At a glance
A phase 3 clinical trial has demonstrated that daraxonrasib significantly improved overall survival and progression-free survival compared to chemotherapy in patients with advanced pancreatic cancer.
It was the first large, randomized trial evaluating a RAS inhibitor to treat pancreatic cancer, one of the deadliest cancers.
RAS inhibitors, which target cancer-driving mutations once thought to be undruggable, bring new hope to patients with some of the hardest-to-treat cancers.
An international phase 3 clinical trial has found that an investigational oral medication (a daily pill) doubled the median overall survival for patients with previously treated metastatic pancreatic cancer, specifically pancreatic ductal carcinoma, compared to standard chemotherapy.
The findings — published May 31 in The New England Journal of Medicine and led by researchers at Harvard Medical School, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and the University of California — support the use of the drug daraxonrasib as the new standard of care for patients whose metastatic pancreatic cancer has progressed after initial treatment.
“It is exciting to see that we may soon be able to help patients with metastatic pancreatic cancer in ways we haven’t been able to before, improving both survival and quality of life,” said senior author Brian Wolpin, HMS professor of medicine at Dana-Farber, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber, and principal investigator of the trial.
While the drug is not yet FDA-approved, the agency previously granted it Breakthrough Therapy status and included it in the National Priority Voucher program to accelerate its review. The FDA also recently allowed patients to enroll in an expanded access protocol.
A tough cancer to treat
Pancreatic ductal adenocarcinoma is the most common and aggressive type of pancreatic cancer, accounting for more than 90 percent of cases. Patients and their doctors often discover the disease after it has metastasized. The current standard of care for most patients is chemotherapy. Many cases prove resistant to the therapy, and a second-line standard-of-care chemotherapy often provides only modest benefit. Few patients survive beyond one year after diagnosis.
The American Cancer Society estimates that nearly 68,000 people in the United States will be diagnosed with pancreatic cancer in 2026 and nearly 53,000 people will die from it.
More than 90 percent of patients with pancreatic cancer have cancer-driving mutations in the KRAS gene, which is in a family of genes known as RAS. Daraxonrasib is a RAS inhibitor; it works like a molecular glue that, together with another protein called cyclophilin A, blocks the signaling of RAS proteins.
After decades of effort, only in the last few years have researchers been able to develop drugs that successfully block one or more RAS mutations. Fundamental discoveries from the lab of Gregory Verdine, the Erving Professor of Chemistry, Emeritus, at Harvard University, contributed to this achievement.
The global phase 3 trial of daraxonrasib, called RASolute 302, was the first to evaluate a RAS inhibitor in a large, randomized trial for patients with pancreatic cancer. It enrolled 500 patients with metastatic pancreatic ductal adenocarcinoma in North America, Europe, and Asia who had already received one round of chemotherapy. Patients were randomized to receive daraxonrasib or a second line of chemotherapy.
Unlike standard chemotherapy, which is administered with intravenous infusions, daraxonrasib is given as a daily oral treatment.
Patients who received daraxonrasib showed meaningful improvements in overall survival compared to those treated with chemotherapy, regardless of RAS mutation status. Those receiving the oral medication lived a median of 13.2 months compared to 6.7 months for those on chemotherapy.
Researchers also observed a reduction in the risk of cancer progression, with a median progression-free survival of 7.2 months among patients on daraxonrasib versus 3.6 months for the chemotherapy group.
Among patients taking the oral medication, 31.6 percent experienced substantial tumor shrinkage or disappearance compared to 11.2 percent of those receiving chemotherapy.
The drug was generally well tolerated with a manageable safety profile and no unexpected safety findings.
“For many years we have wanted to block mutant RAS to treat pancreatic cancer because KRAS mutations are so common in this disease and serve as a main driver for pancreatic cancer growth in the laboratory,” said Wolpin. “These results suggest that the science has guided us in a productive direction.”
Wolpin added that he expects the targeted therapy to be relevant to all patients with pancreatic cancer.
“Were this drug to be approved by the FDA,” he said, “it would mark a dramatic shift in how pancreatic cancer is treated.”
Daraxonrasib is also being trialed in patients with non-small cell lung cancer and could be relevant for patients with colorectal cancer.
Targeting the tumor microenvironment
Beyond the RAS inhibitor, Wolpin and colleagues at Dana-Farber have been busy testing other innovative ways to tackle pancreatic cancer. A small clinical trial published May 25 in Nature Cancer found that activating the vitamin D receptor can help reshape the protective environment surrounding pancreatic tumors in ways that could make the cancer more vulnerable to therapies.
In the trial — co-led by Wolpin and based on foundational research from the Salk Institute — patients with previously untreated metastatic pancreatic cancer received standard chemotherapy with or without paricalcitol, a vitamin D analog that is already FDA-approved for other uses. In patients who received paricalcitol orally or intravenously, the combination was found to be safe and to reduce activation of fibroblasts in the tumor microenvironment.
The trial was not intended to measure how well the approach works in treating pancreatic cancer, yet the researchers noted improved chemotherapy responses and increased progression-free survival at one year among patients who received paricalcitol plus chemotherapy. In addition, they found that patients with high vitamin D receptor expression and who received paricalcitol had the longest overall survival.
The findings set the stage for larger clinical studies designed to evaluate how combining vitamin D analogs with chemotherapy or other cancer therapies impacts survival outcomes.
More cancer research highlights
Wolpin presented the results of the daraxonrasib trial on May 31 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, where the news received a standing ovation. The conference featured reports on other significant findings led by HMS researchers and published in peer-reviewed journals.
For example, Adam Kibel, the HMS Elliott Carr Cutler Professor of Surgery at Brigham and Women’s Hospital, and Mary-Ellen Taplin, HMS professor of medicine at Dana-Farber, presented results from a global phase 3 trial for high-risk localized and locally advanced prostate cancer, published May 31 in The New England Journal of Medicine. The trial found that treating patients with the drug apalutamide plus hormone therapy before and after surgery reduced the risk of metastasis or death by 20 percent. The new approach helped delay the need for subsequent treatments by 33 months.
Adapted from a Dana-Farber news release.
Authorship, funding, disclosures
Eileen M. O’Reilly of Memorial Sloan Kettering and Zev A. Wainberg of the UCLA Jonsson Comprehensive Cancer Center are co-first authors. Additional authors include Andrew E. Hendifar, Mitesh J. Borad, Filippo Pietrantonio, Shubham Pant, Pascal Hammel, Chiara Cremolini, Gulam A. Manji, Paul E. Oberstein, Ignacio Garrido-Laguna, Christoph Springfeld, Nilofer S. Azad, Makoto Ueno, Stephen Y. Chui, Ying Zhang, Hina Patel, Yeonju Lee, Zeena Salman, and the RASolute 302 trial investigators.
This study was supported by Revolution Medicines, the company that developed daraxonrasib.
A full list of disclosures can be found in the paper.
