Recent trials in pancreatic cancer

1. Metastatic PDAC - established first-line advance

• NAPOLI-3, Phase III, 2023: first-line NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin, 5-FU) versus gemcitabine plus nab-paclitaxel in 770 untreated patients with metastatic PDAC.
  • Median overall survival: 11.1 vs 9.2 months
  • HR for death: 0.83
  • Grade 3+ adverse events: 87% vs 86%
    This supports NALIRIFOX as a first-line option for patients with good performance status, alongside established FOLFIRINOX and gemcitabine/nab-paclitaxel. Wainberg et al., Lancet, 2023, PMID: 37708904

2. Second-line metastatic PDAC - mostly negative Phase III results

• TRYBECA-1, Phase III, 2025: eryaspase plus chemotherapy versus chemotherapy alone after progression on first-line therapy, n=512.
  • Overall survival: 7.5 vs 6.7 months, HR 0.92, p=0.374
  • No significant improvement in progression-free survival or response rate.
  • Conclusion: does not support further eryaspase development in PDAC.
    Hammel et al., JCO, 2025, PMID: 41187298
• GEMPAX, Phase III, 2024: gemcitabine plus paclitaxel versus gemcitabine after prior FOLFIRINOX in metastatic PDAC, n=211.
  • Overall survival: 6.4 vs 5.9 months, not significant
  • PFS: 3.1 vs 2.0 months, significant
  • Response: 17.1% vs 4.2%
    The regimen did not meet its survival endpoint and had substantially more grade 3+ toxicity, including thrombocytopenia and neuropathy. De La Fouchardière et al., JCO, 2024, PMID: 38232341
• RASolute 302, Phase III, reported 2026: daraxonrasib, an oral RAS(ON) multiselective inhibitor, was reported to improve overall and progression-free survival over investigator-choice chemotherapy in previously treated metastatic PDAC. This is a potentially important targeted-therapy result, particularly because most PDACs contain RAS pathway mutations. Full peer-reviewed numerical results and regulatory status should be checked before applying it clinically. ESMO report

3. Biomarker-selected and precision approaches

• GV1001 plus gemcitabine/capecitabine, Phase III, 2024: in a selected group with high serum eotaxin, the telomerase peptide vaccine GV1001 improved median overall survival: 11.3 vs 7.5 months and time to progression: 7.3 vs 4.5 months. This was a 148-patient biomarker-selected study and needs external confirmation before becoming standard care. The paper also has a published erratum. Jo et al., British Journal of Cancer, 2024, PMID: 37903909
• AVATAR, Phase III, 2025: whole-exome sequencing plus patient-derived organoids/mouse avatars to direct therapy versus conventional care in advanced PDAC.
  • Median OS: 8.6 vs 8.7 months, no intention-to-treat benefit.
  • The logistical problem was major: only 4 of 39 patients receiving second-line treatment in the experimental arm actually received a matched personalized treatment.
    This shows that precision oncology can be useful for a minority, but the turnaround time is often incompatible with rapidly progressive PDAC. Sarno et al., Clinical Cancer Research, 2025, PMID: 39540844

4. Immunotherapy combinations - no broad breakthrough yet

• Oleclumab plus durvalumab plus gemcitabine/nab-paclitaxel, randomized Phase Ib/II, 2024: targeting CD73 and PD-L1 did not meet the primary response endpoint in unselected metastatic PDAC. Response was 32.9% with the triplet versus 29.0% with chemotherapy; OS HR was 0.75 but the confidence interval crossed 1. A high-CD73 subgroup signal was exploratory only. Coveler et al., Clinical Cancer Research, 2024, PMID: 39106081
• Pembrolizumab plus neoadjuvant chemoradiotherapy, randomized Phase II, 2023: in resectable or borderline-resectable PDAC, addition of pembrolizumab was feasible but did not convincingly increase intratumoral CD8+ T cells. Median OS was 27.8 versus 24.3 months, but the small trial was not designed to establish a survival benefit. Katz et al., JITC, 2023, PMID: 38040420

5. Locally advanced PDAC - local ablation did not improve survival

• PELICAN, randomized trial, 2026: radiofrequency ablation plus chemotherapy versus chemotherapy alone after disease control on induction chemotherapy in unresectable locally advanced pancreatic cancer, n=188.
  • Overall survival from randomization: 12.1 vs 11.6 months, HR 1.07
  • More serious grade 3+ adverse events: 27% vs 11%
  • Worse quality-of-life trajectory with radiofrequency ablation.
    Therefore, RFA should not be added routinely to chemotherapy in this setting. Seelen et al., JAMA Network Open, 2026, PMID: 41915391

Practical summary