TP53 wild-type tumors with pMMR status, and those with TP53 wild-type tumors with mismatch repair-deficient (dMMR) tumors who were medically ineligible for checkpoint inhibitors. The ITT population enrolled 257 patients vs 236 in the mITT population.

It was highlighted that Karyopharm collaborated with Foundation Medicine to create FoundationOne CDx, a tissue-based genomic profiling test, to identify and enroll eligible patients who are TP53 wild-type.

How does selinexor work in endometrial cancer?

Selinexor (Xpovio) is a first-in-class, oral inhibitor of exportin 1 (XPO1), a nuclear export protein. By blocking XPO1, selinexor promotes retention of tumor suppressor proteins, including p53, within the cell nucleus, which is thought to selectively induce death in cancer cells while largely sparing normal cells. This mechanism informed the rationale for testing selinexor specifically in TP53 wild-type disease, where intact p53 signaling could be reactivated.

“While disappointed by these unexpected results, we believe they advance the scientific understanding of XPO1 inhibition for tens of thousands of patients with endometrial cancer worldwide. We are deeply committed to further investigating these data,” stated Reshma Rangwala, MD, PhD, chief medical officer and head of Research at Karyopharm, in the press release.¹ “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.”

What is the regulatory and scientific history with selinexor in this population?

The rationale for XPORT-EC-042 stemmed from an exploratory analysis of the phase 3 SIENDO trial (NCT03555422), in which a prespecified subgroup of patients with TP53 wild-type tumors receiving 80 mg of selinexor maintenance showed a median PFS of 27.4 months vs 5.2 months with placebo (HR, 0.41).²

The developer said they will complete a full evaluation of the XPORT-EC-042 data and present findings at an upcoming meeting while reducing planned investment in the endometrial cancer program to prioritize its myelofibrosis and multiple myeloma pipelines.

References

1. Karyopharm Therapeutics Inc. Karyopharm announces topline results from phase 3 XPORT-EC-042 trial in endometrial cancer. News release. Karyopharm Therapeutics Inc. July 30, 2026. Accessed July 31, 2026. https://tinyurl.com/3e3v8nc6
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. doi:10.1136/ijgc-2024-005412