{"id":"pancreatic-roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/","eras":[{"era":"1935-1980","title":"One operation, and still the only cure","description":"Whipple, Parsons and Mullins described removal of the pancreatic head and duodenum for ampullary cancer in 1935; Traverso and Longmire preserved the pylorus in two patients in 1978 and in their 1980 follow-up of 18 found every patient had pancreatic exocrine insufficiency and needed intensive enzyme replacement. Ninety years on, surgery is the only treatment that cures pancreatic cancer, about one patient in five presents with disease that can be removed, and operative mortality fell through centralisation into high-volume centres rather than through any change in what is removed. The enzyme problem Traverso recorded is still under-treated (Roberts 2019).","status":"historic","refs":[{"id":"paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935","kind":"paper","name":"Treatment of carcinoma of the ampulla of Vater","route":"/key-papers/paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935/","tldr":"The 1935 report in which Allen Whipple and two colleagues described removing the head of the pancreas and the duodenum for cancer at the junction of the bile duct and bowel, the operation that still carries his name and remains the only route to cure."},{"id":"paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978","kind":"paper","name":"Preservation of the pylorus in pancreaticoduodenectomy","route":"/key-papers/paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978/","tldr":"The 1978 report of two patients in whom the surgeons kept the stomach outlet intact during the Whipple operation, the modification most surgeons now use."},{"id":"whipple","kind":"term","name":"Whipple procedure (pancreaticoduodenectomy)","route":"/terms/whipple/","tldr":"The big operation for cancers of the head of the pancreas: the surgeon removes the pancreatic head, the duodenum, the gallbladder and part of the bile duct, then reconnects everything."},{"id":"resectability","kind":"term","name":"Resectable, borderline resectable and unresectable","route":"/terms/resectability/","tldr":"The surgeon's verdict on whether the tumour can be completely removed. Resectable means yes; unresectable means it has wrapped around vital vessels, is too extensive or the patient is too frail; borderline means maybe, especially after chemotherapy shrinks it."},{"id":"robotic-surgery","kind":"technology","name":"Robotic & minimally invasive surgery","route":"/technologies/robotic-surgery/","status":"standard-of-care","tldr":"Surgeons operate through small incisions using robotic arms with tremor-free precision and 3D vision."},{"id":"surgery-roadmap","kind":"roadmap","name":"Surgery roadmap: radical operations → less surgery → no surgery when a drug has done the work","route":"/roadmaps/surgery-roadmap/","tldr":"Surgery cures more cancers than any other treatment. Its story for a century has been learning how much can safely be left in, and now whether the operation is needed at all once drugs and radiation have cleared the tumour."},{"id":"b-surgery-radiation-innovation","kind":"bottleneck","name":"Surgery and radiotherapy cure most, get least","route":"/bottlenecks/b-surgery-radiation-innovation/","tldr":"Surgery and radiotherapy cure more people than drugs do, but attract a fraction of the research investment."},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/","tldr":"Almost every pancreatic tumour carries a KRAS mutation, and for the first time drugs against it work: daraxonrasib nearly doubled survival in previously treated disease in 2026. Pancreatic cancer has been the hardest common cancer to treat once advanced; that is what is starting to change."}],"trials":[],"papers":[{"id":"paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935","name":"Treatment of carcinoma of the ampulla of Vater","route":"/key-papers/paper-whipple-carcinoma-ampulla-of-vater-ann-surg-1935/","journal":"Annals of Surgery","year":1935,"whatItMeans":"Every treatment on this roadmap is either a way to reach this operation, a way to make it work better, or a substitute for patients who cannot have it."},{"id":"paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978","name":"Preservation of the pylorus in pancreaticoduodenectomy","route":"/key-papers/paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978/","journal":"Surgery, Gynecology and Obstetrics","year":1978,"whatItMeans":"The pylorus-preserving Whipple became the standard variant, and the 1980 follow-up is an early record of the exocrine insufficiency that still goes untreated in most patients today."}]},{"era":"1979-1988","title":"A blood marker with a blind spot and an oncogene in nearly every tumour","description":"CA 19-9, the serum marker still used to follow the disease, was shown by Tempero and colleagues in 1987 to be unmakeable by patients who lack the Lewis blood group antigens, so a normal value never rules the cancer out; Fahrmann's 2021 pre-diagnostic study later showed it rises about two years before diagnosis and catches half of early cases at 99 percent specificity. In 1988 Almoguera and Perucho found KRAS codon 12 mutations in 21 of 22 exocrine pancreatic carcinomas, present in primary and metastasis alike: the single most uniform driver in any common cancer, and for 33 years an undruggable one.","status":"historic","refs":[{"id":"paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","kind":"paper","name":"Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer","route":"/key-papers/paper-tempero-ca19-9-lewis-antigens-cancer-res-1987/","tldr":"The 1987 study showing that people who lack the Lewis blood group antigens cannot make the CA 19-9 tumour marker, so in about one patient in ten a normal blood test says nothing about the cancer."},{"id":"paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","kind":"paper","name":"Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection","route":"/key-papers/paper-fahrmann-ca19-9-lead-time-gastroenterology-2021/","tldr":"A 2021 study of stored blood from a US screening trial showing that CA 19-9 starts rising about two years before pancreatic cancer is diagnosed and catches half of early-stage cases in the final six months, so it can anchor a multi-marker early detection test."},{"id":"paper-almoguera-kras-codon-12-pancreatic-cell-1988","kind":"paper","name":"Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes","route":"/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/","tldr":"The 1988 paper that found a mutation in the KRAS gene in 21 of 22 pancreatic cancers, establishing the single most common driver in the disease and the target it took 33 more years to hit."},{"id":"ca19-9","kind":"term","name":"CA 19-9","route":"/terms/ca19-9/","tldr":"A sugar molecule shed into the blood by most pancreatic cancers; useful to follow treatment, not to screen."},{"id":"tumour-markers","kind":"term","name":"Tumour markers (CEA, LDH, chromogranin, thyroglobulin)","route":"/terms/tumour-markers/","tldr":"Substances released into the blood by some cancers that can be measured with a simple test, useful for tracking whether treatment is working or the cancer is coming back, but rarely good enough to diagnose or screen."},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/","tldr":"KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021."},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/","tldr":"KRAS, the most commonly mutated cancer gene, comes in flavours named by the exact amino acid change. G12C (common in smokers' lung cancer) was the first to get a drug; G12D dominates pancreatic and colorectal cancer and its inhibitors are arriving now."},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/","tldr":"The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position."},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/","tldr":"The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug."},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/","tldr":"Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab."}],"trials":[],"papers":[{"id":"paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","name":"Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer","route":"/key-papers/paper-tempero-ca19-9-lewis-antigens-cancer-res-1987/","journal":"Cancer Research","year":1987,"whatItMeans":"The reason a normal CA 19-9 never rules pancreatic cancer out, why Lewis-negative patients need a different marker (CA 125, CEA or CA 19-9-independent panels), and a constraint on every blood-based detection idea on this page."},{"id":"paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","name":"Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection","route":"/key-papers/paper-fahrmann-ca19-9-lead-time-gastroenterology-2021/","journal":"Gastroenterology","year":2021,"whatItMeans":"Fixes the window in which a blood test could plausibly work and shows why CA 19-9 alone is not enough: half of early cases are missed even at diagnosis, and Lewis-negative patients are missed entirely."},{"id":"paper-almoguera-kras-codon-12-pancreatic-cell-1988","name":"Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes","route":"/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/","journal":"Cell","year":1988,"whatItMeans":"The reason pancreatic cancer is the proving ground for RAS drugs: nearly every tumour depends on the same mutant protein, so a drug that works against it works for nearly every patient."}]},{"era":"1997-2010","title":"Gemcitabine, and chemotherapy after surgery","description":"Burris (1997) made gemcitabine the standard for advanced disease on a clinical benefit endpoint and a modest survival gain over fluorouracil, a standard that held for 14 years. The European adjuvant trials then settled what to do after surgery: ESPAC-1 (2004, 289 patients) found five-year survival of 21 percent with chemotherapy against 8 percent without and 10 percent with chemoradiotherapy against 20 percent without; CONKO-001 (2007, 368 patients) roughly doubled disease-free survival with six months of gemcitabine (13.4 versus 6.9 months), confirmed for overall survival in 2013; ESPAC-3 (2010, 1,088 patients) showed fluorouracil and gemcitabine equivalent. Hidalgo's 2010 review marks where the field stood before combination chemotherapy.","status":"historic","refs":[{"id":"paper-burris-gemcitabine-pancreatic-jco-1997","kind":"paper","name":"Burris 1997: gemcitabine becomes the first standard treatment for advanced pancreatic cancer","route":"/key-papers/paper-burris-gemcitabine-pancreatic-jco-1997/","tldr":"A small trial that made gemcitabine the standard chemotherapy for pancreatic cancer for the next fifteen years, on the strength of more patients feeling better on treatment and a modest gain in survival over fluorouracil."},{"id":"paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004","kind":"paper","name":"A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer","route":"/key-papers/paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004/","tldr":"The 2004 European trial that showed chemotherapy after pancreatic cancer surgery doubled five-year survival, while adding radiotherapy to the chemotherapy made survival worse, a result that split European and American practice for a decade."},{"id":"paper-conko-001-adjuvant-gemcitabine-observation-jama-2007","kind":"paper","name":"Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial","route":"/key-papers/paper-conko-001-adjuvant-gemcitabine-observation-jama-2007/","tldr":"The 2007 German and Austrian trial in which six months of gemcitabine after surgery roughly doubled the time before the cancer came back, making gemcitabine the standard after resection until 2017."},{"id":"paper-conko-001-adjuvant-gemcitabine-long-term-oettle-jama-2013","kind":"paper","name":"CONKO-001: adjuvant gemcitabine and long-term outcomes after resected pancreatic cancer","route":"/key-papers/paper-conko-001-adjuvant-gemcitabine-long-term-oettle-jama-2013/","tldr":"Six months of gemcitabine after complete removal of pancreatic cancer doubled the time to relapse and roughly doubled five-year survival, from 10 to 21 percent, in the trial that established adjuvant chemotherapy for the disease."},{"id":"paper-espac-3-fluorouracil-vs-gemcitabine-adjuvant-neoptolemos-jama-2010","kind":"paper","name":"ESPAC-3: adjuvant fluorouracil plus folinic acid versus gemcitabine after pancreatic cancer resection","route":"/key-papers/paper-espac-3-fluorouracil-vs-gemcitabine-adjuvant-neoptolemos-jama-2010/","tldr":"After surgery for pancreatic cancer, six months of gemcitabine gave the same survival as fluorouracil with folinic acid, about 23 months, with half as many serious side effects."},{"id":"paper-hidalgo-pancreatic-cancer-review-nejm-2010","kind":"paper","name":"Pancreatic cancer","route":"/key-papers/paper-hidalgo-pancreatic-cancer-review-nejm-2010/","tldr":"The 2010 New England Journal review that summarised what was known about pancreatic cancer at the end of the gemcitabine era, a year before FOLFIRINOX changed treatment."},{"id":"conko-001","kind":"trial","name":"CONKO-001","route":"/trials/conko-001/","status":"positive","tldr":"CONKO-001 was the trial that made chemotherapy after pancreatic cancer surgery routine: six months of gemcitabine doubled the time before the cancer came back and roughly doubled the share of patients alive at five years, from 10 to 21 percent."},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/","status":"approved","tldr":"A versatile chemotherapy used in pancreatic, bladder, lung, ovarian, breast and biliary cancers, in nasopharyngeal cancer, and as a bladder instillation."},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/","status":"approved","tldr":"The 1957 chemotherapy that remains the backbone of treatment for bowel, stomach, pancreatic, anal, head and neck and breast cancers, and as a cream for skin precancers."},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/","status":"standard-of-care","tldr":"Cytotoxic chemotherapy drugs (platinums, antimetabolites, microtubule agents and topoisomerase inhibitors) kill rapidly dividing cells by damaging DNA or the mitotic spindle. They still cure testicular cancer, lymphoma and leukaemia, and they are the warhead inside antibody-drug conjugates, but a narrow margin between effective and toxic doses is their limitation."},{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/","tldr":"Chemotherapy went from a poison that sometimes worked to the backbone of most cures, and is now being given more precisely: to fewer people, at better doses, and increasingly delivered inside an antibody so that it reaches the tumour and not the whole body."},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/","tldr":"Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind."}],"trials":[{"id":"conko-001","name":"CONKO-001","route":"/trials/conko-001/","outcomes":[{"endpoint":"Disease-free survival","primary":true,"unit":"months","arms":[{"name":"Adjuvant gemcitabine","value":13.4,"note":"95% CI 11.6 to 15.3; 354 patients in the intention-to-treat analysis"},{"name":"Observation","value":6.7,"note":"95% CI 6.0 to 7.5"}],"hr":0.55,"ci":[0.44,0.69],"p":"<0.001","source":"https://doi.org/10.1001/jama.2013.279201"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Adjuvant gemcitabine","value":20.7,"note":"95% CI 14.7 to 26.6"},{"name":"Observation","value":10.4,"note":"95% CI 5.9 to 15.0"}],"hr":0.76,"ci":[0.61,0.95],"p":"0.01","source":"https://doi.org/10.1001/jama.2013.279201"},{"endpoint":"Overall survival at 10 years","unit":"%","arms":[{"name":"Adjuvant gemcitabine","value":12.2,"note":"95% CI 7.3 to 17.2"},{"name":"Observation","value":7.7,"note":"95% CI 3.6 to 11.8"}],"source":"https://doi.org/10.1001/jama.2013.279201"}],"setting":"Macroscopically complete resection of pancreatic cancer in Germany and Austria: six months of adjuvant gemcitabine against observation, with disease-free survival as the primary endpoint","enrolled":368,"enrolledNote":"CONKO-001 has no ClinicalTrials.gov record; the figure is the 368 randomised in the JAMA report (354 in the intention-to-treat analysis); the trial is registered as ISRCTN34802808.","enrolledBasis":"randomised"}],"papers":[{"id":"paper-burris-gemcitabine-pancreatic-jco-1997","name":"Burris 1997: gemcitabine becomes the first standard treatment for advanced pancreatic cancer","route":"/key-papers/paper-burris-gemcitabine-pancreatic-jco-1997/","journal":"Journal of Clinical Oncology","year":1997,"whatItMeans":"This trial introduced a patient-centred composite endpoint and a drug that remained the backbone of pancreatic cancer treatment for a generation. Its small survival gain also shows how low the bar was, which is the context for the FOLFIRINOX and MPACT trials that followed."},{"id":"paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004","name":"A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer","route":"/key-papers/paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"The origin of the European position that adjuvant treatment means chemotherapy alone; CONKO-001, ESPAC-3, ESPAC-4 and PRODIGE 24 all built on it, and the role of radiotherapy remains contested (LAP07, PREOPANC)."},{"id":"paper-conko-001-adjuvant-gemcitabine-observation-jama-2007","name":"Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial","route":"/key-papers/paper-conko-001-adjuvant-gemcitabine-observation-jama-2007/","journal":"JAMA","year":2007,"whatItMeans":"The trial that made adjuvant gemcitabine standard in Europe and the control arm PRODIGE 24 and ESPAC-4 later beat."},{"id":"paper-conko-001-adjuvant-gemcitabine-long-term-oettle-jama-2013","name":"CONKO-001: adjuvant gemcitabine and long-term outcomes after resected pancreatic cancer","route":"/key-papers/paper-conko-001-adjuvant-gemcitabine-long-term-oettle-jama-2013/","journal":"JAMA","year":2013,"whatItMeans":"Adjuvant chemotherapy is standard after pancreatic cancer resection; gemcitabine alone remains the option for patients who cannot tolerate combinations."},{"id":"paper-espac-3-fluorouracil-vs-gemcitabine-adjuvant-neoptolemos-jama-2010","name":"ESPAC-3: adjuvant fluorouracil plus folinic acid versus gemcitabine after pancreatic cancer resection","route":"/key-papers/paper-espac-3-fluorouracil-vs-gemcitabine-adjuvant-neoptolemos-jama-2010/","journal":"JAMA","year":2010,"whatItMeans":"Either regimen was acceptable adjuvant therapy in 2010, with gemcitabine preferred for tolerability; combination regimens (ESPAC-4, PRODIGE 24) have since superseded both."},{"id":"paper-hidalgo-pancreatic-cancer-review-nejm-2010","name":"Pancreatic cancer","route":"/key-papers/paper-hidalgo-pancreatic-cancer-review-nejm-2010/","journal":"New England Journal of Medicine","year":2010,"whatItMeans":"A fixed point for readers who want to see how much, and how little, has changed since 2010."}]},{"era":"2011-2016","title":"Combination chemotherapy for metastatic disease","description":"PRODIGE 4/ACCORD 11 (Conroy 2011, 342 fit patients) gave FOLFIRINOX a median survival of 11.1 months against 6.8 with gemcitabine (hazard ratio 0.57) at the price of neutropenia, diarrhoea and neuropathy; MPACT (Von Hoff 2013, 861 patients) gave gemcitabine with nab-paclitaxel 8.5 against 6.7 months and accepted less fit patients, so fitness rather than stage came to decide the regimen. NAPOLI-1 (2016, 417 patients) added a second line, liposomal irinotecan with fluorouracil, 6.1 against 4.2 months after gemcitabine. Rahib's 2014 projection that pancreatic cancer would become the second cause of cancer death in the United States by 2030 (updated in 2021 to 2040, about 46,000 deaths a year) became the funding argument of the decade.","status":"historic","refs":[{"id":"paper-conroy-folfirinox-pancreatic-nejm-2011","kind":"paper","name":"Conroy 2011: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer (PRODIGE 4/ACCORD 11)","route":"/key-papers/paper-conroy-folfirinox-pancreatic-nejm-2011/","tldr":"A four-drug chemotherapy combination gave fit patients with metastatic pancreatic cancer clearly longer survival than the standard gemcitabine, the first real improvement in the disease in over a decade, at the cost of more side effects."},{"id":"paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","kind":"paper","name":"MPACT (Von Hoff 2013): nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer","route":"/key-papers/paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013/","tldr":"Adding albumin-bound paclitaxel to gemcitabine prolonged survival in metastatic pancreatic cancer in a large international trial, giving patients who are not fit enough for FOLFIRINOX a second effective first-line option."},{"id":"paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","kind":"paper","name":"Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial","route":"/key-papers/paper-napoli-1-nanoliposomal-irinotecan-lancet-2016/","tldr":"The 2016 trial that gave patients whose pancreatic cancer had grown through gemcitabine a proven second treatment: liposomal irinotecan with fluorouracil lengthened survival from about four to six months."},{"id":"paper-rahib-projecting-cancer-deaths-2030-cancerres-2014","kind":"paper","name":"Rahib 2014: projecting US cancer incidence and deaths to 2030","route":"/key-papers/paper-rahib-projecting-cancer-deaths-2030-cancerres-2014/","tldr":"A projection that by 2030 pancreatic and liver cancers would overtake breast, prostate and colorectal cancers to become the second and third leading causes of cancer death in the United States, because progress against the common cancers was not being matched in these two."},{"id":"paper-rahib-projection-us-cancer-2040-jama-netw-open-2021","kind":"paper","name":"Estimated Projection of US Cancer Incidence and Death to 2040","route":"/key-papers/paper-rahib-projection-us-cancer-2040-jama-netw-open-2021/","tldr":"The 2021 update of the projection that pancreatic cancer will become the second leading cause of cancer death in the United States, now dated to 2040 with about 46,000 deaths a year, as deaths from breast, prostate and bowel cancer fall."},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/","status":"standard-of-care","tldr":"FOLFIRINOX is a four-drug chemotherapy combination that, in 2011, became the first treatment to meaningfully extend life in metastatic pancreatic cancer; it is now the standard before and after surgery."},{"id":"gemcitabine-nab-paclitaxel","kind":"drug","name":"Gemcitabine + nab-paclitaxel","route":"/drugs/gemcitabine-nab-paclitaxel/","status":"standard-of-care","tldr":"Gemcitabine plus nab-paclitaxel is the gentler of the two standard chemotherapy backbones for pancreatic cancer, and the base on which most new drugs are being tested."},{"id":"liposomal-irinotecan","kind":"drug","name":"Liposomal irinotecan","route":"/drugs/liposomal-irinotecan/","status":"approved","tldr":"Irinotecan wrapped in a fat bubble so it circulates longer. It is approved for pancreatic cancer, and in bile duct and gallbladder cancer one Korean trial found it helped as second-line treatment while a German trial did not."},{"id":"thierry-conroy","kind":"person","name":"Thierry Conroy","route":"/people/thierry-conroy/","tldr":"Led the FOLFIRINOX trials that gave pancreatic cancer its most active chemotherapy in both metastatic and adjuvant settings."},{"id":"daniel-von-hoff","kind":"person","name":"Daniel D. Von Hoff","route":"/people/daniel-von-hoff/","tldr":"Led the MPACT trial of nab-paclitaxel plus gemcitabine and has run more first-in-human cancer trials than almost anyone."},{"id":"performance-status","kind":"term","name":"Performance status (ECOG, Karnofsky)","route":"/terms/performance-status/","tldr":"A simple score of how well a patient can get about and look after themselves: ECOG 0 is fully active, 1 restricted from strenuous work, 2 up more than half the day, 3 in bed more than half the day, 4 bedbound. It predicts how treatment will be tolerated and gates almost every trial."},{"id":"b-aging-comorbidity","kind":"bottleneck","name":"Older and multimorbid patients are excluded and undertreated","route":"/bottlenecks/b-aging-comorbidity/","tldr":"Most people with cancer are over 65 but most trial patients are younger and fitter. We guess how to treat the majority."},{"id":"b-funding-allocation","kind":"bottleneck","name":"Funding follows fashion, not burden","route":"/bottlenecks/b-funding-allocation/","tldr":"Research money follows visibility, not burden: breast, prostate and leukaemia receive far more funding per death or year of life lost than lung, pancreatic, liver, oesophageal, gastric, bladder and uterine cancers, and metastasis research gets an estimated 5% of funding despite causing most deaths. Advocacy strength and peer review that rewards mechanism explain the skew."}],"trials":[],"papers":[{"id":"paper-conroy-folfirinox-pancreatic-nejm-2011","name":"Conroy 2011: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer (PRODIGE 4/ACCORD 11)","route":"/key-papers/paper-conroy-folfirinox-pancreatic-nejm-2011/","journal":"New England Journal of Medicine","year":2011,"whatItMeans":"FOLFIRINOX and, soon after, gemcitabine plus nab-paclitaxel ended the era of single-agent gemcitabine for metastatic pancreatic cancer. The regimen's modified form later improved survival after surgery in PRODIGE 24, and its toxicity is why fitness, not just stage, decides which treatment a patient is offered."},{"id":"paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","name":"MPACT (Von Hoff 2013): nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer","route":"/key-papers/paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013/","journal":"New England Journal of Medicine","year":2013,"whatItMeans":"With FOLFIRINOX this trial defined the two chemotherapy standards for metastatic pancreatic cancer that still apply, and the gemcitabine and nab-paclitaxel backbone is the comparator in most current first-line pancreatic trials."},{"id":"paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","name":"Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial","route":"/key-papers/paper-napoli-1-nanoliposomal-irinotecan-lancet-2016/","journal":"The Lancet","year":2016,"whatItMeans":"The first approved second-line regimen and the basis of NALIRIFOX, which NAPOLI 3 later moved to first line; it fixed the sequence (gemcitabine-based first, then liposomal irinotecan with fluorouracil) written into the 2018 ASCO guideline."},{"id":"paper-rahib-projecting-cancer-deaths-2030-cancerres-2014","name":"Rahib 2014: projecting US cancer incidence and deaths to 2030","route":"/key-papers/paper-rahib-projecting-cancer-deaths-2030-cancerres-2014/","journal":"Cancer Research","year":2014,"whatItMeans":"This paper reframed pancreatic and liver cancer as the coming burden and is cited in most arguments for investing in them. Its pancreatic cancer projection has been tracking close to reality in the years since."},{"id":"paper-rahib-projection-us-cancer-2040-jama-netw-open-2021","name":"Estimated Projection of US Cancer Incidence and Death to 2040","route":"/key-papers/paper-rahib-projection-us-cancer-2040-jama-netw-open-2021/","journal":"JAMA Network Open","year":2021,"whatItMeans":"Pancreatic cancer's share of cancer deaths rises because it is standing still while others improve; the 2014 projection to 2030 already made it the second cause of cancer death in the UK's peer countries, and this is the funding argument charities on both sides of the Atlantic use."}]},{"era":"2015-2018","title":"Genomes, subtypes and the inherited five percent","description":"Waddell's 100 whole genomes (2015) sorted tumours by structural variation and noticed that four of five patients with BRCA-type defects responded to platinum; Moffitt (2015) separated tumour from stroma computationally and found the classical and basal-like tumour subtypes and two prognostic stromal subtypes; Bailey (2016) grouped 32 mutated genes in 456 tumours into ten pathways and four expression subtypes, the squamous type with the worst prognosis. Hu's 3,030-patient Mayo series (2018) found a pathogenic variant in one of six genes in 5.5 percent of all patients and 5.2 percent of those without a family history, which moved the guidelines to germline testing for everyone.","status":"historic","refs":[{"id":"paper-waddell-whole-genomes-pancreatic-nature-2015","kind":"paper","name":"Whole genomes redefine the mutational landscape of pancreatic cancer","route":"/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/","tldr":"The 2015 whole-genome study of 100 pancreatic cancers that sorted them by how broken their chromosomes were and noticed that the most unstable tumours, often with BRCA-type defects, responded to platinum chemotherapy."},{"id":"paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","kind":"paper","name":"Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma","route":"/key-papers/paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015/","tldr":"The 2015 study that computationally separated cancer cells from the surrounding scar tissue in gene expression data and found two tumour types, classical and basal-like, and two kinds of stroma, each of which predicts survival."},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/","tldr":"The 2016 analysis of 456 pancreatic cancers that grouped 32 recurrently mutated genes into ten pathways and defined four expression subtypes, of which the squamous type has the worst prognosis."},{"id":"paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","kind":"paper","name":"Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer","route":"/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/","tldr":"The 2018 Mayo Clinic study of 3,030 patients that found an inherited fault in one of six genes in 5.5 percent of all pancreatic cancers, including 5.2 percent of patients with no family history, which is why every patient is now offered a germline test."},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/","status":"established","tldr":"Reading all the genes (exome) or the entire DNA (genome) of a tumour, rather than a chosen panel."},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/","status":"established","tldr":"Measuring which genes a tumour is actively using, which reveals its subtype and finds gene fusions."},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/","status":"standard-of-care","tldr":"A test of the DNA you were born with, to find inherited risk genes such as BRCA or Lynch syndrome."},{"id":"gbrca-mutation","kind":"term","name":"Germline BRCA mutation (gBRCA)","route":"/terms/gbrca-mutation/","tldr":"An inherited fault in the BRCA1 or BRCA2 gene, present in every cell from birth, that greatly raises the risk of breast, ovarian, prostate and pancreatic cancer and makes those cancers sensitive to PARP inhibitors and platinum."},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/","tldr":"Germline mutations are inherited and in every cell; somatic mutations arise in the tumour only."},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/","tldr":"The dense scar-like tissue that makes up most of a pancreatic tumour, walling off cancer cells from drugs and immune cells."},{"id":"garvan-institute","kind":"institution","name":"Garvan Institute of Medical Research / Kinghorn Cancer Centre","route":"/institutions/garvan-institute/","tldr":"One of Australia's leading genomics institutes, whose Kinghorn Cancer Centre with St Vincent's pioneered genomics-guided treatment of pancreatic cancer and rare tumours."},{"id":"unc-lineberger","kind":"institution","name":"UNC Lineberger Comprehensive Cancer Center","route":"/institutions/unc-lineberger/","tldr":"Where Charles Perou defined the PAM50 intrinsic subtypes of breast cancer; a public university centre with in-house CAR-T manufacturing."},{"id":"mayo-clinic","kind":"institution","name":"Mayo Clinic","route":"/institutions/mayo-clinic/","tldr":"Consistently the top-ranked US hospital overall, with strong proton therapy and the first US carbon-ion centre under construction."},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/","tldr":"Every tumour is a population of genetically distinct clones: in multi-region sequencing of kidney tumours, roughly two thirds of mutations were missing from at least one region. Treatment kills the dominant clones and leaves resistant minor clones to grow back, yet a single diagnostic biopsy is still treated as the whole disease."},{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/","tldr":"Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer."},{"id":"idea-pdac-surveillance-for-every-germline-carrier","kind":"idea","name":"Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception","route":"/ideas/idea-pdac-surveillance-for-every-germline-carrier/","tldr":"One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically."}],"trials":[],"papers":[{"id":"paper-waddell-whole-genomes-pancreatic-nature-2015","name":"Whole genomes redefine the mutational landscape of pancreatic cancer","route":"/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/","journal":"Nature","year":2015,"whatItMeans":"The genomic case for platinum in BRCA-type pancreatic cancer, four years before POLO built a maintenance strategy on top of it."},{"id":"paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","name":"Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma","route":"/key-papers/paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015/","journal":"Nature Genetics","year":2015,"whatItMeans":"The classical versus basal-like split, later tied to GATA6 expression and to chemotherapy response, is the subtype scheme most likely to reach the clinic; the stromal subtypes are why the desmoplastic stroma is treated as a partner in the disease rather than inert scar."},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/","journal":"Nature","year":2016,"whatItMeans":"With Moffitt's classical and basal-like split (the squamous and basal-like groups overlap) this fixed the molecular vocabulary of the disease and gave Precision-Panc and the UK's Glasgow group their trial framework."},{"id":"paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","name":"Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer","route":"/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/","journal":"JAMA","year":2018,"whatItMeans":"Family history misses most carriers, so the NCCN and ASCO guidelines moved to testing every patient; each carrier found is a family that can be offered surveillance and a patient who may be eligible for platinum and PARP inhibition."}]},{"era":"2017-2025","title":"Adjuvant modified FOLFIRINOX, and the neoadjuvant question","description":"ESPAC-4 (2017) added capecitabine to adjuvant gemcitabine; PRODIGE 24 (2018) replaced both with modified FOLFIRINOX in fit patients, and its five-year report (2022, 493 patients) gave a median survival of 53.5 against 35.5 months (hazard ratio 0.68) and five-year survival of 43.2 against 31.4 percent, adopted by ASCO in 2019. For treatment before surgery, PREOPANC (2020, 246 patients) missed its primary endpoint (16.0 versus 14.3 months) but raised clear-margin resection from 40 to 71 percent and showed a five-year benefit in 2022; ESPAC-5 and Alliance A021501 supported neoadjuvant treatment for borderline resectable disease; NORPACT-1 (2024) and PREOPANC-2 (2025, 375 patients: 21.9 versus 21.3 months for FOLFIRINOX against gemcitabine chemoradiotherapy) left resectable disease unresolved. LAP07 (2016) had shown chemoradiotherapy added nothing to survival in locally advanced disease.","status":"current","refs":[{"id":"espac-4","kind":"trial","name":"ESPAC-4","route":"/trials/espac-4/","status":"positive","tldr":"ESPAC-4 showed that adding the tablet capecitabine to gemcitabine after pancreatic cancer surgery lengthened median survival from 25.5 to 28 months, and the pair became the adjuvant standard for people who cannot tolerate the harsher FOLFIRINOX regimen."},{"id":"paper-espac-4-gemcitabine-capecitabine-adjuvant-neoptolemos-lancet-2017","kind":"paper","name":"ESPAC-4: adjuvant gemcitabine and capecitabine versus gemcitabine monotherapy in resected pancreatic cancer","route":"/key-papers/paper-espac-4-gemcitabine-capecitabine-adjuvant-neoptolemos-lancet-2017/","tldr":"Adding capecitabine to gemcitabine after pancreatic cancer surgery lengthened median survival from 25.5 to 28 months, making the combination a new adjuvant standard."},{"id":"prodige-24","kind":"trial","name":"PRODIGE 24 / CCTG PA6","route":"/trials/prodige-24/","status":"positive","tldr":"Showed that giving the strong four-drug chemotherapy after pancreatic surgery adds years of life for fit patients."},{"id":"paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018","kind":"paper","name":"PRODIGE 24/CCTG PA6: adjuvant modified FOLFIRINOX versus gemcitabine after resection of pancreatic cancer","route":"/key-papers/paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018/","tldr":"Six months of the four-drug combination modified FOLFIRINOX after surgery for pancreatic cancer kept the disease away for almost twice as long as gemcitabine alone and added about a year and a half to median survival. It is the reason fit patients are now offered FOLFIRINOX after a pancreatic operation."},{"id":"paper-prodige-24-five-year-outcomes-jama-oncol-2022","kind":"paper","name":"Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial","route":"/key-papers/paper-prodige-24-five-year-outcomes-jama-oncol-2022/","tldr":"The 2022 five-year report of PRODIGE 24 confirming that modified FOLFIRINOX after pancreatic cancer surgery gives a median survival of about four and a half years against three with gemcitabine, and that 43 percent of patients were alive at five years."},{"id":"paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019","kind":"paper","name":"Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update","route":"/key-papers/paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019/","tldr":"The 2019 American guideline update that made six months of modified FOLFIRINOX the preferred chemotherapy after pancreatic cancer surgery for patients fit enough to take it, on the strength of a single trial."},{"id":"preopanc","kind":"trial","name":"PREOPANC-1","route":"/trials/preopanc/","status":"mixed","tldr":"The Dutch trial testing whether treating before surgery beats operating first. Chemoradiation first fell short at the primary analysis but won at five years, with one in five patients alive against one in fifteen."},{"id":"paper-preopanc-preoperative-chemoradiotherapy-jco-2020","kind":"paper","name":"Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial","route":"/key-papers/paper-preopanc-preoperative-chemoradiotherapy-jco-2020/","tldr":"The 2020 primary report of the Dutch PREOPANC trial: giving chemotherapy and radiotherapy before surgery did not significantly lengthen survival overall, but it raised clear-margin resections from 40 to 71 percent and helped the patients whose tumours were borderline operable."},{"id":"paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022","kind":"paper","name":"PREOPANC long-term results: neoadjuvant gemcitabine-based chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer","route":"/key-papers/paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022/","tldr":"Giving chemotherapy and radiotherapy before the operation, rather than operating first, tripled the share of patients alive at five years in this Dutch trial, with the gain clearest in borderline resectable tumours. It is the strongest randomised case for treating borderline resectable pancreatic cancer before surgery."},{"id":"espac-5","kind":"trial","name":"ESPAC-5","route":"/trials/espac-5/","status":"positive","tldr":"ESPAC-5 randomised people whose pancreatic cancer sat on the border of being removable between going straight to surgery and having two months of chemotherapy or chemoradiotherapy first; those treated first were far more likely to be alive a year later, 78 to 84 percent with chemotherapy against 39 percent with immediate surgery, which supports treating before operating in borderline disease."},{"id":"paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023","kind":"paper","name":"ESPAC5: immediate surgery versus short-course neoadjuvant chemotherapy or chemoradiotherapy for borderline resectable pancreatic cancer","route":"/key-papers/paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023/","tldr":"In this four-arm British trial, two months of chemotherapy before surgery for borderline resectable pancreatic cancer doubled the share of patients alive at one year compared with operating straight away, even though the same proportion got to an operation."},{"id":"paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022","kind":"paper","name":"Alliance A021501: preoperative modified FOLFIRINOX with or without hypofractionated radiotherapy for borderline resectable pancreatic cancer","route":"/key-papers/paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022/","tldr":"In the first randomised US trial of neoadjuvant treatment for borderline resectable pancreatic cancer, eight cycles of modified FOLFIRINOX alone gave two-thirds of patients an 18-month survival, while replacing the last cycle with short-course radiotherapy did worse and that arm was stopped early."},{"id":"paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024","kind":"paper","name":"NORPACT-1: neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer","route":"/key-papers/paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024/","tldr":"Giving FOLFIRINOX before surgery did not help people with clearly resectable pancreatic head cancer: fewer were alive at 18 months than those who went straight to surgery."},{"id":"paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025","kind":"paper","name":"Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial","route":"/key-papers/paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025/","tldr":"The 2025 Dutch trial in which eight cycles of FOLFIRINOX before surgery, with no treatment afterwards, gave the same survival (about 22 months) as the older gemcitabine chemoradiotherapy schedule, so either can be used but neither is clearly better."},{"id":"lap07","kind":"trial","name":"LAP07","route":"/trials/lap07/","status":"negative","tldr":"LAP07 tested whether adding radiotherapy after four months of chemotherapy helps people whose pancreatic cancer has not spread but cannot be removed; it did not lengthen life, although it did keep the tumour in check locally for longer, and adding erlotinib to gemcitabine did not help either."},{"id":"paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016","kind":"paper","name":"LAP07: chemoradiotherapy versus chemotherapy after four months of gemcitabine in locally advanced pancreatic cancer","route":"/key-papers/paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016/","tldr":"Adding radiotherapy after four months of chemotherapy did not help people with unresectable, non-metastatic pancreatic cancer live longer, though it delayed local growth; adding erlotinib to gemcitabine did not help either."},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/","status":"standard-of-care","tldr":"FOLFIRINOX is a four-drug chemotherapy combination that, in 2011, became the first treatment to meaningfully extend life in metastatic pancreatic cancer; it is now the standard before and after surgery."},{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/","status":"approved","tldr":"Capecitabine (Xeloda) is a tablet form of the chemotherapy fluorouracil. It is a backbone of treatment for bowel cancer and a standard option in advanced breast cancer."},{"id":"resection-margins","kind":"term","name":"Resection margins (R0 / R1 / R2)","route":"/terms/resection-margins/","tldr":"Whether the edge of the removed tissue is free of cancer. R0 means clear under the microscope, R1 means microscopic cancer at the edge, R2 means visible tumour left behind. R0 is what 'complete resection' means."},{"id":"total-neoadjuvant-therapy","kind":"term","name":"Total neoadjuvant therapy (TNT, rectal cancer)","route":"/terms/total-neoadjuvant-therapy/","tldr":"Giving all the chemotherapy and radiotherapy for rectal cancer before surgery rather than splitting it around the operation. It improves completion of chemotherapy, shrinks more tumours completely, and makes avoiding surgery possible for some patients."},{"id":"unicancer","kind":"company","name":"UNICANCER","route":"/companies/unicancer/","tldr":"UNICANCER is the network of France's comprehensive cancer centres and its academic trials sponsor."},{"id":"erasmus-mc","kind":"institution","name":"Erasmus MC Cancer Institute","route":"/institutions/erasmus-mc/","tldr":"Rotterdam's OECI-accredited comprehensive cancer centre, where peptide receptor radionuclide therapy with lutetium-177 was pioneered and Europe's largest screening trials were led."},{"id":"marc-besselink","kind":"person","name":"Marc G. Besselink","route":"/people/marc-besselink/","tldr":"Dutch surgeon who leads the PREOPANC trials testing chemotherapy or chemoradiation before pancreatic cancer surgery."},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/","tldr":"A phase 3 trial takes years and hundreds of millions of dollars, and often answers a question that has already moved on."},{"id":"idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","kind":"idea","name":"Chemotherapy before surgery for every resectable pancreatic cancer, settled by the two perioperative trials rather than assumed","route":"/ideas/idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease/","tldr":"Giving chemotherapy before the operation is standard when the tumour is borderline operable, but for tumours that can be removed straight away two trials have failed to show it beats operating first. Two more, one Dutch and one American, are directly comparing chemotherapy before and after surgery with chemotherapy after alone; the proposal is to wait for them and to pool them."}],"trials":[{"id":"espac-4","name":"ESPAC-4","route":"/trials/espac-4/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Adjuvant gemcitabine + capecitabine","n":364,"value":28,"note":"95% CI 23.5 to 31.5"},{"name":"Adjuvant gemcitabine","n":366,"value":25.5,"note":"95% CI 22.7 to 27.9"}],"hr":0.82,"ci":[0.68,0.98],"p":"0.032","source":"https://doi.org/10.1016/S0140-6736(16)32409-6"},{"endpoint":"Patients with grade 3 to 4 adverse events","unit":"%","arms":[{"name":"Adjuvant gemcitabine + capecitabine","n":359,"value":63,"note":"226 of 359 patients, 608 events"},{"name":"Adjuvant gemcitabine","n":366,"value":54,"note":"196 of 366 patients, 481 events"}],"source":"https://doi.org/10.1016/S0140-6736(16)32409-6"},{"endpoint":"Overall survival, long-term follow-up (median 104 months)","unit":"months","arms":[{"name":"Adjuvant gemcitabine + capecitabine","n":365,"value":31.6,"note":"95% CI 26.5 to 38.0"},{"name":"Adjuvant gemcitabine","n":367,"value":28.4,"note":"95% CI 25.2 to 32.0"}],"hr":0.83,"ci":[0.71,0.98],"p":"0.031","source":"https://doi.org/10.1200/JCO.24.01118"},{"endpoint":"Overall survival after R0 resection (long-term)","unit":"months","arms":[{"name":"Adjuvant gemcitabine + capecitabine","value":49.9,"note":"95% CI 39.0 to 82.3"},{"name":"Adjuvant gemcitabine","value":32.2,"note":"95% CI 27.9 to 41.6"}],"hr":0.63,"ci":[0.47,0.84],"p":"0.002","source":"https://doi.org/10.1200/JCO.24.01118"}],"setting":"Resected pancreatic ductal adenocarcinoma within 12 weeks of surgery in the United Kingdom, Germany, France and Sweden: six cycles of adjuvant gemcitabine alone against gemcitabine plus capecitabine, with overall survival as the primary endpoint","enrolled":732,"enrolledNote":"ESPAC-4 has no ClinicalTrials.gov record; the figure is the 732 enrolled in the Lancet report, of whom 730 were analysed (366 gemcitabine, 364 gemcitabine plus capecitabine); the trial is registered as ISRCTN96397434.","enrolledBasis":"registered"},{"id":"prodige-24","name":"PRODIGE 24 / CCTG PA6","route":"/trials/prodige-24/","outcomes":[{"endpoint":"Disease-free survival","primary":true,"unit":"months","arms":[{"name":"Adjuvant mFOLFIRINOX","n":247,"value":21.6},{"name":"Adjuvant gemcitabine","n":246,"value":12.8}],"hr":0.58,"ci":[0.46,0.73],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1809775"},{"endpoint":"Overall survival (5-year update)","unit":"months","arms":[{"name":"Adjuvant mFOLFIRINOX","value":53.5},{"name":"Adjuvant gemcitabine","value":35.5}],"hr":0.68,"source":"https://jamanetwork.com/journals/jamaoncology/fullarticle/2795896"}],"setting":"Adjuvant therapy after resection of PDAC: mFOLFIRINOX vs gemcitabine","enrolled":493,"enrolledBasis":"registry"},{"id":"preopanc","name":"PREOPANC-1","route":"/trials/preopanc/","outcomes":[{"endpoint":"Overall survival (long-term)","primary":true,"unit":"%","arms":[{"name":"Neoadjuvant chemoradiotherapy, 5-year OS","n":119,"value":20.5},{"name":"Upfront surgery, 5-year OS","n":127,"value":6.5}],"hr":0.73,"ci":[0.56,0.96],"p":"0.025","source":"https://ascopubs.org/doi/10.1200/JCO.21.02233"},{"endpoint":"Overall survival (primary analysis, intention to treat)","unit":"months","arms":[{"name":"Neoadjuvant gemcitabine chemoradiotherapy, surgery, adjuvant gemcitabine","n":119,"value":16},{"name":"Upfront surgery, adjuvant gemcitabine","n":127,"value":14.3}],"hr":0.78,"ci":[0.58,1.05],"p":"0.096","source":"https://doi.org/10.1200/JCO.19.02274"},{"endpoint":"R0 resection rate among resected patients","unit":"%","arms":[{"name":"Neoadjuvant chemoradiotherapy","n":72,"value":71,"note":"51 of 72"},{"name":"Upfront surgery","n":92,"value":40,"note":"37 of 92"}],"p":"<0.001","source":"https://doi.org/10.1200/JCO.19.02274"}],"setting":"Resectable and borderline-resectable PDAC at 16 Dutch centres: neoadjuvant gemcitabine-based chemoradiation (36 Gy in 15 fractions), surgery and adjuvant gemcitabine vs upfront surgery and adjuvant gemcitabine","enrolled":246,"enrolledBasis":"registry"},{"id":"espac-5","name":"ESPAC-5","route":"/trials/espac-5/","outcomes":[{"endpoint":"Resection rate","primary":true,"unit":"%","arms":[{"name":"Immediate surgery","n":31,"value":68,"note":"21 of 31"},{"name":"Neoadjuvant therapy arms combined","n":55,"value":55,"note":"30 of 55"}],"p":"0.33","source":"https://doi.org/10.1016/S2468-1253(22)00348-X"},{"endpoint":"Overall survival at 1 year","unit":"%","arms":[{"name":"Immediate surgery","n":31,"value":39,"note":"95% CI 24 to 61"},{"name":"Neoadjuvant gemcitabine + capecitabine","n":19,"value":78,"note":"95% CI 60 to 100"},{"name":"Neoadjuvant FOLFIRINOX","n":20,"value":84,"note":"95% CI 70 to 100"},{"name":"Neoadjuvant capecitabine-based chemoradiotherapy","n":16,"value":60,"note":"95% CI 37 to 97"}],"p":"0.0028","source":"https://doi.org/10.1016/S2468-1253(22)00348-X"},{"endpoint":"Disease-free survival at 1 year from surgery","unit":"%","arms":[{"name":"Immediate surgery","value":33,"note":"95% CI 19 to 58"},{"name":"Neoadjuvant therapy arms combined","value":59,"note":"95% CI 46 to 74"}],"hr":0.53,"ci":[0.28,0.98],"p":"0.016","source":"https://doi.org/10.1016/S2468-1253(22)00348-X"},{"endpoint":"R0 resection among resected patients","unit":"%","arms":[{"name":"Immediate surgery","n":21,"value":14},{"name":"Neoadjuvant therapy arms combined","n":30,"value":23}],"p":"0.49","source":"https://doi.org/10.1016/S2468-1253(22)00348-X"}],"setting":"Borderline resectable pancreatic cancer in the United Kingdom and Germany: immediate surgery against short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX or capecitabine-based chemoradiotherapy, each followed by surgery and adjuvant chemotherapy, with recruitment and resection rate as the primary endpoints of a four-arm feasibility trial","enrolled":90,"enrolledNote":"ESPAC-5 has no ClinicalTrials.gov record and the Lancet Gastroenterology and Hepatology report does not print a registry id; the figure is the 90 patients randomised between 2014 and 2018 (86 analysed).","enrolledBasis":"randomised"},{"id":"lap07","name":"LAP07","route":"/trials/lap07/","outcomes":[{"endpoint":"Overall survival from first randomisation, chemoradiotherapy against chemotherapy (second randomisation)","primary":true,"unit":"months","arms":[{"name":"Capecitabine-based chemoradiotherapy after 4 months of chemotherapy","value":15.2,"note":"95% CI 13.9 to 17.3; 269 patients in the second randomisation"},{"name":"Two further months of chemotherapy","value":16.5,"note":"95% CI 14.5 to 18.5"}],"hr":1.03,"ci":[0.79,1.34],"p":"0.83","source":"https://doi.org/10.1001/jama.2016.4324"},{"endpoint":"Overall survival, gemcitabine against gemcitabine plus erlotinib (first randomisation)","unit":"months","arms":[{"name":"Gemcitabine","n":223,"value":13.6,"note":"95% CI 12.3 to 15.3"},{"name":"Gemcitabine + erlotinib","n":219,"value":11.9,"note":"95% CI 10.4 to 13.5"}],"hr":1.19,"ci":[0.97,1.45],"p":"0.09","source":"https://doi.org/10.1001/jama.2016.4324"},{"endpoint":"Local progression","unit":"%","arms":[{"name":"Capecitabine-based chemoradiotherapy","value":32},{"name":"Chemotherapy alone","value":46}],"p":"0.03","source":"https://doi.org/10.1001/jama.2016.4324"}],"setting":"Locally advanced unresectable pancreatic cancer: a first randomisation to four months of gemcitabine with or without erlotinib, then for patients without progression a second randomisation to capecitabine-based chemoradiotherapy (54 Gy) or two further months of chemotherapy","enrolled":449,"enrolledNote":"The registry gives an estimated 820; the JAMA report enrolled 449 patients, 442 of whom had the first randomisation and 269 the second.","enrolledBasis":"registered"}],"papers":[{"id":"paper-espac-4-gemcitabine-capecitabine-adjuvant-neoptolemos-lancet-2017","name":"ESPAC-4: adjuvant gemcitabine and capecitabine versus gemcitabine monotherapy in resected pancreatic cancer","route":"/key-papers/paper-espac-4-gemcitabine-capecitabine-adjuvant-neoptolemos-lancet-2017/","journal":"The Lancet","year":2017,"whatItMeans":"Gemcitabine plus capecitabine became the adjuvant standard after resection and remains the option for patients unfit for modified FOLFIRINOX."},{"id":"paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018","name":"PRODIGE 24/CCTG PA6: adjuvant modified FOLFIRINOX versus gemcitabine after resection of pancreatic cancer","route":"/key-papers/paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"Modified FOLFIRINOX is the adjuvant standard for patients who recover well from a pancreatic resection and can tolerate combination chemotherapy; gemcitabine-based regimens remain for those who cannot."},{"id":"paper-prodige-24-five-year-outcomes-jama-oncol-2022","name":"Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial","route":"/key-papers/paper-prodige-24-five-year-outcomes-jama-oncol-2022/","journal":"JAMA Oncology","year":2022,"whatItMeans":"The best survival ever recorded in a pancreatic cancer trial, and the benchmark every perioperative trial (PREOPANC-3, Alliance A021806) and every adjuvant RAS inhibitor or vaccine trial (RASolute 304, IMCODE003) now has to beat or add to."},{"id":"paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019","name":"Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update","route":"/key-papers/paper-asco-potentially-curable-pancreatic-guideline-update-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"The formal adoption of PRODIGE 24 into practice; every later debate about giving chemotherapy before rather than after surgery starts from this recommendation."},{"id":"paper-preopanc-preoperative-chemoradiotherapy-jco-2020","name":"Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial","route":"/key-papers/paper-preopanc-preoperative-chemoradiotherapy-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"The trial that made neoadjuvant treatment standard for borderline resectable disease and opened the still unresolved question for resectable disease, which PREOPANC-2, NORPACT-1, PREOPANC-3 and Alliance A021806 inherited."},{"id":"paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022","name":"PREOPANC long-term results: neoadjuvant gemcitabine-based chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer","route":"/key-papers/paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"Neoadjuvant treatment is now the standard for borderline resectable pancreatic cancer, and PREOPANC is the trial guidelines cite; the follow-on PREOPANC-2 tested FOLFIRINOX in the same setting."},{"id":"paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023","name":"ESPAC5: immediate surgery versus short-course neoadjuvant chemotherapy or chemoradiotherapy for borderline resectable pancreatic cancer","route":"/key-papers/paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023/","journal":"The Lancet Gastroenterology and Hepatology","year":2023,"whatItMeans":"ESPAC5 supports neoadjuvant chemotherapy over immediate surgery in borderline resectable disease and points to FOLFIRINOX as the regimen to build on."},{"id":"paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022","name":"Alliance A021501: preoperative modified FOLFIRINOX with or without hypofractionated radiotherapy for borderline resectable pancreatic cancer","route":"/key-papers/paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022/","journal":"JAMA Oncology","year":2022,"whatItMeans":"Neoadjuvant modified FOLFIRINOX without routine radiotherapy became the reference approach for borderline resectable disease in North America; radiotherapy is reserved for selected patients or trials."},{"id":"paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024","name":"NORPACT-1: neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer","route":"/key-papers/paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024/","journal":"The Lancet Gastroenterology and Hepatology","year":2024,"whatItMeans":"Upfront surgery followed by adjuvant chemotherapy remains standard for clearly resectable pancreatic cancer; neoadjuvant treatment belongs in trials or borderline disease."},{"id":"paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025","name":"Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial","route":"/key-papers/paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025/","journal":"The Lancet Oncology","year":2025,"whatItMeans":"Together with NORPACT-1 this left the neoadjuvant question for resectable disease open: FOLFIRINOX before surgery is not proven superior to alternatives, and the comparison against upfront surgery with adjuvant modified FOLFIRINOX is what PREOPANC-3 and Alliance A021806 are running."},{"id":"paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016","name":"LAP07: chemoradiotherapy versus chemotherapy after four months of gemcitabine in locally advanced pancreatic cancer","route":"/key-papers/paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016/","journal":"JAMA","year":2016,"whatItMeans":"Consolidation chemoradiotherapy is optional in locally advanced pancreatic cancer, used for local control rather than survival; erlotinib has no role."}]},{"era":"2019-2022","title":"The first biomarker-directed drug, and the first stromal failure","description":"POLO (Golan 2019, 154 patients) gave maintenance olaparib to germline BRCA carriers whose metastatic disease had not progressed on 16 weeks of platinum: progression-free survival hazard ratio 0.53, the first biomarker-directed approval in the disease, and in the 2022 final analysis no overall survival gain (hazard ratio 0.83). ASCO's 2020 update made germline and tumour testing for BRCA, mismatch repair deficiency and TRK fusions routine, each pointing at a drug for a few percent of patients (olaparib, pembrolizumab, larotrectinib, entrectinib), and zenocutuzumab later added NRG1 fusions. The same year HALO-301 (494 patients) showed that dissolving the tumour's hyaluronan raised response rate (47 versus 36 percent) without changing survival (11.2 versus 11.5 months), as Özdemir's 2014 mouse work had warned that removing fibroblasts made tumours worse.","status":"current","refs":[{"id":"polo","kind":"trial","name":"POLO","route":"/trials/polo/","status":"mixed","tldr":"The first biomarker-directed drug approval in pancreatic cancer, for the roughly 5-7% with inherited BRCA mutations, though it did not extend overall survival."},{"id":"paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","kind":"paper","name":"POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019/","tldr":"In patients with inherited BRCA mutations whose pancreatic cancer had been held in check by platinum chemotherapy, switching to the tablet olaparib roughly doubled the time before the disease grew again compared with placebo. It was the first biomarker-driven approval in pancreatic cancer."},{"id":"paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","kind":"paper","name":"POLO final overall survival: maintenance olaparib versus placebo in germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022/","tldr":"The final results of POLO showed that olaparib did not lengthen overall survival on average, although about twice as many patients on olaparib were alive at three years, and the drug delayed the time until a second treatment was needed."},{"id":"paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020","kind":"paper","name":"Metastatic Pancreatic Cancer: ASCO Guideline Update","route":"/key-papers/paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020/","tldr":"The 2020 American guideline update that told doctors to test every treatment-eligible patient with metastatic pancreatic cancer for inherited BRCA changes, mismatch repair deficiency and TRK fusions, because each now had a drug attached."},{"id":"paper-halo-301-pegvorhyaluronidase-jco-2020","kind":"paper","name":"Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma","route":"/key-papers/paper-halo-301-pegvorhyaluronidase-jco-2020/","tldr":"The 2020 trial of an enzyme meant to dissolve the dense matrix around pancreatic tumours so chemotherapy could reach them: more tumours shrank, but patients lived no longer, and the drug was abandoned."},{"id":"paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","kind":"paper","name":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","route":"/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/","tldr":"The 2014 mouse study showing that removing the scar-forming cells around pancreatic tumours made the cancers more aggressive and the mice die sooner, the warning that the stroma is not simply an obstacle to be cleared."},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/","status":"approved","tldr":"Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer."},{"id":"zenocutuzumab","kind":"drug","name":"Zenocutuzumab","route":"/drugs/zenocutuzumab/","status":"approved","tldr":"Zenocutuzumab is the first drug for cancers driven by NRG1 gene fusions, working by blocking HER3 from receiving its growth signal."},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/","status":"approved","tldr":"Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA)."},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/","tldr":"DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum."},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/","tldr":"PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive."},{"id":"germline-to-parp","kind":"pairing","name":"Germline BRCA test → adjuvant PARP inhibitor","route":"/pairings/germline-to-parp/","tldr":"A blood test for inherited BRCA mutations unlocks a year of olaparib after surgery, which improves survival."},{"id":"platinum-sensitivity","kind":"term","name":"Platinum-sensitive / platinum-resistant","route":"/terms/platinum-sensitivity/","tldr":"Whether a cancer that responded to platinum chemotherapy came back more than six months later (sensitive, so platinum can be used again) or sooner (resistant, so something else is needed). The dividing line shapes ovarian and small-cell lung cancer treatment."},{"id":"cancer-associated-fibroblasts","kind":"term","name":"Cancer-associated fibroblasts (CAFs)","route":"/terms/cancer-associated-fibroblasts/","tldr":"The scaffolding cells that tumours recruit to build scar-like tissue around themselves. They feed the cancer, block drugs and immune cells, and carry the FAP protein that PET scans can now see."},{"id":"talia-golan","kind":"person","name":"Talia Golan","route":"/people/talia-golan/","tldr":"Led POLO, the first biomarker-driven trial in pancreatic cancer, which brought olaparib to BRCA carriers."},{"id":"hedy-kindler","kind":"person","name":"Hedy L. Kindler","route":"/people/hedy-kindler/","tldr":"Senior investigator of POLO and a leader in mesothelioma trials, including the ASCO guidelines for the disease."},{"id":"eric-van-cutsem","kind":"person","name":"Eric Van Cutsem","route":"/people/eric-van-cutsem/","tldr":"Led CRYSTAL, which established cetuximab in RAS wild-type colorectal cancer, and has shaped ESMO's GI guidelines for two decades."},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/","tldr":"AstraZeneca is the most ADC-committed large pharma, co-owner of Enhertu and Datroway, with deep targeted-therapy and radiopharma bets."},{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/","tldr":"Negative trials, failed drugs and abandoned programmes are rarely published, so the same mistakes are repeated."},{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/","tldr":"Most tumours keep the immune system out or asleep, so immunotherapy helps only a minority."},{"id":"idea-pdac-stromal-reprogramming-not-depletion","kind":"idea","name":"Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint","route":"/ideas/idea-pdac-stromal-reprogramming-not-depletion/","tldr":"Pancreatic tumours are mostly scar tissue. The first attempt to dissolve it, an enzyme given with chemotherapy to nearly 500 patients, shrank more tumours but did not lengthen life, and mouse work showed that stripping out the scar-forming cells made cancers worse. The proposal is to test drugs that change what the stroma does rather than remove it, in trials measured on survival."}],"trials":[{"id":"polo","name":"POLO","route":"/trials/polo/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Olaparib maintenance","n":92,"value":7.4},{"name":"Placebo","n":62,"value":3.8}],"hr":0.53,"ci":[0.35,0.82],"p":"0.004","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1903387"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Olaparib maintenance","value":19,"note":"Not significant"},{"name":"Placebo","value":19.2}],"hr":0.83,"source":"https://ascopubs.org/doi/10.1200/JCO.21.01604"}],"setting":"Germline BRCA-mutated metastatic PDAC not progressed on ≥16 weeks of platinum: olaparib maintenance vs placebo","enrolled":154,"enrolledBasis":"registry"}],"papers":[{"id":"paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","name":"POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"Germline testing for every pancreatic cancer patient, platinum first line for BRCA carriers, and olaparib maintenance for those who respond are all downstream of POLO."},{"id":"paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","name":"POLO final overall survival: maintenance olaparib versus placebo in germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"Olaparib maintenance remains a standard option because of its progression-free benefit, tolerability and long-term survivors, but patients should know that it has not been shown to extend average survival."},{"id":"paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020","name":"Metastatic Pancreatic Cancer: ASCO Guideline Update","route":"/key-papers/paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"The document that made biomarker testing part of routine pancreatic cancer care in the United States; the 2018 version it built on fixed the second-line chemotherapy sequence still used in most guidelines."},{"id":"paper-halo-301-pegvorhyaluronidase-jco-2020","name":"Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma","route":"/key-papers/paper-halo-301-pegvorhyaluronidase-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"The definitive negative result for first-generation stromal targeting: a biomarker-selected population, a drug that did what it was designed to do to the matrix, and no survival benefit; the stroma ideas on this page start from here."},{"id":"paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","name":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","route":"/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/","journal":"Cancer Cell","year":2014,"whatItMeans":"Together with the negative HALO-301 trial of hyaluronidase this ended the first, blunt version of stromal targeting; second-generation ideas aim to reprogramme rather than remove the stroma."}]},{"era":"2005-2022","title":"Surveillance for carriers and the new-onset diabetes signal","description":"Chari's Minnesota cohort (2005) found pancreatic cancer in 0.85 percent of 2,122 people diagnosed with diabetes after 50 within three years, eight times the expected rate; Sharma's ENDPAC score (2018) used weight change, glucose change and age at onset to concentrate that risk into a group with 3.6 percent prevalence, and Fahrmann (2021) showed CA 19-9 rising from two years before diagnosis. For people with inherited risk, the CAPS programme reported in 2018 that 9 of 10 cancers found under surveillance were resectable, published consensus rules in 2020 (start at 50 or 55, endoscopic ultrasound and MRI annually, research settings only) and in 2022 (CAPS5, 1,461 people) found 7 of 9 cancers at stage I, with a median survival of 9.8 years for screen-detected against 1.5 years for cancers found outside surveillance. The 20,000-person PRECEDE cohort is the scale-up.","status":"current","refs":[{"id":"paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005","kind":"paper","name":"Probability of pancreatic cancer following diabetes: a population-based study","route":"/key-papers/paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005/","tldr":"The 2005 Minnesota study that found about 1 in 100 people who develop diabetes after 50 is diagnosed with pancreatic cancer within three years, eight times the expected rate, which made new diabetes a possible early warning."},{"id":"paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018","kind":"paper","name":"Model to Determine Risk of Pancreatic Cancer in Patients With New-Onset Diabetes","route":"/key-papers/paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018/","tldr":"The 2018 Mayo Clinic score, called ENDPAC, that uses weight change, blood sugar change and age at diabetes onset to pick out the new diabetics whose risk of pancreatic cancer is high enough to scan."},{"id":"paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","kind":"paper","name":"Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection","route":"/key-papers/paper-fahrmann-ca19-9-lead-time-gastroenterology-2021/","tldr":"A 2021 study of stored blood from a US screening trial showing that CA 19-9 starts rising about two years before pancreatic cancer is diagnosed and catches half of early-stage cases in the final six months, so it can anchor a multi-marker early detection test."},{"id":"paper-canto-caps-long-term-surveillance-gastroenterology-2018","kind":"paper","name":"Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance","route":"/key-papers/paper-canto-caps-long-term-surveillance-gastroenterology-2018/","tldr":"The 2018 Johns Hopkins report of 354 people with inherited or family risk scanned for up to 16 years: 7 percent progressed to cancer or a high-grade precursor, 9 of the 10 cancers found by the scans were operable, and 85 percent of those patients were alive at three years."},{"id":"paper-caps-consortium-surveillance-recommendations-gut-2020","kind":"paper","name":"Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium","route":"/key-papers/paper-caps-consortium-surveillance-recommendations-gut-2020/","tldr":"The 2020 international consensus on who should have regular pancreatic scans because of family history or an inherited gene change, when to start, which scans to use and what the surveillance is trying to find."},{"id":"paper-dbouk-caps5-stage-survival-jco-2022","kind":"paper","name":"The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival","route":"/key-papers/paper-dbouk-caps5-stage-survival-jco-2022/","tldr":"The 2022 report from eight US centres: among 1,461 people at high inherited risk under regular scanning, most pancreatic cancers were caught at stage I, and across all the CAPS cohorts patients whose cancer was found by surveillance lived a median of nearly ten years against a year and a half for those found outside it."},{"id":"precede","kind":"trial","name":"PRECEDE","route":"/trials/precede/","status":"recruiting","tldr":"PRECEDE is a very large international study following people whose genes or family history put them at high risk of pancreatic cancer, with yearly scans and stored blood samples, to find out how to catch the cancer early enough to cure it; it is still enrolling towards 20,000 participants."},{"id":"pancreatic-surveillance","kind":"technology","name":"High-risk pancreatic surveillance (CAPS / PRECEDE)","route":"/technologies/pancreatic-surveillance/","status":"established","tldr":"Yearly MRI or endoscopic ultrasound for people with inherited risk, which catches pancreatic cancers while they are still operable."},{"id":"mced","kind":"technology","name":"Multi-cancer early detection (MCED)","route":"/technologies/mced/","status":"phase-3","tldr":"A single blood test intended to screen for dozens of cancers at once, including ones with no screening today."},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/","status":"standard-of-care","tldr":"A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour."},{"id":"galleri","kind":"drug","name":"Galleri","route":"/drugs/galleri/","status":"phase-3","tldr":"A blood test screening for more than 50 cancers at once, before the FDA in September 2026."},{"id":"ppv","kind":"term","name":"Positive predictive value (PPV)","route":"/terms/ppv/","tldr":"Positive predictive value (PPV) is the chance that a positive test result is actually right: true positives divided by all positives. Because it falls as a disease becomes rarer, even a specific screening test gives mostly false alarms when prevalence is low, which is why PPV decides whether a multi-cancer blood test is useful."},{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/","tldr":"Johns Hopkins is the birthplace of cancer genomics (Vogelstein), MSI-high immunotherapy (Le, Diaz), and liquid biopsy and MCED science (CancerSEEK)."},{"id":"diane-simeone","kind":"person","name":"Diane M. Simeone","route":"/people/diane-simeone/","tldr":"Pancreatic cancer surgeon-scientist who directs UC San Diego Moores Cancer Center, an NCI-designated comprehensive cancer center."},{"id":"early-detection-roadmap","kind":"roadmap","name":"Early detection roadmap: organ screening → blood tests for many cancers","route":"/roadmaps/early-detection-roadmap/","tldr":"From mammograms and colonoscopies to a single blood draw that might screen for dozens of cancers, with the FDA's first decision imminent."},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/","tldr":"Screening exists for only a few cancers. Pancreatic, ovarian, liver, oesophageal and most lung cancers are found when cure is unlikely."},{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/","tldr":"Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer."},{"id":"idea-mced-new-onset-diabetes","kind":"idea","name":"Blood-based pancreatic cancer detection in new-onset diabetes","route":"/ideas/idea-mced-new-onset-diabetes/","tldr":"Adults who suddenly develop diabetes after 50 have several times the usual risk of pancreatic cancer. Test their blood."},{"id":"idea-pdac-new-onset-diabetes-risk-score-pathway","kind":"idea","name":"Run the ENDPAC score on every new diabetes diagnosis after 50 and scan the high scorers","route":"/ideas/idea-pdac-new-onset-diabetes-risk-score-pathway/","tldr":"About 1 in 100 people who develop diabetes after 50 has a pancreatic cancer behind it. A score built from weight change, blood sugar change and age, calculable from records already in primary care, picks out a group where the rate is nearer 1 in 30; the proposal is to scan that group rather than wait for symptoms."},{"id":"idea-pdac-surveillance-for-every-germline-carrier","kind":"idea","name":"Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception","route":"/ideas/idea-pdac-surveillance-for-every-germline-carrier/","tldr":"One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically."}],"trials":[],"papers":[{"id":"paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005","name":"Probability of pancreatic cancer following diabetes: a population-based study","route":"/key-papers/paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005/","journal":"Gastroenterology","year":2005,"whatItMeans":"The observation behind every new-onset diabetes strategy: a 1 percent prevalence is a hundred times the general population's and high enough for a blood test or scan to have a useful positive predictive value."},{"id":"paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018","name":"Model to Determine Risk of Pancreatic Cancer in Patients With New-Onset Diabetes","route":"/key-papers/paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018/","journal":"Gastroenterology","year":2018,"whatItMeans":"A scoring tool that needs no new test and can run in primary care records; it turns the 1 percent of Chari's cohort into a 3.6 percent group in whom imaging or a blood test becomes defensible."},{"id":"paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","name":"Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection","route":"/key-papers/paper-fahrmann-ca19-9-lead-time-gastroenterology-2021/","journal":"Gastroenterology","year":2021,"whatItMeans":"Fixes the window in which a blood test could plausibly work and shows why CA 19-9 alone is not enough: half of early cases are missed even at diagnosis, and Lewis-negative patients are missed entirely."},{"id":"paper-canto-caps-long-term-surveillance-gastroenterology-2018","name":"Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance","route":"/key-papers/paper-canto-caps-long-term-surveillance-gastroenterology-2018/","journal":"Gastroenterology","year":2018,"whatItMeans":"The first long-term evidence that surveillance in high-risk people finds operable cancers, and the source of the imaging features that trigger surgery in the CAPS recommendations."},{"id":"paper-caps-consortium-surveillance-recommendations-gut-2020","name":"Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium","route":"/key-papers/paper-caps-consortium-surveillance-recommendations-gut-2020/","journal":"Gut","year":2020,"whatItMeans":"The rulebook behind the CAPS cohorts and the UK EUROPAC programme; it is also the reason surveillance for carriers is not yet a routine NHS service, because the consortium itself asked for it to stay within research until benefit was shown."},{"id":"paper-dbouk-caps5-stage-survival-jco-2022","name":"The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival","route":"/key-papers/paper-dbouk-caps5-stage-survival-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"The stage shift the pancreatic cancer page quotes (about three in four surveillance-detected cancers at stage I) and the strongest argument for offering surveillance to every germline carrier found by universal testing, which the NHS does not yet do outside research."}]},{"era":"2013-2026","title":"KRAS becomes druggable","description":"Ostrem and Shokat (2013) found the switch-II pocket on KRAS G12C; CodeBreaK 100 (Strickler 2023) gave sotorasib a 21 percent response and 6.9-month survival in the 1 to 2 percent of pancreatic cancers with that mutation, and KRYSTAL-1 did the same for adagrasib. The common alleles needed different chemistry: Holderfield (2024) described the RAS(ON) tri-complex inhibitors that clamp active mutant and wild-type RAS, and daraxonrasib, the clinical compound, nearly doubled survival in RASolute 302 (2026, 500 patients after one line of chemotherapy: 13.2 versus 6.7 months, hazard ratio 0.40), becoming the first RAS inhibitor approved for pancreatic cancer in August 2026. The G12D-selective zoldonrasib and the combination with daraxonrasib (RASolute 309) follow; resistance through secondary RAS mutations and receptor bypass is already described.","status":"current","refs":[{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/","tldr":"Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state."},{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","kind":"paper","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/","tldr":"The first KRAS-blocking pill shrank tumours in about one in five patients with heavily pretreated pancreatic cancer carrying the G12C mutation and controlled the disease in most for a few months. Modest as that is, it was the first direct hit on the gene that drives nearly every pancreatic cancer."},{"id":"paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","kind":"paper","name":"KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer","route":"/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/","tldr":"Adagrasib, the second KRAS G12C pill, shrank tumours in about a third of patients with pancreatic cancer and in two in five with bile duct cancer in this basket study, with disease control for several months."},{"id":"paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","kind":"paper","name":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","route":"/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/","tldr":"The 2024 Nature paper describing the chemistry behind daraxonrasib: a reversible drug that clamps the active form of every RAS protein, mutant or normal, and shrank tumours across RAS-driven models."},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/","status":"positive","tldr":"The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history."},{"id":"paper-daraxonrasib-pancreatic-n-engl-j-med-2026","kind":"paper","name":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","route":"/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/","tldr":"Phase 2 or 3 results paper on Daraxonrasib in Pancreatic ductal adenocarcinoma, in New England Journal of Medicine (2026), one of the most cited Europe PMC records with Daraxonrasib in its title."},{"id":"nct07805954","kind":"trial","name":"Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mut","route":"/trials/nct07805954/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib, Gemcitabine, Paclitaxel / nab-paclitaxel in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/","status":"phase-2","tldr":"The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding."},{"id":"elironrasib","kind":"drug","name":"Elironrasib","route":"/drugs/elironrasib/","status":"phase-2","tldr":"A next-generation KRAS G12C drug that hits the active form of the protein, from the same company as daraxonrasib."},{"id":"mrtx1133","kind":"drug","name":"MRTX1133","route":"/drugs/mrtx1133/","status":"phase-1","tldr":"MRTX1133 was the first potent chemical tool against KRAS G12D, and proved the mutation could be drugged even though it lacks the reactive handle G12C has."},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/","status":"approved","tldr":"Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure."},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/","status":"approved","tldr":"Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer."},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/","tldr":"KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021."},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/","status":"approved","tldr":"Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021."},{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/","tldr":"The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer."},{"id":"g12d-plus-pan-ras","kind":"pairing","name":"G12D-selective + pan-RAS(ON) inhibitor (zoldonrasib + daraxonrasib)","route":"/pairings/g12d-plus-pan-ras/","tldr":"A drug that hits the exact mutation plus a drug that hits every RAS protein, so the tumour cannot escape through a wild-type RAS cousin."},{"id":"kevan-shokat","kind":"person","name":"Kevan M. Shokat","route":"/people/kevan-shokat/","tldr":"The chemist whose lab found the hidden pocket in KRAS G12C that made the 'undruggable' target druggable."},{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/","tldr":"Revolution Medicines is the leading RAS company, with daraxonrasib in phase 3 for pancreatic cancer."},{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/","tldr":"Amgen invented the BiTE T-cell engager format and the first KRAS inhibitor."},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/","tldr":"Pioneer of checkpoint inhibitors (Opdivo, Yervoy), now betting on the first successful bispecific ADC and alpha radiopharmaceuticals."},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/","tldr":"The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug."},{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/","tldr":"Nearly every targeted therapy stops working within months to a few years as the tumour adapts."},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes."},{"id":"idea-ras-inhibitor-neoadjuvant-pdac","kind":"idea","name":"RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable","route":"/ideas/idea-ras-inhibitor-neoadjuvant-pdac/","tldr":"If daraxonrasib shrinks metastatic tumours this well, use it before surgery to make more locally advanced tumours operable."}],"trials":[{"id":"rasolute-302","name":"RASolute 302","route":"/trials/rasolute-302/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Daraxonrasib","value":13.2},{"name":"Chemotherapy (gemcitabine/nab-paclitaxel or mFOLFOX6)","value":6.7}],"hr":0.4,"source":"https://clinicaltrials.gov/study/NCT06625320"},{"endpoint":"Progression-free survival by blinded independent central review (overall population)","unit":"months","arms":[{"name":"Daraxonrasib","n":248,"value":7.2,"note":"95% CI 5.7 to 7.5"},{"name":"Chemotherapy (mFOLFIRINOX, gemcitabine/nab-paclitaxel, FOLFOX or liposomal irinotecan with 5-FU/LV)","n":252,"value":3.6,"note":"95% CI 2.9 to 4.2"}],"hr":0.49,"ci":[0.38,0.64],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"},{"endpoint":"Objective response rate by blinded independent central review (overall population)","unit":"%","arms":[{"name":"Daraxonrasib","n":248,"value":30,"note":"95% CI 25 to 36"},{"name":"Chemotherapy","n":252,"value":11,"note":"95% CI 7 to 15"}],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"}],"setting":"Metastatic PDAC after one prior line of chemotherapy: daraxonrasib vs investigator's choice chemotherapy","enrolled":500,"enrolledBasis":"registry"}],"papers":[{"id":"paper-ostrem-kras-g12c-nature-2013","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/","journal":"Nature","year":2013,"whatItMeans":"The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets."},{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Sotorasib is a guideline-listed later-line option for the 1 to 2 percent of pancreatic cancers with KRAS G12C, and the proof that KRAS in pancreatic cancer is druggable; the larger opportunity lies with inhibitors of G12D and pan-RAS drugs."},{"id":"paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","name":"KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer","route":"/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/","journal":"Journal of Clinical Oncology","year":2023,"whatItMeans":"Adagrasib joins sotorasib as a later-line option for KRAS G12C pancreatic cancer in guidelines; both drugs are the template for the G12D and pan-RAS inhibitors now in pancreatic trials."},{"id":"paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","name":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","route":"/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/","journal":"Nature","year":2024,"whatItMeans":"The mechanism that let one drug address G12D, G12V and G12R together, which is why the RASolute 302 trial could enrol unselected pancreatic cancer and nearly double survival."},{"id":"paper-daraxonrasib-pancreatic-n-engl-j-med-2026","name":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","route":"/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/","journal":"New England Journal of Medicine","year":2026,"whatItMeans":"One of the most cited trial reports Europe PMC returns for Daraxonrasib in Pancreatic ductal adenocarcinoma, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure."}]},{"era":"2023-2026","title":"Vaccines that last, a device that adds months, and a first-line chemotherapy answer","description":"Rojas (2023) showed an individualised mRNA neoantigen vaccine, autogene cevumeran, raised T cells in half of 16 resected patients, and Sethna (2025) that at 3.2 years those responders had mostly not relapsed (median recurrence-free survival not reached versus 13.4 months) with vaccine-induced clones estimated to live 7.7 years on average; the randomised IMCODE003 is enrolling 260 patients. The off-the-shelf KRAS vaccine ELI-002 7P missed in AMPLIFY-7P (2026). NAPOLI 3 (2023) made NALIRIFOX a first-line option over gemcitabine with nab-paclitaxel, and PANOVA-3 (2025, 571 patients) gave tumour treating fields with that chemotherapy a survival of 16.2 against 14.2 months in locally advanced disease (hazard ratio 0.82), the basis of the 2026 Optune Pax approval, without improving progression-free survival.","status":"current","refs":[{"id":"paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","kind":"paper","name":"Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer","route":"/key-papers/paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023/","tldr":"Individualised mRNA vaccines encoding up to 20 of each patient's tumour mutations generated strong T-cell responses in half of pancreatic cancer patients after surgery, and those responders had far fewer relapses."},{"id":"paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","kind":"paper","name":"RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer","route":"/key-papers/paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025/","tldr":"The 2025 follow-up of the personalised mRNA vaccine trial in pancreatic cancer: at three years, patients whose immune systems responded to the vaccine had still mostly not relapsed, and the T cells the vaccine made were predicted to live for years."},{"id":"nct05968326","kind":"trial","name":"A Study of the Efficacy and Safety of Adjuvant Autogene Cevumeran Plus Atezolizumab and mFOLFIRINOX Versus mFOLFIRINOX Alone in Participants With Resected PDAC","route":"/trials/nct05968326/","status":"active","tldr":"A phase 2 trial of Autogene cevumeran and Atezolizumab in pancreatic ductal adenocarcinoma, run by Genentech, Inc., active and no longer recruiting."},{"id":"amplify-7p","kind":"trial","name":"AMPLIFY-7P","route":"/trials/amplify-7p/","status":"negative","tldr":"The randomised test of an off-the-shelf KRAS vaccine after pancreatic surgery. It missed its primary goal in June 2026."},{"id":"eli-002-7p","kind":"drug","name":"ELI-002 7P","route":"/drugs/eli-002-7p/","status":"phase-2","tldr":"A ready-made vaccine against the seven commonest KRAS mutations, given after pancreatic cancer surgery. Its phase 2 missed the main goal in 2026 but showed signs of activity."},{"id":"autogene-cevumeran","kind":"drug","name":"Autogene cevumeran","route":"/drugs/autogene-cevumeran/","status":"phase-2","tldr":"Autogene cevumeran is BioNTech and Genentech's personalised mRNA vaccine encoding each patient's own tumour neoantigens. In a small phase 1 in resected pancreatic cancer, half of patients mounted T-cell responses and stayed free of recurrence far longer; phase 2 IMCODE003 tests whether that holds."},{"id":"neoantigen-mrna-vaccine","kind":"technology","name":"Personalised neoantigen (mRNA) vaccines","route":"/technologies/neoantigen-mrna-vaccine/","status":"phase-3","tldr":"A vaccine made for one patient, encoding the unique mutations in their own tumour, to train the immune system to hunt it."},{"id":"shared-antigen-vaccine","kind":"technology","name":"Off-the-shelf cancer vaccines","route":"/technologies/shared-antigen-vaccine/","status":"phase-3","tldr":"Off-the-shelf cancer vaccines target antigens shared across patients, such as mutant KRAS or HER2 peptides, so they are made in advance rather than per person. Sipuleucel-T is still the only approved therapeutic cancer vaccine in the US; tolerance to self-antigens and weak past results hold them back."},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/","tldr":"A protein fragment created by a tumour mutation that the immune system has never seen before, so it can attack it without harming normal cells."},{"id":"vinod-balachandran","kind":"person","name":"Vinod P. Balachandran","route":"/people/vinod-balachandran/","tldr":"Surgeon-scientist whose personalised mRNA vaccine trial showed pancreatic cancer can provoke lasting T-cell immunity."},{"id":"ugur-sahin","kind":"person","name":"Uğur Şahin","route":"/people/ugur-sahin/","tldr":"Immunologist who built individualised mRNA neoantigen vaccines for cancer, the platform later used for COVID-19."},{"id":"biontech","kind":"company","name":"BioNTech","route":"/companies/biontech/","tldr":"From COVID vaccine to a broad oncology pipeline: personalised vaccines, ADCs from China, and a PD-L1×VEGF bispecific sold to BMS for $11B."},{"id":"elicio-therapeutics","kind":"company","name":"Elicio Therapeutics","route":"/companies/elicio-therapeutics/","tldr":"Small biotech developing lymph-node-targeted KRAS vaccines for pancreatic and colorectal cancer."},{"id":"idea-shared-kras-vaccine-adjuvant","kind":"idea","name":"Off-the-shelf KRAS vaccines after pancreatic cancer surgery","route":"/ideas/idea-shared-kras-vaccine-adjuvant/","tldr":"Almost every pancreatic cancer shares one of a handful of KRAS mutations. A pre-made vaccine against them could be given to every patient after surgery."},{"id":"napoli-3","kind":"trial","name":"NAPOLI 3","route":"/trials/napoli-3/","status":"positive","tldr":"The first head-to-head trial of the two chemotherapy backbones, won narrowly by the four-drug regimen."},{"id":"paper-napoli-3-lancet-2023","kind":"paper","name":"NAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancer","route":"/key-papers/paper-napoli-3-lancet-2023/","tldr":"NAPOLI-3 randomised 770 patients with untreated metastatic pancreatic cancer to NALIRIFOX, a four-drug regimen built on liposomal irinotecan, or to gemcitabine plus nab-paclitaxel, the doublet most patients receive. NALIRIFOX lengthened life and delayed progression, the first positive first-line trial in a decade, though conventional FOLFIRINOX remains the usual choice where affordable."},{"id":"nalirifox","kind":"drug","name":"NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)","route":"/drugs/nalirifox/","status":"approved","tldr":"NALIRIFOX is a version of FOLFIRINOX using a liposome-wrapped irinotecan, approved in 2024 as a first-line option for metastatic pancreatic cancer."},{"id":"panova-3","kind":"trial","name":"PANOVA-3","route":"/trials/panova-3/","status":"positive","tldr":"PANOVA-3 is the trial behind the 2026 approval of a wearable electric-field device for pancreatic cancer, the first new approval in locally advanced disease in decades."},{"id":"paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025","kind":"paper","name":"Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study","route":"/key-papers/paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025/","tldr":"The 2025 trial in which a wearable device delivering alternating electric fields to the abdomen, added to chemotherapy, lengthened survival in locally advanced pancreatic cancer from about 14 to 16 months and delayed the onset of pain."},{"id":"optune","kind":"drug","name":"Optune / Optune Pax (TTFields)","route":"/drugs/optune/","status":"approved","tldr":"Optune is a wearable device delivering electric fields that disrupt cell division. It is approved for glioblastoma and, in 2026, pancreatic cancer."},{"id":"ttfields","kind":"technology","name":"Tumour treating fields (TTFields)","route":"/technologies/ttfields/","status":"approved","tldr":"Wearable electrodes that deliver alternating electric fields disrupting cancer cell division."},{"id":"novocure","kind":"company","name":"Novocure","route":"/companies/novocure/","tldr":"Novocure makes Optune tumour treating fields, approved in glioblastoma, lung, mesothelioma, and (2026) pancreatic cancer."},{"id":"devices-roadmap","kind":"roadmap","name":"Devices and physical therapies roadmap: heat and light → electric fields and focused sound → drug-releasing implants","route":"/roadmaps/devices-roadmap/","tldr":"Devices treat cancer with physics rather than chemistry: heat, cold, light, electric fields and sound. After decades at the margins, several now have randomised proof and approvals, and the next generation aims to prime the immune system as it destroys the tumour."},{"id":"immunotherapy-roadmap","kind":"roadmap","name":"Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity","route":"/roadmaps/immunotherapy-roadmap/","tldr":"The immunotherapy roadmap is a 130-year arc from injecting bacteria into tumours to releasing immune brakes, and now to designing the immune response itself with vaccines, engagers, and cells."},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/","tldr":"Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating."}],"trials":[{"id":"amplify-7p","name":"AMPLIFY-7P","route":"/trials/amplify-7p/","outcomes":[{"endpoint":"Disease-free survival (ITT)","primary":true,"unit":"months","arms":[{"name":"ELI-002 7P","note":"Primary endpoint not met (sponsor release, 15 June 2026); ITT hazard ratio and medians not disclosed."},{"name":"Observation"}],"source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"},{"endpoint":"Disease-free survival at 3 months (landmark)","unit":"%","arms":[{"name":"ELI-002 7P","value":90.3},{"name":"Observation","value":76.6}],"p":"0.022","source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"},{"endpoint":"Disease-free survival, R0-resected subgroup (post hoc)","unit":"months","arms":[{"name":"ELI-002 7P","value":23.8,"note":"Post hoc analysis of 121 R0-resected patients; hypothesis-generating only."},{"name":"Observation","value":12.8}],"hr":0.65,"p":"0.048","source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"}],"setting":"Adjuvant mKRAS PDAC after surgery and chemotherapy: ELI-002 7P vs observation","enrolled":158,"enrolledBasis":"registry"},{"id":"napoli-3","name":"NAPOLI 3","route":"/trials/napoli-3/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"NALIRIFOX","n":383,"value":11.1},{"name":"Gemcitabine + nab-paclitaxel","n":387,"value":9.2}],"hr":0.83,"ci":[0.7,0.99],"p":"0.036","source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01366-1/fulltext"}],"setting":"First-line metastatic PDAC: NALIRIFOX vs gemcitabine + nab-paclitaxel","enrolled":770,"enrolledBasis":"registry"},{"id":"panova-3","name":"PANOVA-3","route":"/trials/panova-3/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"TTFields + gemcitabine/nab-paclitaxel","n":284,"value":16.2},{"name":"Gemcitabine/nab-paclitaxel","n":287,"value":14.2}],"hr":0.82,"ci":[0.68,0.99],"p":"0.039","source":"https://ascopubs.org/doi/10.1200/JCO.25.00361"},{"endpoint":"Pain-free survival","unit":"months","arms":[{"name":"TTFields + gemcitabine/nab-paclitaxel","value":15.2,"note":"95% CI 10.3 to 22.8"},{"name":"Gemcitabine/nab-paclitaxel","value":9.1,"note":"95% CI 7.4 to 12.7"}],"hr":0.74,"ci":[0.56,0.97],"p":"0.027","source":"https://doi.org/10.1200/JCO-25-00746"}],"setting":"Unresectable locally advanced PDAC: TTFields + gemcitabine/nab-paclitaxel vs chemotherapy alone","enrolled":571,"enrolledBasis":"registry"}],"papers":[{"id":"paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","name":"Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer","route":"/key-papers/paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023/","journal":"Nature","year":2023,"whatItMeans":"Pancreatic cancer was thought to be immunologically inert because of its low mutation burden; this study showed that with the right vaccine platform its few neoantigens can still be targeted. It is the strongest human evidence so far that personalised cancer vaccines can generate durable, tumour-specific immunity, and it justifies the randomised trials now running in pancreatic cancer and melanoma. Benefit is not yet proven, because responders may simply have had more immunogenic tumours."},{"id":"paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","name":"RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer","route":"/key-papers/paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025/","journal":"Nature","year":2025,"whatItMeans":"The strongest human evidence that a cancer vaccine can make durable T cells in a tumour with few mutations; the randomised phase 2 IMCODE003 (260 patients, primary completion listed for January 2031) is the test of whether that translates into fewer relapses."},{"id":"paper-napoli-3-lancet-2023","name":"NAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancer","route":"/key-papers/paper-napoli-3-lancet-2023/","journal":"The Lancet","year":2023,"whatItMeans":"For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head."},{"id":"paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025","name":"Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study","route":"/key-papers/paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025/","journal":"Journal of Clinical Oncology","year":2025,"whatItMeans":"The evidence behind the 2026 approval of Optune Pax for locally advanced disease, the first new approval in that setting in decades, and an unusual case of a survival gain without a progression-free survival gain."}]},{"era":"2026-2031","title":"What the registry says is coming","description":"The RAS inhibitor moves earlier: RASolute 303 (daraxonrasib alone or with gemcitabine and nab-paclitaxel first line, 900 estimated participants, primary completion June 2028), RASolute 304 (adjuvant daraxonrasib after resection, 500, May 2029) and RASolute 309 (zoldonrasib with daraxonrasib against chemotherapy first line in G12D disease, 400, March 2029), with Incyte's G12D inhibitor in DAWN-303 (588, September 2028). The perioperative question is being answered by PREOPANC-3 (perioperative against adjuvant modified FOLFIRINOX, 378 estimated, January 2027) and Alliance A021806 (358, December 2028). IMCODE003 tests the vaccine (260, January 2031) and PRECEDE follows 20,000 high-risk people to December 2030. RASolute 302 itself lists study completion for December 2027 and AMPLIFY-7P for November 2026.","status":"emerging","refs":[{"id":"nct07491445","kind":"trial","name":"Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma","route":"/trials/nct07491445/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib, Gemcitabine, Paclitaxel / nab-paclitaxel in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"nct07252232","kind":"trial","name":"Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)","route":"/trials/nct07252232/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"nct07805954","kind":"trial","name":"Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mut","route":"/trials/nct07805954/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib, Gemcitabine, Paclitaxel / nab-paclitaxel in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"nct07522073","kind":"trial","name":"A Study to Evaluate Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D-Mutated Metastatic Pancreatic Ductal Adenocarcinoma","route":"/trials/nct07522073/","status":"recruiting","tldr":"A phase 3 trial testing INCB161734 in pancreatic ductal adenocarcinoma, now recruiting."},{"id":"nct07262567","kind":"trial","name":"Phase III Study to Compare GFH375 and Chemotherapy in Patients With KRAS G12D-Mutant Metastatic Pancreatic Cancer","route":"/trials/nct07262567/","status":"recruiting","tldr":"A phase 3 trial testing GFH375 in pancreatic ductal adenocarcinoma, now recruiting."},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/","status":"positive","tldr":"The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history."},{"id":"amplify-7p","kind":"trial","name":"AMPLIFY-7P","route":"/trials/amplify-7p/","status":"negative","tldr":"The randomised test of an off-the-shelf KRAS vaccine after pancreatic surgery. It missed its primary goal in June 2026."},{"id":"nct05968326","kind":"trial","name":"A Study of the Efficacy and Safety of Adjuvant Autogene Cevumeran Plus Atezolizumab and mFOLFIRINOX Versus mFOLFIRINOX Alone in Participants With Resected PDAC","route":"/trials/nct05968326/","status":"active","tldr":"A phase 2 trial of Autogene cevumeran and Atezolizumab in pancreatic ductal adenocarcinoma, run by Genentech, Inc., active and no longer recruiting."},{"id":"precede","kind":"trial","name":"PRECEDE","route":"/trials/precede/","status":"recruiting","tldr":"PRECEDE is a very large international study following people whose genes or family history put them at high risk of pancreatic cancer, with yearly scans and stored blood samples, to find out how to catch the cancer early enough to cure it; it is still enrolling towards 20,000 participants."},{"id":"preopanc","kind":"trial","name":"PREOPANC-1","route":"/trials/preopanc/","status":"mixed","tldr":"The Dutch trial testing whether treating before surgery beats operating first. Chemoradiation first fell short at the primary analysis but won at five years, with one in five patients alive against one in fifteen."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/","status":"phase-2","tldr":"The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding."},{"id":"autogene-cevumeran","kind":"drug","name":"Autogene cevumeran","route":"/drugs/autogene-cevumeran/","status":"phase-2","tldr":"Autogene cevumeran is BioNTech and Genentech's personalised mRNA vaccine encoding each patient's own tumour neoantigens. In a small phase 1 in resected pancreatic cancer, half of patients mounted T-cell responses and stayed free of recurrence far longer; phase 2 IMCODE003 tests whether that holds."},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/","status":"approved","tldr":"Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021."},{"id":"pancreatic-surveillance","kind":"technology","name":"High-risk pancreatic surveillance (CAPS / PRECEDE)","route":"/technologies/pancreatic-surveillance/","status":"established","tldr":"Yearly MRI or endoscopic ultrasound for people with inherited risk, which catches pancreatic cancers while they are still operable."},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes."},{"id":"idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","kind":"idea","name":"Chemotherapy before surgery for every resectable pancreatic cancer, settled by the two perioperative trials rather than assumed","route":"/ideas/idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease/","tldr":"Giving chemotherapy before the operation is standard when the tumour is borderline operable, but for tumours that can be removed straight away two trials have failed to show it beats operating first. Two more, one Dutch and one American, are directly comparing chemotherapy before and after surgery with chemotherapy after alone; the proposal is to wait for them and to pool them."},{"id":"idea-pdac-surveillance-for-every-germline-carrier","kind":"idea","name":"Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception","route":"/ideas/idea-pdac-surveillance-for-every-germline-carrier/","tldr":"One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically."}],"trials":[{"id":"rasolute-302","name":"RASolute 302","route":"/trials/rasolute-302/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Daraxonrasib","value":13.2},{"name":"Chemotherapy (gemcitabine/nab-paclitaxel or mFOLFOX6)","value":6.7}],"hr":0.4,"source":"https://clinicaltrials.gov/study/NCT06625320"},{"endpoint":"Progression-free survival by blinded independent central review (overall population)","unit":"months","arms":[{"name":"Daraxonrasib","n":248,"value":7.2,"note":"95% CI 5.7 to 7.5"},{"name":"Chemotherapy (mFOLFIRINOX, gemcitabine/nab-paclitaxel, FOLFOX or liposomal irinotecan with 5-FU/LV)","n":252,"value":3.6,"note":"95% CI 2.9 to 4.2"}],"hr":0.49,"ci":[0.38,0.64],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"},{"endpoint":"Objective response rate by blinded independent central review (overall population)","unit":"%","arms":[{"name":"Daraxonrasib","n":248,"value":30,"note":"95% CI 25 to 36"},{"name":"Chemotherapy","n":252,"value":11,"note":"95% CI 7 to 15"}],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"}],"setting":"Metastatic PDAC after one prior line of chemotherapy: daraxonrasib vs investigator's choice chemotherapy","enrolled":500,"enrolledBasis":"registry"},{"id":"amplify-7p","name":"AMPLIFY-7P","route":"/trials/amplify-7p/","outcomes":[{"endpoint":"Disease-free survival (ITT)","primary":true,"unit":"months","arms":[{"name":"ELI-002 7P","note":"Primary endpoint not met (sponsor release, 15 June 2026); ITT hazard ratio and medians not disclosed."},{"name":"Observation"}],"source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"},{"endpoint":"Disease-free survival at 3 months (landmark)","unit":"%","arms":[{"name":"ELI-002 7P","value":90.3},{"name":"Observation","value":76.6}],"p":"0.022","source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"},{"endpoint":"Disease-free survival, R0-resected subgroup (post hoc)","unit":"months","arms":[{"name":"ELI-002 7P","value":23.8,"note":"Post hoc analysis of 121 R0-resected patients; hypothesis-generating only."},{"name":"Observation","value":12.8}],"hr":0.65,"p":"0.048","source":"https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/"}],"setting":"Adjuvant mKRAS PDAC after surgery and chemotherapy: ELI-002 7P vs observation","enrolled":158,"enrolledBasis":"registry"},{"id":"preopanc","name":"PREOPANC-1","route":"/trials/preopanc/","outcomes":[{"endpoint":"Overall survival (long-term)","primary":true,"unit":"%","arms":[{"name":"Neoadjuvant chemoradiotherapy, 5-year OS","n":119,"value":20.5},{"name":"Upfront surgery, 5-year OS","n":127,"value":6.5}],"hr":0.73,"ci":[0.56,0.96],"p":"0.025","source":"https://ascopubs.org/doi/10.1200/JCO.21.02233"},{"endpoint":"Overall survival (primary analysis, intention to treat)","unit":"months","arms":[{"name":"Neoadjuvant gemcitabine chemoradiotherapy, surgery, adjuvant gemcitabine","n":119,"value":16},{"name":"Upfront surgery, adjuvant gemcitabine","n":127,"value":14.3}],"hr":0.78,"ci":[0.58,1.05],"p":"0.096","source":"https://doi.org/10.1200/JCO.19.02274"},{"endpoint":"R0 resection rate among resected patients","unit":"%","arms":[{"name":"Neoadjuvant chemoradiotherapy","n":72,"value":71,"note":"51 of 72"},{"name":"Upfront surgery","n":92,"value":40,"note":"37 of 92"}],"p":"<0.001","source":"https://doi.org/10.1200/JCO.19.02274"}],"setting":"Resectable and borderline-resectable PDAC at 16 Dutch centres: neoadjuvant gemcitabine-based chemoradiation (36 Gy in 15 fractions), surgery and adjuvant gemcitabine vs upfront surgery and adjuvant gemcitabine","enrolled":246,"enrolledBasis":"registry"}],"papers":[]},{"era":"What sets the pace","title":"Late presentation, fitness, wasting and who gets treated at all","description":"Four things no trial on this page has fixed. Four in five patients present with disease that cannot be removed, and neither the new-onset diabetes score nor carrier surveillance has yet been shown in a prospective trial to change that at population scale. Half of patients are not fit for FOLFIRINOX-class chemotherapy, and the pivotal trials enrolled the fit half; whether RAS inhibitors change that is being measured. Cachexia and exocrine insufficiency stop treatment being delivered, enzyme replacement reaches about one patient in five in UK primary care data (Roberts 2019) and cachexia has its first mechanism-based drug (ponsegromab 2024) but no phase 3. And in England and Wales the National Pancreatic Cancer Audit reports each year how many patients receive any active treatment and how quickly, which the UK and NHS page holds; each has an idea on this page.","status":"current","refs":[{"id":"paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019","kind":"paper","name":"Enzyme replacement improves survival among patients with pancreatic cancer: Results of a population based study","route":"/key-papers/paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019/","tldr":"A 2019 study of UK primary care records finding that only about one in five people with pancreatic cancer was prescribed the digestive enzyme capsules that replace what the diseased pancreas no longer makes, and that those who were lived markedly longer."},{"id":"paper-groarke-ponsegromab-cancer-cachexia-nejm-2024","kind":"paper","name":"Ponsegromab for the Treatment of Cancer Cachexia","route":"/key-papers/paper-groarke-ponsegromab-cancer-cachexia-nejm-2024/","tldr":"The 2024 phase 2 trial in which an antibody blocking the hormone GDF-15 helped patients with cancer-related wasting, a third of them with pancreatic cancer, gain about two to three kilograms in twelve weeks and become more active."},{"id":"paper-fearon-lancet-oncol","kind":"paper","name":"Definition and classification of cancer cachexia: an international consensus","route":"/key-papers/paper-fearon-lancet-oncol/","tldr":"Paper cited by one term page, one bottleneck page and eleven idea pages, indexed on Europe PMC as PubMed record 21296615 and published in The Lancet Oncology; the citing pages link this DOI, which is how the record was matched."},{"id":"ponsegromab","kind":"drug","name":"Ponsegromab","route":"/drugs/ponsegromab/","status":"phase-3","tldr":"Ponsegromab is a monoclonal antibody from Pfizer, in registered phase 3 trials for pancreatic ductal adenocarcinoma."},{"id":"performance-status","kind":"term","name":"Performance status (ECOG, Karnofsky)","route":"/terms/performance-status/","tldr":"A simple score of how well a patient can get about and look after themselves: ECOG 0 is fully active, 1 restricted from strenuous work, 2 up more than half the day, 3 in bed more than half the day, 4 bedbound. It predicts how treatment will be tolerated and gates almost every trial."},{"id":"obstructive-jaundice","kind":"term","name":"Obstructive jaundice and biliary obstruction","route":"/terms/obstructive-jaundice/","tldr":"Yellowing of the skin and eyes because a tumour blocks the bile duct, most often pancreatic or bile duct cancer. It causes itching, infection risk and dark urine, and it must be relieved (usually with a stent) before chemotherapy can be given safely."},{"id":"biliary-stent","kind":"term","name":"Stenting (biliary, oesophageal, airway)","route":"/terms/biliary-stent/","tldr":"Placing a small mesh or plastic tube to hold open a duct or passage that a tumour is squeezing shut, relieving jaundice, swallowing difficulty or breathlessness."},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/","tldr":"Screening exists for only a few cancers. Pancreatic, ovarian, liver, oesophageal and most lung cancers are found when cure is unlikely."},{"id":"b-aging-comorbidity","kind":"bottleneck","name":"Older and multimorbid patients are excluded and undertreated","route":"/bottlenecks/b-aging-comorbidity/","tldr":"Most people with cancer are over 65 but most trial patients are younger and fitter. We guess how to treat the majority."},{"id":"b-cachexia-supportive","kind":"bottleneck","name":"Cachexia, toxicity and the limits of the patient","route":"/bottlenecks/b-cachexia-supportive/","tldr":"Cancer cachexia, the muscle and fat wasting driven by tumour and host inflammatory signals, affects most patients with advanced pancreatic, gastric and lung cancer, and treatment-limiting toxicities decide what dose a patient can receive. Only Japan has an approved cachexia drug, and supportive care research gets a small share of funding relative to its effect."},{"id":"b-care-fragmentation","kind":"bottleneck","name":"Fragmented care and guideline gaps","route":"/bottlenecks/b-care-fragmentation/","tldr":"Patients fall between specialists, wait for referrals and often do not get the treatment guidelines say they should."},{"id":"b-knowledge-diffusion","kind":"bottleneck","name":"Knowledge reaches practice too slowly","route":"/bottlenecks/b-knowledge-diffusion/","tldr":"Knowledge diffusion is slow: it takes years for a proven result to change what most patients receive, and no one can keep up with the literature."},{"id":"survivorship-roadmap","kind":"roadmap","name":"Supportive care and survivorship roadmap: making treatment bearable → proving it extends life → caring for tens of millions afterwards","route":"/roadmaps/survivorship-roadmap/","tldr":"Supportive care began as the drugs that let people get through chemotherapy. It is now a discipline with randomised proof that exercise, early palliative care and symptom monitoring lengthen life, and its next task is organised lifelong care for the growing population of people living after cancer."},{"id":"idea-pdac-new-onset-diabetes-risk-score-pathway","kind":"idea","name":"Run the ENDPAC score on every new diabetes diagnosis after 50 and scan the high scorers","route":"/ideas/idea-pdac-new-onset-diabetes-risk-score-pathway/","tldr":"About 1 in 100 people who develop diabetes after 50 has a pancreatic cancer behind it. A score built from weight change, blood sugar change and age, calculable from records already in primary care, picks out a group where the rate is nearer 1 in 30; the proposal is to scan that group rather than wait for symptoms."},{"id":"idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials","kind":"idea","name":"Embed cachexia treatment in chemotherapy trials: weight, muscle and treatment delivery as co-primary endpoints","route":"/ideas/idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials/","tldr":"Most people with pancreatic cancer lose muscle and weight in a way food alone cannot reverse, and that wasting is a common reason chemotherapy is cut or stopped. A 2024 trial showed an antibody against the hormone GDF-15 restored weight and activity in twelve weeks, a third of the patients having pancreatic cancer. The proposal is to test it inside the chemotherapy trials, not alongside them."},{"id":"idea-pdac-enzyme-replacement-prescribing-by-default","kind":"idea","name":"Pancreatic enzyme replacement by default: prescribe at diagnosis, audit the rate, and run the trial that settles survival","route":"/ideas/idea-pdac-enzyme-replacement-prescribing-by-default/","tldr":"The pancreas makes the enzymes that digest food, and a cancer in it, or the operation to remove it, leaves most patients unable to absorb what they eat. Capsules replacing those enzymes are cheap and recommended, yet UK records show only one patient in five was prescribed them. The proposal is to prescribe by default at diagnosis, publish each hospital's rate, and run the trial never done."},{"id":"idea-pdac-uk-active-treatment-rate-audit-and-target","kind":"idea","name":"Raise the share of UK patients who receive any active treatment, and publish it by trust","route":"/ideas/idea-pdac-uk-active-treatment-rate-audit-and-target/","tldr":"In England and Wales a national audit now reports each year what share of people diagnosed with pancreatic cancer receive any treatment aimed at the cancer, how many are discussed by a specialist team and how many see a specialist nurse. The proposal is a national target for the treatment rate, published by hospital, so the trusts furthest behind are visible."},{"id":"idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway","kind":"idea","name":"A fast-track pathway from suspicion to treatment for pancreatic cancer in the NHS, measured from first scan to first treatment","route":"/ideas/idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway/","tldr":"Pancreatic cancer grows and spreads quickly, and delays between the scan that finds it, the specialist meeting, the biopsy, the bile duct stent and the first chemotherapy or operation are measured in weeks. The proposal is a dedicated fast-track pathway with a national standard for the interval from first imaging to first treatment, reported by the audit."}],"trials":[],"papers":[{"id":"paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019","name":"Enzyme replacement improves survival among patients with pancreatic cancer: Results of a population based study","route":"/key-papers/paper-roberts-pert-survival-pancreatic-cancer-pancreatology-2019/","journal":"Pancreatology","year":2019,"whatItMeans":"Enzyme replacement is cheap, guideline-recommended (NICE NG85) and under-prescribed; the National Pancreatic Cancer Audit now reports the prescribing rate as a performance indicator, which the UK and NHS page tracks."},{"id":"paper-groarke-ponsegromab-cancer-cachexia-nejm-2024","name":"Ponsegromab for the Treatment of Cancer Cachexia","route":"/key-papers/paper-groarke-ponsegromab-cancer-cachexia-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"The first drug to reverse cancer cachexia mechanistically rather than by appetite stimulation, in a disease where weight loss stops chemotherapy being delivered; the phase 3 programme and the question of survival remain."},{"id":"paper-fearon-lancet-oncol","name":"Definition and classification of cancer cachexia: an international consensus","route":"/key-papers/paper-fearon-lancet-oncol/","journal":"The Lancet Oncology","year":2011,"whatItMeans":"One term page, one bottleneck page and eleven idea pages on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."}]}],"watch":[{"item":"RASolute 302 primary completion on the registry (daraxonrasib versus chemotherapy, previously treated metastatic disease, 500 participants, actual; published and approved 2026)","expected":"2026-06","source":"https://clinicaltrials.gov/study/NCT06625320","refs":[{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/","status":"positive","tldr":"The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"paper-daraxonrasib-pancreatic-n-engl-j-med-2026","kind":"paper","name":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","route":"/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/","tldr":"Phase 2 or 3 results paper on Daraxonrasib in Pancreatic ductal adenocarcinoma, in New England Journal of Medicine (2026), one of the most cited Europe PMC records with Daraxonrasib in its title."}]},{"item":"AMPLIFY-7P study completion (ELI-002 7P adjuvant KRAS vaccine, 158 participants; primary completion 20 April 2026, actual)","expected":"2026-11","source":"https://clinicaltrials.gov/study/NCT05726864","refs":[{"id":"amplify-7p","kind":"trial","name":"AMPLIFY-7P","route":"/trials/amplify-7p/","status":"negative","tldr":"The randomised test of an off-the-shelf KRAS vaccine after pancreatic surgery. It missed its primary goal in June 2026."},{"id":"eli-002-7p","kind":"drug","name":"ELI-002 7P","route":"/drugs/eli-002-7p/","status":"phase-2","tldr":"A ready-made vaccine against the seven commonest KRAS mutations, given after pancreatic cancer surgery. Its phase 2 missed the main goal in 2026 but showed signs of activity."},{"id":"shared-antigen-vaccine","kind":"technology","name":"Off-the-shelf cancer vaccines","route":"/technologies/shared-antigen-vaccine/","status":"phase-3","tldr":"Off-the-shelf cancer vaccines target antigens shared across patients, such as mutant KRAS or HER2 peptides, so they are made in advance rather than per person. Sipuleucel-T is still the only approved therapeutic cancer vaccine in the US; tolerance to self-antigens and weak past results hold them back."}]},{"item":"PREOPANC-3 primary completion: perioperative versus adjuvant modified FOLFIRINOX for resectable pancreatic cancer (378 estimated participants; active, not recruiting)","expected":"2027-01","source":"https://clinicaltrials.gov/study/NCT04927780","refs":[{"id":"preopanc","kind":"trial","name":"PREOPANC-1","route":"/trials/preopanc/","status":"mixed","tldr":"The Dutch trial testing whether treating before surgery beats operating first. Chemoradiation first fell short at the primary analysis but won at five years, with one in five patients alive against one in fifteen."},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/","status":"standard-of-care","tldr":"FOLFIRINOX is a four-drug chemotherapy combination that, in 2011, became the first treatment to meaningfully extend life in metastatic pancreatic cancer; it is now the standard before and after surgery."},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/","tldr":"Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind."},{"id":"idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","kind":"idea","name":"Chemotherapy before surgery for every resectable pancreatic cancer, settled by the two perioperative trials rather than assumed","route":"/ideas/idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease/","tldr":"Giving chemotherapy before the operation is standard when the tumour is borderline operable, but for tumours that can be removed straight away two trials have failed to show it beats operating first. Two more, one Dutch and one American, are directly comparing chemotherapy before and after surgery with chemotherapy after alone; the proposal is to wait for them and to pool them."}]},{"item":"RASolute 302 study completion on the registry","expected":"2027-12","source":"https://clinicaltrials.gov/study/NCT06625320","refs":[{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/","status":"positive","tldr":"The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."}]},{"item":"RASolute 303 primary completion: daraxonrasib alone or with gemcitabine and nab-paclitaxel versus chemotherapy, first line metastatic (900 estimated participants; recruiting)","expected":"2028-06","source":"https://clinicaltrials.gov/study/NCT07491445","refs":[{"id":"nct07491445","kind":"trial","name":"Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma","route":"/trials/nct07491445/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib, Gemcitabine, Paclitaxel / nab-paclitaxel in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"gemcitabine-nab-paclitaxel","kind":"drug","name":"Gemcitabine + nab-paclitaxel","route":"/drugs/gemcitabine-nab-paclitaxel/","status":"standard-of-care","tldr":"Gemcitabine plus nab-paclitaxel is the gentler of the two standard chemotherapy backbones for pancreatic cancer, and the base on which most new drugs are being tested."},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes."}]},{"item":"DAWN-303 primary completion: chemotherapy with or without INCB161734 in untreated KRAS G12D metastatic disease (588 estimated participants; recruiting)","expected":"2028-09-15","source":"https://clinicaltrials.gov/study/NCT07522073","refs":[{"id":"nct07522073","kind":"trial","name":"A Study to Evaluate Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D-Mutated Metastatic Pancreatic Ductal Adenocarcinoma","route":"/trials/nct07522073/","status":"recruiting","tldr":"A phase 3 trial testing INCB161734 in pancreatic ductal adenocarcinoma, now recruiting."},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/","status":"approved","tldr":"Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021."},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes."}]},{"item":"Alliance A021806 primary completion: perioperative versus adjuvant modified FOLFIRINOX for resectable pancreatic cancer (358 participants, actual; active, not recruiting)","expected":"2028-12-31","source":"https://clinicaltrials.gov/study/NCT04340141","refs":[{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/","status":"standard-of-care","tldr":"FOLFIRINOX is a four-drug chemotherapy combination that, in 2011, became the first treatment to meaningfully extend life in metastatic pancreatic cancer; it is now the standard before and after surgery."},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/","tldr":"Neoadjuvant therapy is treatment given before surgery, adjuvant therapy is treatment given after it, and perioperative therapy is both. Neoadjuvant treatment shrinks tumours and shows whether the drug works in the living patient; adjuvant treatment aims to kill microscopic disease left behind."},{"id":"idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","kind":"idea","name":"Chemotherapy before surgery for every resectable pancreatic cancer, settled by the two perioperative trials rather than assumed","route":"/ideas/idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease/","tldr":"Giving chemotherapy before the operation is standard when the tumour is borderline operable, but for tumours that can be removed straight away two trials have failed to show it beats operating first. Two more, one Dutch and one American, are directly comparing chemotherapy before and after surgery with chemotherapy after alone; the proposal is to wait for them and to pool them."}]},{"item":"RASolute 309 primary completion: zoldonrasib plus daraxonrasib versus gemcitabine and nab-paclitaxel, first line KRAS G12D metastatic disease (400 estimated participants; recruiting)","expected":"2029-03","source":"https://clinicaltrials.gov/study/NCT07805954","refs":[{"id":"nct07805954","kind":"trial","name":"Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mut","route":"/trials/nct07805954/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib, Gemcitabine, Paclitaxel / nab-paclitaxel in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/","status":"phase-2","tldr":"The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"g12d-plus-pan-ras","kind":"pairing","name":"G12D-selective + pan-RAS(ON) inhibitor (zoldonrasib + daraxonrasib)","route":"/pairings/g12d-plus-pan-ras/","tldr":"A drug that hits the exact mutation plus a drug that hits every RAS protein, so the tumour cannot escape through a wild-type RAS cousin."},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/","tldr":"The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes."}]},{"item":"RASolute 304 primary completion: adjuvant daraxonrasib in resected pancreatic ductal adenocarcinoma (500 estimated participants; recruiting)","expected":"2029-05-10","source":"https://clinicaltrials.gov/study/NCT07252232","refs":[{"id":"nct07252232","kind":"trial","name":"Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)","route":"/trials/nct07252232/","status":"recruiting","tldr":"A phase 3 trial of Daraxonrasib in pancreatic ductal adenocarcinoma, run by Revolution Medicines, Inc., now recruiting."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"prodige-24","kind":"trial","name":"PRODIGE 24 / CCTG PA6","route":"/trials/prodige-24/","status":"positive","tldr":"Showed that giving the strong four-drug chemotherapy after pancreatic surgery adds years of life for fit patients."}]},{"item":"PRECEDE (Pancreatic Cancer Early Detection Consortium) primary completion: 20,000 estimated high-risk participants under surveillance (recruiting)","expected":"2030-12-31","source":"https://clinicaltrials.gov/study/NCT04970056","refs":[{"id":"precede","kind":"trial","name":"PRECEDE","route":"/trials/precede/","status":"recruiting","tldr":"PRECEDE is a very large international study following people whose genes or family history put them at high risk of pancreatic cancer, with yearly scans and stored blood samples, to find out how to catch the cancer early enough to cure it; it is still enrolling towards 20,000 participants."},{"id":"pancreatic-surveillance","kind":"technology","name":"High-risk pancreatic surveillance (CAPS / PRECEDE)","route":"/technologies/pancreatic-surveillance/","status":"established","tldr":"Yearly MRI or endoscopic ultrasound for people with inherited risk, which catches pancreatic cancers while they are still operable."},{"id":"idea-pdac-surveillance-for-every-germline-carrier","kind":"idea","name":"Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception","route":"/ideas/idea-pdac-surveillance-for-every-germline-carrier/","tldr":"One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically."}]},{"item":"IMCODE003 primary completion: adjuvant autogene cevumeran plus atezolizumab and modified FOLFIRINOX versus modified FOLFIRINOX alone after resection (260 estimated participants; phase 2; active, not recruiting)","expected":"2031-01-01","source":"https://clinicaltrials.gov/study/NCT05968326","refs":[{"id":"nct05968326","kind":"trial","name":"A Study of the Efficacy and Safety of Adjuvant Autogene Cevumeran Plus Atezolizumab and mFOLFIRINOX Versus mFOLFIRINOX Alone in Participants With Resected PDAC","route":"/trials/nct05968326/","status":"active","tldr":"A phase 2 trial of Autogene cevumeran and Atezolizumab in pancreatic ductal adenocarcinoma, run by Genentech, Inc., active and no longer recruiting."},{"id":"autogene-cevumeran","kind":"drug","name":"Autogene cevumeran","route":"/drugs/autogene-cevumeran/","status":"phase-2","tldr":"Autogene cevumeran is BioNTech and Genentech's personalised mRNA vaccine encoding each patient's own tumour neoantigens. In a small phase 1 in resected pancreatic cancer, half of patients mounted T-cell responses and stayed free of recurrence far longer; phase 2 IMCODE003 tests whether that holds."},{"id":"neoantigen-mrna-vaccine","kind":"technology","name":"Personalised neoantigen (mRNA) vaccines","route":"/technologies/neoantigen-mrna-vaccine/","status":"phase-3","tldr":"A vaccine made for one patient, encoding the unique mutations in their own tumour, to train the immune system to hunt it."},{"id":"paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","kind":"paper","name":"RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer","route":"/key-papers/paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025/","tldr":"The 2025 follow-up of the personalised mRNA vaccine trial in pancreatic cancer: at three years, patients whose immune systems responded to the vaccine had still mostly not relapsed, and the T cells the vaccine made were predicted to live for years."}]}]}