A New Drug Just Changed The Conversation Around Pancreatic Cancer — And Experts Say This Is Only The Beginning

“With this new therapy, we now can double the length of their lives,” Dr. Diane Simeone, director of the Moores Cancer Center at UC San Diego Health, tells SurvivorNet. “This is really a first-generation RAS therapeutic, but now we can build upon this — perhaps move this kind of therapy into first line, and probably most importantly, figure out what are the best combinations with this therapy that will provide even more durable responses for patients.”

Researchers at ASCO, the largest cancer conference in the world, presented the results of a landmark clinical trial testing daraxonrasib in patients with advanced pancreatic cancer. The trial, called RASolute 302, compared daraxonrasib directly against standard second-line chemotherapy in 500 patients whose cancer had progressed after an initial treatment.

The results, published simultaneously in the New England Journal of Medicine, showed that patients taking daraxonrasib lived twice as long as those receiving chemotherapy. Median overall survival was 13.2 months with daraxonrasib, compared to 6.6 months with chemotherapy: a 60% reduction in the risk of death.

For a disease where second-line chemotherapy has historically offered a median survival of around six months, that is a major improvement.

What Makes This Drug Different

To understand why researchers are excited, you need to know about a gene called KRAS.

More than 90% of pancreatic cancers carry a mutation (a kind of permanent “on switch”) in the KRAS gene. When KRAS is mutated, it sends unrelenting signals to cancer cells telling them to grow and spread. For years, scientists considered KRAS essentially impossible to target with a drug. The protein was too smooth, too slippery; there was nowhere for a drug molecule to get a grip.

“KRAS is mutated in 92 to 93% of pancreas cancers, but it has been felt to be undruggable,” Dr. Simeone explains. “And by astounding work by teams of investigators using very innovative approaches, we have now been able to develop new therapies that target KRAS and are having an impact.”

About a decade ago, chemists figured out how to design drugs that could lock onto a specific version of mutant KRAS called G12C. Two of those drugs are now approved for lung and colorectal cancers. But KRAS G12C is rare in pancreatic cancer, showing up in only about 1 to 2% of cases. So those breakthroughs largely left pancreatic cancer patients behind.

Daraxonrasib works differently. Instead of targeting just one specific mutation, it blocks the active form of RAS proteins across multiple mutations, including KRAS G12D, G12V, and G12R, which together account for the vast majority of pancreatic cancer cases. It’s taken as a daily pill.

The older drugs were like a key that only opened one specific lock. Daraxonrasib is designed to work on nearly the entire lock family.

RASolute 302: Breaking Down The Data

The RASolute 302 trial enrolled 500 patients across 59 sites in six countries. All had metastatic pancreatic cancer that had progressed after one prior treatment. Half received daraxonrasib (a 300 mg pill, taken once daily at home). The other half received the oncologist’s choice of standard chemotherapy.

The results were striking across every measure that matters:

• Patients on daraxonrasib lived a median of 13.2 months, versus 6.6 months for those on chemotherapy.
• At 12 months, more than half the patients on daraxonrasib were still alive (53%), compared to fewer than 1 in 5 on chemotherapy.
• The tumor shrank or responded meaningfully in 33% of patients on daraxonrasib, versus 12% on chemotherapy.

Beyond survival, the drug also significantly delayed two things that matter enormously to patients living with this disease: pain and decline in quality of life. Patients on daraxonrasib went 9 months before experiencing meaningful worsening of pain, compared to 3.7 months on chemotherapy. For overall quality of life, the difference was 5.6 months versus 2.4 months.

“Today is step one, but a big breakthrough because we really haven’t been able to find things that are effective beyond standard chemotherapy, except in rare instances,” Dr. Simeone tells SurvivorNet.

The Side Effects: An Honest Picture

Like any cancer therapy, daraxonrasib is not without side effects.

The most common was rash, which affected about 86% of patients, a significant number, though most cases were mild. Diarrhea, mouth sores, nausea, and vomiting were also common. About 57% of patients on daraxonrasib had a treatment-related side effect that led to a dose modification, while 36% required a dose reduction. Grade 3 or higher treatment-related side effects occurred in about 44%.

Very few, just over 1%, had to stop treatment entirely because of them, compared to 11% of patients who stopped chemotherapy.

Even with side effects, patients on daraxonrasib stayed on treatment for a median of 6.2 months. Patients on chemotherapy stayed on for roughly 1.5 to 3 months, depending on the regimen.

“The tough thing is there are side effects that come with these drugs — pretty significant rash, and there can be GI side effects, nausea, which can be debilitating for some patients. So I think as we develop second and third generations of this class of drugs and try to mitigate some of these side effects, that’s going to be very helpful for patients,” Dr. Simeone explains.

Importantly, the data also showed something that matters a great deal for quality of life. Daraxonrasib caused far less peripheral neuropathy (the painful nerve damage that plagues many patients on platinum-based regimens)  than chemotherapy: 1.7% versus 25.2% and caused far less anemia and neutropenia than chemotherapy.

What The Trial Results Mean For Patients

Daraxonrasib is not yet approved by the FDA. It’s still in clinical trials, and the phase 3 results presented at ASCO will be a key part of any future approval decision.

If you have advanced pancreatic cancer and haven’t yet had genetic testing done on your tumor, ask your oncologist about it. Molecular testing (sometimes called biomarker testing or next-generation sequencing) can identify which KRAS mutation your cancer carries. That information matters, both for understanding your disease and for determining eligibility for trials like RASolute 302 and others that are currently enrolling.

Clinical trials are worth asking about. The RASolute 302 trial is ongoing at sites across the country. Your oncologist can tell you whether you might qualify.

Finally, the broader meaning of what happened at ASCO this week goes beyond one drug. Daraxonrasib is the first RAS(ON) multi-selective inhibitor to show this kind of activity in pancreatic cancer. Several other drugs targeting RAS through different mechanisms are now entering clinical trials. The field is moving towards a genuine change in the scientific landscape.

This Is Step One

Dr. Simeone notes that she’s been working on pancreatic cancer for nearly 30 years. When she started her career as a faculty physician, the five-year survival rate was approximately 5%. Today it is 13%. Progress has been agonizingly slow, until now.

“Anything that we can bring to patients with pancreatic cancer that can change survival is amazing,” she says. “I just want to let you know: we just made a major advance, and there’s a lot more to come. We’re just starting to get a whole new level of momentum.”

The RASolute 302 results are a beginning, not an end. The same class of drugs that daraxonrasib belongs to is now being studied in combination with other agents, earlier in treatment, and in patients who haven’t yet received any therapy. If those trials confirm the same magnitude of benefit, or greater, the entire treatment landscape for pancreatic cancer could look different within a few years.

For patients living with this disease right now, the most important message from ASCO this week is that the biology that made pancreatic cancer so hard to treat for so long is finally being cracked. Not completely, not yet, but the door that was closed for thirty years is opening.

Questions To Ask Your Doctor

• Has my tumor been tested for KRAS mutations? If so, which mutation do I have?
• Am I a candidate for any clinical trials involving RAS-targeted therapies?
• Is daraxonrasib or RASolute 302 something I should consider?
• What are my current second-line treatment options, and how do they compare to what’s being studied?
• What supportive care is available if I experience side effects from a new treatment?

Learn more about SurvivorNet's rigorous medical review process.

---