KPTI Selinexor Fails Phase 3 Endometrial Cancer Trial

Karyopharm Therapeutics (KPTI) reported on July 30 that its Phase 3 XPORT-EC-042 trial of selinexor as maintenance therapy in TP53 wild-type advanced or recurrent endometrial cancer failed to meet its primary endpoint of progression-free survival.

The trial randomized 257 patients (mITT population n=236) to selinexor or placebo as maintenance following chemotherapy or chemo plus a checkpoint inhibitor. Median PFS was 12.75 months in the selinexor arm versus 7.43 months for placebo, a 5.3-month numerical advantage. The hazard ratio was 0.76, but the 95% confidence interval of 0.51 to 1.12 crossed 1.0, and the one-sided p-value of 0.0791 fell short of significance. Only 106 PFS events had been observed at data cutoff, which likely contributed to the wide interval. The drug showed biological activity, but the trial was underpowered to prove it.

Karyopharm trades at $1.92 with a market cap near $159 million, making it a microcap whose value depends on expanding selinexor beyond its two approved indications: multiple myeloma (in combination with bortezomib and dexamethasone) and diffuse large B-cell lymphoma (as a single agent). Selinexor works by inhibiting XPO1, a nuclear export protein that shuttles tumor suppressor proteins out of the cell nucleus. Blocking XPO1 traps those proteins inside the nucleus, restoring their ability to suppress tumor growth. The endometrial cancer program was a push into solid tumors, a harder setting for a drug with established hematologic activity.

The failure narrows Karyopharm’s near-term pipeline to a single catalyst: an sNDA filing planned for August 2026 seeking accelerated approval of selinexor plus ruxolitinib in myelofibrosis. That filing is based on the Phase 3 SENTRY trial (N=353), which met its first co-primary endpoint of SVR35 (spleen volume reduction of at least 35% at week 24) with a near-doubling of response rates versus placebo plus ruxolitinib. The FDA agreed in writing that SVR35 qualifies as a reasonably likely surrogate endpoint for accelerated approval. The trial also showed a promising overall survival signal and reductions in variant allele frequency, hinting at disease modification.

Myelofibrosis is currently treated exclusively with JAK inhibitors: ruxolitinib (Incyte’s Jakafi), fedratinib, pacritinib, and momelotinib. If approved, selinexor plus ruxolitinib would be the first combination therapy incorporating a novel drug class. Karyopharm will request Priority Review, which if granted would put a PDUFA date roughly six months after FDA receipt, placing a decision in early-to-mid 2027. The company plans to submit the sNDA in August.

The endometrial cancer readout shows the risk of extending XPO1 inhibition into solid tumors, where the biology may be less favorable than in hematologic malignancies. Analysts had already cut Karyopharm price targets aggressively, with HC Wainwright reducing from $13 to $3 and Piper Sandler from $16 to $7, reflecting diminished expectations ahead of the XPORT-EC-042 readout.

What to watch next: the August sNDA submission for selinexor plus ruxolitinib in myelofibrosis and whether the FDA grants Priority Review. That decision determines whether Karyopharm gets a 6-month or 10-month review window, and it is now the company’s only near-term value driver.

Source: Karyopharm XPORT-EC-042 topline results press release | XPORT-EC-042 on ClinicalTrials.gov (NCT05611931)