Overview
Pancreatic adenocarcinoma remains one of the most challenging malignancies with limited systemic treatment options. Standard chemotherapy regimens include FOLFIRINOX and gemcitabine-based combinations for metastatic disease. For patients with germline BRCA mutations, PARP inhibitor maintenance therapy has shown significant survival benefit.
Treatment Landscape
First-Line Metastatic Disease:
- FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) for good performance status patients
- Gemcitabine + nab-paclitaxel for less fit patients
BRCA-Mutated Disease:
- Platinum-based chemotherapy followed by olaparib maintenance (POLO trial)
Epidemiology & Impact
Pancreatic cancer is the third leading cause of US cancer death with approximately 66,440 cases and 51,980 deaths in 2025, projected to become second by 2030. Five-year survival is approximately 13%. Approximately 80% present unresectable. Risk factors include smoking, obesity, diabetes, chronic pancreatitis, and germline BRCA/PALB2/ATM/Lynch mutations.
Molecular Biology & Biomarkers
PDAC is defined by four drivers: KRAS (90%), TP53 (70%), CDKN2A (50-70%), SMAD4 (55%). Approximately 25% have actionable alterations: BRCA1/2 (5-7%), NTRK fusions, MSI-high (1-2%), HER2 amplification (2-3%). KRAS G12D inhibitors in development could impact the largest mutant population.
Evolving Treatment Landscape
FOLFIRINOX and gemcitabine-nab-paclitaxel are first-line. Neoadjuvant therapy is increasingly favored. Olaparib maintenance benefits germline BRCA-mutated PDAC. KRAS G12C inhibitors are available for the small subset; G12D inhibitors are in trials. Molecular profiling at diagnosis is recommended to identify the 25% with actionable targets.
Approved Therapies
Treatment Strategies
First-Line Selection
For patients with good performance status (ECOG 0-1) and adequate organ function, FOLFIRINOX remains the preferred regimen with median overall survival of approximately 11 months. For patients who cannot tolerate intensive therapy, gemcitabine plus nab-paclitaxel offers a balance of efficacy and tolerability with median overall survival of 8.5 months.
Second-Line Options
After progression on first-line gemcitabine-based therapy, liposomal irinotecan (Onivyde) combined with 5-FU and leucovorin has demonstrated survival benefit compared to 5-FU/leucovorin alone. For patients who received FOLFIRINOX first-line, gemcitabine-based regimens are appropriate second-line options.
BRCA-Mutated Disease
Approximately 5-7% of pancreatic cancer patients harbor germline BRCA1/2 mutations. These patients should receive platinum-based first-line chemotherapy (FOLFIRINOX or gemcitabine/cisplatin). Those achieving disease control for ≥16 weeks qualify for olaparib maintenance, which significantly prolongs progression-free survival (7.4 vs 3.8 months in the POLO trial).
Emerging Therapies
Clinical trials are investigating novel targeted therapies for KRAS G12C mutations, combination immunotherapy strategies, and precision medicine approaches based on genomic profiling. Enrollment in clinical trials should be considered for all eligible patients given the limited approved treatment options.