Pancreatic Cancer: A Treatment History and New Hope

Posted in Announcements

Inspired by a Recent Grand Rounds Presentation by the Ruesch Center’s Ben Weinberg, MD.

By Marion Hartley, PhD

A Survival History

Five-year survival for pancreatic cancer—for all stages combined—was only about 3% in the 1970s, and has improved to only roughly 13% today. Progress still lags far behind that of other cancers. (Figure 1)

Why is Pancreatic Cancer a Leading Cause of Cancer-Related Death? 

There is no effective early screening test. Most patients are diagnosed at advanced stages, when surgery—the only potential cure—is usually not possible. 

However, surgery alone yields a 5-year survival rate of only about 29%, and the median survival is less than 2 years. 

Better treatments are needed for both resectable and advanced/metastatic disease.

Pancreatic Cancer Treatment 

The pancreas is a busy area of the body. It is right underneath the stomach, right near all these very important blood vessels and nerves. Whether a tumor can be surgically removed depends mainly on its proximity to major blood vessels. Specialized surgeons, such as those at MedStar Georgetown University Hospital, may operate in cases that others consider inoperable. 

Resectable tumors have no contact with arteries or very little contact with veins. Traditionally, these patients underwent surgery first, followed by chemotherapy (adjuvant therapy) to clean up remaining cancer cells. However, pancreatic surgery is highly invasive, and more than half of patients experience severe complications or rapid cancer recurrence, leaving them too weak ever to receive post-surgical chemotherapy.

Borderline resectable tumors have some vessel involvement and may become operable after additional therapy. 

Locally advanced unresectable tumors are more than halfway wrapped around the artery and veins. Patients with locally advanced unresectable tumors are treated with chemotherapy, with a potential role for radiation, and maybe a few will respond well enough to this treatment that they become surgical candidates. Treatment mostly follows that for incurable metastatic disease.

Metastatic disease, up until last month, was treated mostly with chemotherapy, and sometimes some palliative radiation. FOLFIRINOX extends patient survival to 1 year. Gemcitabine/nab-paclitaxel provides less survival benefit than FOLFIRINOX but is a good option if patients cannot tolerate aggressive therapy. 

Adjuvant vs. Neoadjuvant therapy

To improve outcomes of patients with resectable tumors or borderline resectable tumors, chemotherapy is now often given before surgery (neoadjuvant) instead of only after (adjuvant).

The benchmark neoadjuvant chemotherapy is the powerful drug combination FOLFIRINOX, although Gemcitabine plus Nab-Paclitaxel is an alternative for those who cannot tolerate FOLFIRINOX. 

The adoption of neoadjuvant chemotherapy offers several major benefits: It hits the cancer early, and patients receive treatment when they are at their strongest and healthiest, enabling them to undergo potentially curative surgery; it can shrink difficult tumors, making them much easier and safer for surgeons to fully remove. In borderline resectable cases, the standard neoadjuvant treatment involves chemotherapy, sometimes with radiation therapy.  Neoadjuvant therapy raises the five-year survival rate to 20–21%, compared to 6.5% for upfront surgery.

There is concern that giving a few months of chemotherapy before surgery might make patients miss their opportunity for surgery if they don’t respond to the therapy. Therefore, the Ruesch Center is currently participating in an ongoing national clinical trial [NCT04340141] comparing 4 months of chemotherapy, followed by surgery, followed by another 2 months of chemotherapy, versus upfront surgery followed by 6 months of chemotherapy.  This should determine whether we should be giving chemotherapy to patients who could go straight to surgery.

Further Improving Response to Surgery 

Several investigations are underway. For example, early studies—some of which the Ruesch Center is involved in—are testing cancer vaccines, including personalized mRNA and off-the-shelf vaccines, for patients with early-stage, resectable tumors. It seems that those who respond may have fewer recurrences of cancer after surgery.

Improving Advanced and Metastatic Cancer Treatment

KRAS is the major signaling pathway, and 90% to 92% have a KRAS mutation. However, other mutations are at play. For example, about 5–7% of patients have mutations in DNA repair genes (like BRCA1/2), making them sensitive to platinum-based chemotherapy and PARP inhibitors. Rare mutations, such as NRG1 fusions, also have targeted therapies.

Drugging the Undruggable: Daraxonrasib

The highlight of Dr. Weinberg’s talk and the cancer community was the landmark FDA approval of daraxonrasib (brand name Rasonque), an oral, first-in-class, multi-selective RAS(ON) inhibitor. 

For decades, KRAS was considered “undruggable”—until now!

Daraxonrasib uses a unique mechanism to block cancer-driving RAS signals, and in the “RASolute 302” global phase 3 trial, daraxonrasib doubled the median survival compared with standard chemotherapy in previously treated patients with metastatic pancreatic cancer (13.2 vs. 6.7 months) (Figure 2).

The remarkable reduction in the risk of death was so exciting after so many years of virtually no meaningful progress that when the results were presented at this year’s American Society of Clinical Oncology annual meeting, it drew a standing ovation!

Beyond second-line use, the FDA label includes a critical provision allowing daraxonrasib to be used in the first-line setting for patients who are unfit for or unable to tolerate multi-agent intravenous chemotherapy.

What’s Next: Overcoming Resistance and Combination Cocktails

While Daraxonrasib marks a historic leap, Dr. Weinberg emphasized that the journey is far from over. Daraxonrasib is not without side effects, and resistance eventually develops—most commonly through KRAS gene amplification or reactivation of its downstream pathways, such as the MAPK pathway.

To build on this foundation, ongoing research at institutions like Georgetown is focusing on new targeted combinations, such as combining RAS inhibitors with mutant-selective drugs (e.g., KRAS G12D inhibitors). Other strategies include modification of the tumor’s stroma (surrounding environment) and immunotherapy: Preclinical model experiments led by Georgetown Lombardi’s Dr. Louis Weiner demonstrate that pairing daraxonrasib with stroma-modifying agents (such as BioXcel 701) and immune checkpoint inhibitors (such as pembolizumab) increases immune cell (T cell and NK cell) infiltration into the tumor, which creates durable immune memory. In preclinical studies, Dr. Weiner’s team is also engineering NK cells (natural killer cells) to release enzymes that can break down the dense wall of scar tissue surrounding pancreatic tumors called fibrosis and eat it away” [Marwa Afifi, PhD].

Other potential pancreatic cancer treatments include the drug proglumide, an extremely well-tolerated medicine traditionally prescribed for peptic ulcers and gastritis, which is being tested in clinical trials at the Ruesch Center [Dr. Jill Smith, MD].

Summary 

With Daraxonrasib’s approval, pancreatic cancer has officially entered the era of precision targeted therapy. Doctors now have access to a powerful targeted weapon against the core driver of pancreatic cancer, bringing long-awaited hope to patients and doctors alike.

FIGURE 1

Figure 1. Trends in 5-year relative survival rates across selected cancer types, 1975 era (blue bars) vs. 2025 era (green bars). This bar chart contrasts historical and modern-day clinical outcomes for seven distinct malignancies, illustrating a 50-year trajectory of oncology progress.

All data are sourced from population-based registries within the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program.

FIGURE 2

Figure 2. Survival Breakthrough for Patients with Metastatic Pancreatic Cancer (1970–2026).

For decades, standard treatments provided only a few months of life: an average of 3.0 months from the 1970s through the 1990s and roughly 6.0 months with modern combination chemotherapy. However, a landmark 2026 clinical trial showed that the new oral drug daraxonrasib nearly doubled patient survival to an unprecedented 13.2 months, compared to 6.7 months for those who stayed on standard chemotherapy.

Source: Historical oncology benchmarks and data from the Phase III RASolute 302 clinical trial (published in The New England Journal of Medicine, 2026).