Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that typically doesn't respond well to standard treatments. In fact, research shows only a small percentage of people with this cancer are alive five years after diagnosis.
The poor outcomes have prompted further research to better understand the disease. In recent years, scientists have learned more about gene changes, called mutations, that drive PDAC. One of the most important happens in a gene called KRAS, which belongs to the RAS family of genes.
"KRAS mutations are present in 95% of pancreatic cancers, and there are new therapies that are being actively developed to target and block KRAS signaling pathway," says Brandon Huffman, MD, an assistant professor of medicine at Harvard Medical School and a medical oncologist at Dana-Farber Cancer Institute in Boston.
These new targeted drugs set the stage for more personalized treatment strategies. Therapies may one day soon be tailored to your specific gene changes, instead of a one-size-fits-all approach.
What Are the Standard Treatment Options for PDAC With RAS Mutations?
Though there's much excitement about targeted drugs, standard treatments, like chemotherapy, and sometimes surgery or radiation, are still the main approaches used for PDAC.
"For most patients with KRAS-mutated PDAC, systemic therapy remains the backbone of treatment," says Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center.
Chemotherapy
Pant says chemotherapy is typically the first-line therapy if you have PDAC, with or without a KRAS mutation.
Chemo kills cancer cells in your body or controls their growth. Usually, two or more chemo medicines are given together as a combination treatment.
The chemo drugs most often used to treat PDAC are:
- FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin, and leucovorin)
- Gemcitabine + nab-paclitaxel
Surgery
Surgery to remove your tumor is an option if the cancer hasn't spread outside of your pancreas. It's the only way to potentially cure PDAC.
The most common surgery for pancreatic tumors is called the Whipple procedure. During this operation, your surgeon removes:
- Parts of your pancreas
- Intestine
- Lymph nodes
- Gallbladder
- Bile duct
- Parts of your stomach (sometimes)
Radiation therapy
Doctors may suggest radiation therapy to treat certain PDAC tumors. It can be done to shrink tumors before surgery or to ease pain.
This treatment uses high-energy X-rays to target tumors.
Different types of radiation are used. The one your doctor chooses will depend on your tumor and treatment goals.
What Targeted Therapies Are in Development?
Pant says there are multiple KRAS-targeted therapies in clinical and preclinical development. Targeted drugs focus on proteins in cancer cells. Unlike traditional chemo, they only zero in on these specific proteins, so they don't kill both cancerous and healthy cells.
You will likely need to take part in a clinical trial to receive one of these targeted medicines. Or your doctor can prescribe one off-label. That means you can take the drugs for a purpose they weren't officially approved to treat.
Before you enroll in a trial, you'll need to have your tumor tested to find out exactly what type of KRAS mutation, if any, you have.
"There are multiple variants of KRAS mutations, such as KRAS G12, G12V, G12R, G12C, G13D, Q161H, etc.," Huffman says.
To test for mutations, doctors can remove a small piece of tissue from your tumor via a biopsy. Or they can perform a special blood test. If you test positive for a certain KRAS mutation, you may benefit from a medicine that's currently in development.
"We have limited publicly available targeted KRAS inhibitors that slow the growth of cancer," Huffman says.
Though there are only a few options available right now, these medicines have opened the door for more breakthroughs. This is a big deal because KRAS mutations were once considered "undruggable."
Targeted drugs
Some key KRAS-targeted drugs in development are:
- Adagrasib (Krazati) and sotorasib (Lumakras). These medicines are FDA-approved to treat lung cancers with a KRAS G12C mutation. Doctors can prescribe them off-label for PDAC with G12C changes. But only about 1%-2% of PDAC patients have this specific mutation.
- RAS(ON)/multi-KRAS inhibitors. Daraxonrasib (Rasonque) targets several KRAS mutations in pancreatic cancer. It works by blocking RAS proteins, which fuel cancer cell growth. By shutting down these proteins, daraxonrasib can slow cancer cell growth and may cause cancer cells to die. Early studies have shown promising results. "What we know from a press release from the company who manufactures the drug is that the median survival when using daraxonrasib was 13.2 months, compared to 6.7 months with standard chemotherapy, which effectively reduces the risk of death by 60%," Huffman says. On August 26, 2026, the FDA approved daraxonrasib (Rasonque) for adults with metastatic PDAC who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. It is the first RAS inhibitor to receive FDA approval.
- Direct KRAS G12D inhibitors. The medicine MRTX1133 is the first to specifically block the KRAS G12D defect. This mutation is in about 45% of pancreatic cancer tumors. MRTX1133 and other medicines like it are currently being tested in clinical trials.
- G12 degrader drugs. Setidegrasib (ASP3082) breaks down and removes the KRAS protein, instead of blocking it. In a small trial, 24% of patients with PDAC who took setidegrasib saw their tumors shrink.
What New Treatments Are on the Horizon?
There are many new emerging treatments for PDAC with KRAS mutations. More than 60 RAS drugs are in development.
Some of these novel drugs under study work like daraxonrasib, targeting multiple RAS proteins at once. Others block the activation of KRAS or cut off special signaling pathways that KRAS uses.
Scientists are also testing an mRNA vaccine for PDAC with KRAS mutations. The vaccine is designed to train your immune system to identify and attack cancer cells that carry a KRAS mutation. It's still in the experimental stages, but early trials have shown positive findings. Results from a phase 1 study found that nearly 90% of people who had an immune response to the vaccine were alive up to six years after their last treatment.
Takeaways
PDAC is a cancer that's known for being hard to treat. But innovative therapies that target the KRAS mutation represent a new advancement in treatment. You can access some of these medicines if you take part in a clinical trial. Or your doctor can prescribe an FDA-approved targeted drug off-label. The hope is that scientists will fine-tune how these medicines work and that they will soon become more widely available to people with PDAC.
Show Sources
Photo Credit: iStock/Getty Images
SOURCES:
Brandon Huffman, MD, assistant professor of medicine, Harvard Medical School; medical oncologist, Dana-Farber Cancer Institute, Boston.
Shubham Pant, MD, MBBS, professor, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center.
World Journal of Gastrointestinal Oncology: "Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy."
Pancreatic Cancer Action Network (PanCAN): "Pancreatic Cancer Diagnoses and Mortality Rates Climb; Five-Year Survival Rate for Pancreatic Cancer Stalls at 13%," "RAS Mutations and Pancreatic Cancer," "5 Things to Know About Targeting Mutant KRAS in Pancreatic Cancer," "PanCAN Statement on Positive Overall Survival Results from Revolution Medicines Phase III Trial."
Dana-Farber Cancer Institute: "RAS and Pancreatic Cancer: What You Need to Know."
Biomedicines: "Targeted Therapies in Pancreatic Cancer: A New Era of Precision Medicine."
UT MD Anderson Cancer Center: "Pancreatic Cancer Treatment."
Johns Hopkins Medicine. "Radiation Therapy for Pancreatic Cancer."
Journal of Clinical Oncology: "Exploring predictive factors for detecting KRAS mutations in pancreatic cancer using liquid biopsy."
The Lancet Oncology: "Undruggable KRAS – time to rebrand?"
Lustgarten Pancreatic Cancer Research: "From Undruggable to Unstoppable: The State of KRAS Drug Development in Pancreatic Cancer."
The New England Journal of Medicine: "Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer."
UCLA Health: "Targeted therapy drug shows early promise against KRAS-driven lung and pancreatic cancers."
PNAS: "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction."
International Review of Cell and Molecular Biology: "Targeting KRAS and SHP2 signaling pathways for immunomodulation and improving treatment outcomes in solid tumors."
Memorial Sloan Kettering Cancer Center: "Investigational Pancreatic Cancer Vaccine Shows Lasting Results in Early Trial, Supporting Continued Testing."
