Second-line / Previously Treated Metastatic Pancreatic Cancer (mPDAC)

Authored by Allyson Ocean, published on 2026-10-08 16:49:46.0

The algorithm appropriately emphasizes performance status, prior therapy, organ function, goals of care, molecular profiling, clinical trials, and early supportive care. Nal-IRI plus 5-FU/leucovorin after gemcitabine-based therapy has direct randomized evidence, whereas later-line gemcitabine/nab-paclitaxel and FOLFIRINOX rely more on guideline consensus, extrapolation, and patient selection. Daraxonrasib is supported by the 2026 phase III publication and FDA approval, but the algorithm's RAS-based gating appears inconsistent with the trial population and broad FDA indication.

  1. Patient with metastatic pancreatic adenocarcinoma previously treated with one prior line of therapy (5-fluorouracil (5-FU) based or gemcitabine-based regimen)
    Radiographically confirmed metastatic disease ECOG PS 0–2; disease progression on ≥1 prior systemic therapy for metastatic disease Adequate organ function (Clinical trial participation always encouraged)
    • Assess performance status, prior therapy, organ function, goals of care
      PS and organ function are core determinants of whether multi-agent chemotherapy is appropriate versus single-agent therapy or best supportive care, and goals-of-care discussions are recommended throughout metastatic PDAC management.
      • Comprehensive molecular profiling (NGS ± ctDNA if tissue limited)
        Test for KRAS, NRAS, HRAS mutation status Ideally performed at initial diagnosis for all patients; repeat ctDNA/NGS if prior results unavailable or insufficient. See testing algorithm: Molecular Testing for Pancreatic Cancer.
        • Eligible for daraxonrasib?
          FDA indication: Metastatic pancreatic adenocarcinoma. Received at least one prior systemic therapy OR not a candidate for multiagent systemic therapy. No contraindication or other clinical reason to avoid treatment.
          • Standard systemic therapy based on prior regimen exposure; consider clinical trial; best supportive care (BSC)
            Nal-IRI + 5-FU/LV Gemcitabine + nab-paclitaxel FOLFIRINOX (if PS 0–1 and appropriate) Consider clinical trial Best supportive care Wild-type KRAS tumors are not candidates for daraxonrasib.
            • At progression (consider trial, alternate standard regimen, BSC)
              Consider clinical trial Alternate standard regimen not previously received Best supportive care
          • Daraxonrasib + best supportive care (BSC)
            Daraxonrasib + Best Supportive Care (BSC): Daraxonrasib 300 mg orally once daily (continuous). Continue until disease progression, unacceptable toxicity, or patient withdrawal. Monitor: CBC, CMP, Mg, Phos; assess AEs and adherence. Jump to algorithm for Daraxonrasib Toxicity Prevention and Management in Pancreatic Cancer
            • At progression (consider trial, alternate systemic therapy, BSC)
              Consider clinical trial Standard cytotoxic chemotherapy options (e.g., nal-IRI + 5-FU/LV, gemcitabine + nab-paclitaxel, FOLFIRINOX if appropriate); Best supportive care
  2. NOTE
    Early palliative/supportive care integration is recommended throughout treatment. Algorithm informed by phase III RASolute-302 results published in NEJM (2026). Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. FDA Approved Rasonque (daraxonrasib) on August 26th, 2026 for the treatment of adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. Jump to algorithm on Daraxonrasib Toxicity Prevention and Management in Pancreatic Cancer.
  3. Jump to first-line algorithm: Initial Treatment for Metastatic Pancreatic Cancer
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