A Breakthrough in Pancreatic Cancer Therapy: The Triple-Drug Strategy

Pancreatic cancer remains one of the most lethal malignancies in modern oncology, characterized by late diagnosis, aggressive biology, and profound resistance to conventional therapies. Despite decades of research, five-year survival rates have remained stubbornly low, underscoring the urgent need for innovative treatment approaches. Against this bleak backdrop, a groundbreaking study led by Mariano Barbacid at the Spanish National Cancer Research Centre (CNIO) has offered a rare and compelling glimpse of hope. The study demonstrated that a newly designed triple-drug therapy was able to completely eradicate pancreatic tumors in preclinical models, with no evidence of relapse after treatment cessation. In the study led by Mariano Barbacid, researchers tested a novel triple-drug therapy that completely eliminated pancreatic tumors in mouse models with no relapse observed after treatment — a rare and promising outcome in pancreatic cancer research. The three drugs used in the combination were:

1) Daraxonrasib – an experimental inhibitor targeting the KRAS oncogene pathway, which is mutated in the vast majority of pancreatic cancers.
2) Afatinib – an approved drug that inhibits ERBB family kinases, used in certain lung cancers and here applied to block a key upstream signaling pathway that helps pancreatic tumors grow.
3) SD36 – a research compound that functions as a proteolysis targeting chimera (PROTAC) to degrade the STAT3 protein, a signaling molecule that can enable tumors to escape from targeted therapies.

By combining these three agents — each attacking different molecular routes the cancer cells rely on — the therapy prevented resistance and led to sustained tumor regression after the treatment ended in the animal models. The significance of this finding lies not only in tumor regression, but in the durability of the response. Pancreatic ductal adenocarcinoma (PDAC) is notorious for recurring even after initially successful treatment, driven by complex molecular pathways, dense stromal barriers, and therapy-resistant cancer cell populations. Barbacid’s team approached this challenge by targeting multiple, complementary signaling mechanisms simultaneously. Rather than relying on a single molecular target—an approach that has repeatedly failed in pancreatic cancer—the triple-drug regimen was designed to block parallel survival pathways that tumors use to escape therapeutic pressure.

At the core of this strategy was a deep understanding of oncogenic KRAS signaling, a hallmark mutation present in the vast majority of pancreatic cancers. While KRAS itself has historically been considered “undruggable,” the CNIO team focused on inhibiting key downstream effectors and cooperating pathways essential for tumor maintenance. By combining three agents with distinct but synergistic mechanisms of action, the therapy effectively dismantled the tumor’s ability to adapt, survive, and regenerate. The result was not merely tumor shrinkage, but complete tumor elimination in experimental models.

Equally striking was the absence of relapse following treatment withdrawal. In oncology, especially in pancreatic cancer, relapse is often considered inevitable due to residual disease or dormant cancer stem cells. The lack of tumor recurrence in this study suggests that the therapy may be capable of eliminating not only bulk tumor cells, but also the subpopulations responsible for long-term disease persistence. This finding challenges long-held assumptions about the biological inevitability of recurrence in pancreatic cancer and opens the door to the possibility of durable remission—or even cure—in a disease long thought to be incurable.

Beyond its immediate scientific impact, this study also has broader implications for the future of cancer drug development. It reinforces the growing recognition that complex cancers require equally sophisticated treatment strategies. Rationally designed combination therapies, grounded in molecular biology rather than trial-and-error chemotherapy pairing, may represent the next frontier in oncology. Moreover, the work exemplifies the power of translational research, where decades of fundamental cancer biology are directly leveraged to produce clinically meaningful advances.

While further validation and human clinical trials are necessary before this therapy can be applied in clinical practice, the results reported by Barbacid and colleagues mark a pivotal moment in pancreatic cancer research. For patients, clinicians, and researchers alike, this study offers something that has long been in short supply in the field: credible optimism. If these findings translate successfully to humans, they could redefine the therapeutic landscape of pancreatic cancer and serve as a model for tackling other treatment-resistant malignancies.