Pancreatic cancer in 2025: Have we found a solution?

Table 1 Summary of target therapy

Category	Details
Homologous recombination deficiency	Prevalence: Mutations in homologous recombination genes (BRCA1, BRCA2, PALB2) are found in 15%-19% of patients with PDAC. Therapeutic response: Patients with HRD show improved PFS and OS after platinum-based chemotherapy and PARPi. Retrospective analysis: In a study of patients treated with FOLFIRINOX, the ORR was significantly higher in BRCA1/BRCA2 mutated patients (71.4%) compared to non-mutated patients (13.9%). Platinum-based therapy response: A separate retrospective study reported an ORR of 58% in patients with germline BRCA and PALB2 mutations compared to 21% in the control group
PARPi trials	POLO trial: This trial evaluated olaparib as maintenance therapy for patients with germline BRCA1/BRCA2 mutations who had stable or responding disease after 4 months of platinum-based chemotherapy. The study found a significant increase in PFS (7.4 months for olaparib vs 3.8 months for placebo), although there was no significant difference in OS (19 months for olaparib vs 19.2 months for placebo). FDA approval: Olaparib has been approved as maintenance therapy for platinum-sensitive metastatic PDAC patients with BRCA1/BRCA2 mutations whose disease has not progressed after at least 16 weeks of first-line platinum-based treatment. RUCAPANC2 trial: This phase II single-arm trial demonstrated that rucaparib, administered as maintenance therapy in patients with advanced pancreatic cancer harboring germline or somatic BRCA or PALB2 mutations, achieved a median OS of 23.5 months. Reversion variants: In a study by Reiss et al[145], 16.6% of patients whose disease progressed on maintenance PARPi developed BRCA or PALB2 reversion variants, which restored the function of the BRCA or PALB2 proteins. Patients with these reversion variants experienced rapid resistance to PARPi (PFS of 3.7 months vs 12.5 months; P = 0.001) and had significantly poorer OS (6.2 months vs 23.0 months; P < 0.0001)
KRAS mutations	Prevalence: KRAS mutations are present in 90%-92% of PDAC cases, classifying them into KRASmut and KRASwt subtypes. Common mutations: The most frequent KRAS mutations include G12D (40%), G12V (29%), G12R (15%), and G12C (approximately 1%). Therapeutic challenge: Currently, there are no FDA-approved therapies specifically targeting KRASmut PDAC, making it a significant area of unmet medical need
KRAS G12C inhibitors	Inhibitors: Adagrasib and sotorasib are small-molecule covalent inhibitors that irreversibly bind to KRAS G12C, trapping it in its inactive guanosine diphosphate-bound state. Clinical trials: Both inhibitors have shown promising results in patients with KRAS G12C mutations in the CodeBreak 100 and KRYSTAL-1 trials, demonstrating efficacy and manageable safety profiles. Other inhibitors: Additional KRAS G12C inhibitors currently in clinical trials include JDQ443 (No. NCT04699188), JAB-21822 (No. NCT05002270), D-1553 (No. NCT04585035), GDC-6036 (No. NCT04449874), LY3537982 (No. NCT04956640), and BI-1823911 (No. NCT04973163)
KRAS G12D inhibitors	MRTX-1133: A novel inhibitor specifically targeting KRAS G12D mutations, currently in phase I clinical trials, has shown promising preclinical data. RMC-6236: This inhibitor targets multiple RAS variants and is undergoing a phase I study. The most recent analysis indicated a 14 + week disease control rate of 87% in patients with KRAS G12X mutations, with a median PFS of 8.1 months. RASolute 302 trial: A phase 3 randomized trial evaluating the efficacy of RMC-6236 in second-line metastatic PDAC, regardless of RAS status, is currently ongoing
KRAS wild-type PDAC	Genetic fusions: KRASwt PDAC can harbor rare gene fusions involving FGFR2, RAF, ALK, RET, MET, NTRK1, ROS1, ERBB4, NRG1, and FGFR3, which may provide opportunities for personalized therapeutic approaches. FDA approvals: Zenocutuzumab has received FDA approval for advanced or metastatic NRG1 fusion-positive pancreatic cancer. The combination of dabrafenib and trametinib, targeting BRAF V600E mutations, was investigated in the NCI-MATCH trial and the ROAR basket trial, demonstrating efficacy and a manageable toxicity profile. Ongoing trials: A phase II trial (No. NCT04390243) is currently investigating the combination of encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor) in patients with pretreated metastatic PDAC with somatic BRAF V600E mutations
Microsatellite instability	Prevalence: MSI-H/dMMR occurs in only 1% of PDAC cases, which limits the applicability of immunotherapy. Therapeutic response: Pembrolizumab has been granted full FDA approval for unresectable MSI-H/dMMR solid tumors based on positive outcomes from clinical trials (KEYNOTE-158, KEYNOTE-164, KEYNOTE-051). However, response rates in PDAC patients treated with pembrolizumab were lower (18.2%) compared to other non-colorectal cancers (31%-48.5%). Real-world data: Retrospective studies from the Mayo Clinic and the AGEO European cohort suggest better outcomes for MSI-H/dMMR PDAC patients, supporting the use of immune checkpoint inhibitors

HRD: Homologous recombination deficiency; PDAC: Pancreatic ductal adenocarcinoma; PFS: Progression-free survival; OS: Overall survival; PARPi: Poly (adenosine diphosphate-ribose) polymerase inhibitors; ORR: Overall response rate; FDA: Food and Drug Administration; KRASmut: KRAS mutant; KRASwt: KRAS wild type; MSI-H/dMMR: Microsatellite instability and deficiency mismatch repair proteins; AGEO: Association des Gastro-Enterologue Oncologues.