Teaching pack: Pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma is defined by late presentation, a near-universal KRAS mutation (G12D ~40%, G12V ~30%, G12R ~15%, G12C ~1-2%; ~10% KRAS-wild-type with actionable fusions in NRG1, NTRK, ALK, or BRAF), a desmoplastic stroma that occupies most of the tumour, and an immunologically cold microenvironment. Surgery is the only cure and only ~20% of patients present resectable; five-year survival remains ~13% overall but exceeds 40% for resected patients who complete adjuvant mFOLFIRINOX.

For thirty years the story was chemotherapy: gemcitabine (1997), FOLFIRINOX (2011), gemcitabine/nab-paclitaxel (2013), adjuvant mFOLFIRINOX (PRODIGE 24, 2018), NALIRIFOX (2024), with olaparib maintenance for germline BRCA carriers (POLO, 2019) and zenocutuzumab for NRG1 fusions (2024) as the only biomarker-directed drugs. 2026 changed the trajectory. Optune Pax tumour treating fields were approved for locally advanced disease (PANOVA-3). Daraxonrasib, a pan-RAS(ON) inhibitor, nearly doubled overall survival in previously treated metastatic disease in RASolute 302 (13.2 vs 6.7 months, HR 0.40), presented in the ASCO 2026 plenary with simultaneous NEJM publication; regulatory filing is expected under a national priority voucher. The G12D-selective zoldonrasib, combined with daraxonrasib or with chemotherapy, produced response rates never before seen in this disease.

• First TTFields approval (2026).
• Pan-RAS inhibitors with unprecedented OS in phase 1/2.
• Personalised vaccines with durable immunity.
• RASolute 302 (2026): first targeted therapy to nearly double survival in pancreatic cancer; daraxonrasib heading for approval.
• G12D-selective zoldonrasib combinations with 50% response rates in previously treated disease.
• Adjuvant mFOLFIRINOX gives median OS beyond 4 years in resected fit patients.

1. 1935Whipple describes pancreaticoduodenectomy
2. 1982KRAS identified as a human oncogene
3. 1997Gemcitabine approved
4. 1997Gemcitabine approved
5. 2011FOLFIRINOX improves survival
6. 2011FOLFIRINOX: OS 11.1 vs 6.8 months
7. 2013Gemcitabine + nab-paclitaxel (MPACT)
8. 2018Adjuvant mFOLFIRINOX (PRODIGE 24)
9. 2019POLO: olaparib maintenance in gBRCA
10. 2019POLO: olaparib maintenance in gBRCA

• Daraxonrasib (product)
• Autogene cevumeran (product)
• Sonesitatug vedotin (product)
• FAP-2286 (177Lu / 68Ga) (product)
• FAPI PET (technology)
• Galleri (product)
• Satricabtagene autoleucel (product)
• Zoldonrasib (product)
• Elironrasib (product)
• MRTX1133 (product)
• ELI-002 7P (product)
• RASolute 302 (trial)

• NAPOLI 3 (phase 3, n=770): Overall survival: 11.1 months vs 9.2 months, HR 0.83
• PRODIGE 24 / CCTG PA6 (phase 3, n=493): Disease-free survival: 21.6 months vs 12.8 months, HR 0.58
• PANOVA-3 (phase 3, n=571): Overall survival: 16.2 months vs 14.2 months, HR 0.82
• PREOPANC-1 / PREOPANC-2 (phase 3, n=246): Overall survival (long-term): 20.5% vs 6.5%, HR 0.73
• RASolute 302 (phase 3, n=460): Overall survival: 13.2 months vs 6.7 months, HR 0.4
• POLO (phase 3, n=154): Progression-free survival: 7.4 months vs 3.8 months, HR 0.53

• Late diagnosis; no screening.
• Dense stroma blocks drug delivery.
• Immunologically cold.
• Resistance to RAS(ON) inhibitors: secondary RAS mutations, RTK bypass, and adaptive feedback are already described; combination strategies are unproven in phase 3.
• Half of patients are too frail for FOLFIRINOX-class regimens; RAS inhibitors may change this but toxicity (rash, stomatitis) is not trivial.
• No population screening; MCED sensitivity for stage I PDAC is low and PPV in average-risk adults is poor.

1. What is daraxonrasib and where does it stand?
   Answer

   Revolution Medicines' pan-RAS(ON) tri-complex inhibitor; phase 3 RASolute 302 in second-line pancreatic cancer (reported OS benefit, HR 0.40 per the pancreatic spike), with first-line and NSCLC phase 3 trials ongoing.
2. What was the first approval in nearly thirty years specific to locally advanced pancreatic cancer?
   Answer

   Optune Pax (tumour treating fields) with gemcitabine/nab-paclitaxel, approved Q1 2026 on PANOVA-3.
3. Why is pancreatic cancer so hard to treat with immunotherapy?
   Answer

   It is immunologically cold: dense desmoplastic stroma blocks drug and T-cell entry, low mutational burden gives few neoantigens, and an immunosuppressive myeloid microenvironment. Vaccines (autogene cevumeran) and RAS inhibitors that may increase antigen presentation are the main hopes.
4. My relative has metastatic pancreatic cancer. How do we find a clinical trial?
   Answer

   Ask the oncologist about trials at the treating centre and referral to an NCI-designated or major academic centre; search ClinicalTrials.gov (status recruiting, condition pancreatic cancer, filter by location); OnCo's cancer page has a live recruiting-trials list; ask about RAS inhibitor trials such as daraxonrasib.
5. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.
6. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.

• Wikipedia: https://en.wikipedia.org/wiki/Pancreatic_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455