Italy recorded an estimated 13,585 new cases of pancreatic cancer in 2024, and more than 90% of them were pancreatic ductal adenocarcinoma (PDAC). With five-year survival of 11% in men and 12% in women, it is one of the hardest cancers to treat. Diagnosis often comes late, because the symptoms are vague or non-specific, and existing treatments have limited efficacy.
Michele Reni uses the image of an iceberg to describe PDAC. Reni is associate professor of Medical Oncology at Vita-Salute San Raffaele University (UniSR) and directs the strategic clinical coordination programme of the Pancreas Center at IRCCS San Raffaele Hospital, a research hospital recognised by the Italian Ministry of Health. “Standard imaging only sees the visible part of the disease, and we don’t know its real extent: most of it stays submerged, out of sight. This tumour behaves differently from others. In more than 50% of patients it already shows detectable metastases in the liver, peritoneum, lungs or distant lymph nodes at diagnosis. What sets it apart, though, is that metastases are almost always there, even when imaging cannot pick them up.”
PDAC is surrounded by a dense stroma of inflammatory cells, fibres and connective tissue that keeps T lymphocytes from getting in and attacking the tumour. This feature may also explain why immunotherapies such as immune checkpoint inhibitors, which release the brakes on T cells, fail in PDAC.
“The pathologist Aldo Scarpa describes PDAC as a scar with some cells inside it: a tumour with few cells, wrapped in a kind of tough rind. It isn’t entirely clear whether this armour is the body’s attempt to protect itself from the tumour, or a shield the tumour builds against the immune system. What we know is that attempts to break it down have failed more than once and, in some cases, made the disease more aggressive,” says Reni. All of this means that treatment options for PDAC are still limited. Chemotherapy relies on a small number of drugs, while surgery and radiotherapy are only possible in selected cases.
More than 90% of pancreatic tumours carry an acquired mutation in the KRAS gene, a member of the RAS family. KRAS encodes a protein that normally regulates cell proliferation. When the gene is mutated, the protein stays permanently switched on, driving uncontrolled cell growth and, ultimately, cancer. Researchers have tried many times to find drugs that target this mechanism, without success. Most drugs work by binding to a precise spot on their target, such as a cavity or “pocket” in its structure, and blocking it, much as a doorstop keeps a door from closing. RAS, however, has a fairly smooth surface, so it is hard for a drug to latch on and block it.
An important step towards targeting RAS came in May 2026 at the annual meeting of the American Society of Clinical Oncology (ASCO), with the presentation of daraxonrasib, a new RAS inhibitor for people with metastatic PDAC refractory to first-line therapy, meaning their disease had not responded to the first treatment they received. In a phase 3 trial of 500 patients published in the New England Journal of Medicine, daraxonrasib nearly doubled median overall survival, to 13.2 months compared with 6.7 months for chemotherapy alone. In other words, about half of the patients who received the drug were still alive after 13.2 months, while half of those who received chemotherapy alone were still alive after 6.7 months.
The oncology community worldwide welcomed the phase 3 result, and daraxonrasib has become an additional tool for blocking the mechanism behind most metastatic PDAC. In August 2026, the US Food and Drug Administration (FDA) approved daraxonrasib for people with metastatic PDAC who have not responded to at least one systemic therapy or who cannot receive systemic combination therapy, that is, several drugs given together.
The European Medicines Agency (EMA) launched a phased review of daraxonrasib in July 2026, assessing the data as they become available in order to shorten the evaluation. In October 2026, its Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorisation for adults with metastatic PDAC who have already received at least one systemic therapy. The final decision, which makes the authorisation valid across the European Union, now rests with the European Commission.
“RAS inhibition with daraxonrasib marks the beginning of a change in the treatment of pancreatic cancer, a disease that has historically resisted many types of therapy,” says Reni, who has published a commentary on the drug’s potential in Med. These results matter, but they need to be read with caution. The data published in the New England Journal of Medicine come from an interim analysis, carried out before the trial’s results had fully matured, and patients have been followed for only a short time: too short to tell whether the drug changes the long-term course of the disease.
The control group, against which the patients receiving the drug were compared, is also methodologically weak. “Fifteen per cent of the patients assigned to chemotherapy did not actually receive any treatment. Most of those in the chemotherapy group also received regimens that are not supported by scientific evidence. This trial design, together with the short follow-up, does not allow definitive conclusions about the full potential of daraxonrasib. We need more mature data to understand how far this drug can change the course of the disease, or whether the disease will quickly become resistant to it, as has already happened with other RAS inhibitors. It’s likely that PDAC treatment will eventually combine RAS inhibitors such as daraxonrasib with chemotherapy and other options,” Reni explains.
Reni has been searching for new treatments for pancreatic cancer for more than thirty years, with practical support from patient associations such as Codice Viola and My Everest. This work led to PAXG, a treatment regimen based on four chemotherapy drugs, whose results in resectable and borderline resectable PDAC were presented at the 2025 ASCO annual meeting and later published in The Lancet. The phase 3 CASSANDRA trial compared PAXG with mFOLFIRINOX, the standard chemotherapy for pancreatic cancer, given before surgery.
“Compared with mFOLFIRINOX, PAXG extended event-free survival. Three years after the start of treatment, the proportion of patients free of relapse, progression or other treatment failure was more than double that seen with mFOLFIRINOX,” says Reni, who is now taking this research further with a new project, Loch Ness. The name refers to the hidden part of the disease that remains after surgery: invisible cells that can resurface as a recurrence. “The study is aimed at patients who have had surgery after PAXG. It will compare low-dose maintenance therapy with the current practice of giving no further treatment once combined chemotherapy and surgery are complete. It doesn’t assume that the problem is solved and the tumour completely removed. It tries to intervene before the disease becomes visible again.”
Reni also leads the GIOTTO project, dedicated to people aged 75 to 85, who are often under-represented in clinical trials on this disease. The aim is to identify the most suitable chemotherapy for this age group, taking into account the impact of treatment on people’s quality of life as well as on the tumour itself.
Alongside conventional clinical trials of drugs and therapies, Reni works to improve the management of patients with pancreatic cancer and to make it as timely as possible. One example is the ANITA observational registry, which he set up in around forty Italian centres under the aegis of the Associazione Italiana per lo Studio del Pancreas (Italian Association for the Study of the Pancreas) to collect data on treatment outcomes in clinical practice and understand where disease management could improve.
“The question we ask ourselves is this: why can the same treatment give different results depending on how it is administered and how early the problems caused by the disease or the therapy are identified? To answer it, you need a multidisciplinary approach in the true sense of the word, starting with the patient’s medical history. Oncologists have to ask: is the patient eating? Are they losing weight even though they eat? What are their stools like? These are not strictly oncological questions.” Yet the answers help build the most complete clinical picture possible, so that doctors can choose the chemotherapy regimen best suited to each person and their disease.
Another example is the stent, a small tube placed in a patient’s bile ducts when the tumour presses on them and blocks them. Oncologists need to bear in mind that the stent can itself become blocked or infected: it therefore has to be monitored with blood tests, and dialogue with the endoscopist, the specialist who places it, is essential. “These precautions make it possible to act quickly on any complications and avoid hospital admissions, long breaks in treatment and further growth of the disease. They are details you won’t find in university textbooks, but they make the difference in treatment.”
With this in mind, Reni’s team supports the Pancreatic Oncology Preceptorship, backed by the Fondazione Paola Marella. The programme aims to build an oncology community of professionals from small and medium-sized centres, who spend a week alongside colleagues at larger centres that treat more cases of pancreatic cancer. The goal is to make effective care widely available and closer to patients’ homes, reaching people in areas without large hospitals so that they do not have to travel.
Working with difficult tumours such as PDAC is demanding, professionally and personally. Anyone who chooses this path, and anyone who wants to practise medicine in general, must hold on to the deep humanity of the profession. They also need to keep a healthy critical spirit and not passively accept academic dogma simply because that’s how it’s always been done. Clinical guidelines are indispensable for guiding the medical community and reaching shared decisions based on the best scientific evidence available at a given time. “But we must always remember that guidelines are written by people. And people, whatever their profession or level of education, bring with them biases, errors and conflicts of interest. That’s why I give students who want to study medicine three pieces of advice: build and cultivate critical thinking; train your attention to detail, perhaps even by reading detective novels, and if something in a patient’s clinical picture doesn’t add up, don’t dismiss it out of hand. And above all, before you put on the white coat, try putting yourself in the shoes of the person in front of you. Protect your humanity,” Reni concludes.
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