Adding the investigational drug elraglusib to standard first-line gemcitabine and nab-paclitaxel (GnP) may extend the lives of some patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to phase 2 data presented at the ASCO Gastrointestinal Cancers Symposium 2026.

Among 233 patients with previously untreated disease, the addition of elraglusib to GnP doubled 12-month overall survival — from 22.3% to 44.4%. Median overall survival improved from 7.2 months with GnP alone to 10.1 months with the combination therapy (hazard ratio [HR], 0.62; P = .02).

“This is a very difficult disease where incremental advances matter,” Devalingam Mahalingam, MD, PhD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, said during his presentation.

Elraglusib is a novel small molecule inhibitor of glycogen synthase kinase (GSK)-3-beta, which plays a role in tumor growth and immune evasion. In a previous, single-arm study of 42 patients with advanced PDAC, elraglusib plus GnP showed clinical activity against the disease.

“What we’re seeing here is a signal that targeting GSK-3-beta biology in combination with standard chemotherapy may translate into a clinically meaningful benefit for some patients,” Mahalingam said of the new findings.

Most patients with PDAC present with advanced or metastatic disease, when the prognosis is poor. Real-world data suggest a median overall survival of just 6-9 months, underscoring an urgent need for novel therapies that can “broadly improve outcomes for our patients,” Mahalingam said.

GSK-3-beta is a cellular regulator involved in glucose metabolism, insulin signaling, and stem cell differentiation — but in cancer, it is co-opted for tumor growth, fibrosis, and immune evasion.

Elraglusib, according to Mahalingam, has a multimodal mechanism of action that enhances chemotherapy cytotoxicity and regulates antitumor immune cell response.

The randomized phase 2 study involved previously untreated patients with metastatic PDAC who received standard GnP chemotherapy plus elraglusib (n = 155; median age, 65 years) or GnP alone (n = 78; median age, 68 years).

Elraglusib was given intravenously once a week, with treatment continued until disease progression or unacceptable toxicity. Eligibility criteria were broad, Mahalingam noted, with no exclusion for low albumin or high disease burden.

In addition to the improvements in median and 12-month overall survival, the advantage with elraglusib was maintained beyond 1 year, Mahalingam reported, with a 2-year overall survival rate of 12.9% with the combination therapy compared with GnP alone.

Vishwanath Sathyanarayanan, MD, ASCO expert in gastrointestinal cancers, called the data “promising.”

“Metastatic pancreatic adenocarcinoma has a dismal prognosis,” said Sathyanarayanan, of Apollo Hospitals in Bangalore, India. If these data are confirmed in a phase 3 trial, he told Medscape Medical News, elraglusib plus GnP “will definitely address an unmet need.”

In terms of the phase 2 study’s secondary endpoints, progression-free survival and objective response rate were numerically better with elraglusib, but the differences were not statistically significant: Median progression-free survival was 5.6 months with elraglusib and 5.1 months with GnP alone (HR, 0.83), while the objective response rates were 28.4% and 21.8%, respectively.

Mahalingam said those findings suggest that the survival benefit with elraglusib “may not solely depend on a response that we typically expect for some studies.”

Immunophenotyping of pre- and post-dose tumor samples showed that treatment with elraglusib, but not GnP alone, was associated with an increase in CD8+ and granzyme B+ cells, which, Mahalingam said, is “suggestive of an immunomodulatory mechanism of action.”

As for adverse events, the most common side effects with elraglusib were transient visual impairment (68%), fatigue (63%), and neutropenia (any grade, 63%; grade 3 or worse, 53.5%).

Among the study’s limitations was its open-label design, which led to some patients dropping out after randomization to the GnP-only arm. In addition, median overall survival in the GnP-only group was worse than that seen in some recent trials, including NAPOLI-3 and MPACT — although, Mahalingam noted, it was in line with real-world data.

While more work is needed, he said, the survival benefit in this phase 2 study “lays the foundation for GSK-3-beta inhibition in pancreatic cancer, along with other tumor types as well.”

The study was funded by Actuate Therapeutics, Inc., and several authors disclosed having relationships with the company. Sathyanarayanan disclosed receiving honoraria from Alkem Laboratories, AstraZeneca, Glenmark, and Intas, among others.