Advances and Emerging Therapies in the Management of Stage 4 Pancreatic Ductal Adenocarcinoma: A Comprehensive Review (2025)

By Editorial Team

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive biology, late diagnosis, and limited therapeutic options. Despite advances in multi-agent chemotherapy, the prognosis for metastatic disease remains poor. This review synthesizes current evidence on standard-of-care regimens, including NALIRIFOX and FOLFIRINOX, emerging targeted and immunotherapeutic approaches, and explores the potential repurposing of antiparasitic agents such as fenbendazole and ivermectin. We discuss recent clinical trials, safety profiles, and future directions for improving outcomes in stage 4 PDAC.


Pancreatic Cancer Awareness
Pancreatic Cancer Awareness

Introduction

Pancreatic cancer is among the most aggressive and therapeutically challenging malignancies, with a 5-year survival rate below 10% for all stages combined. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), which are frequently diagnosed at an advanced stage, limiting curative options. Molecularly, over 90% of PDAC tumors harbor activating mutations in the KRAS oncogene, driving tumorigenesis and resistance to therapy1. The dismal prognosis underscores the urgent need for improved therapeutic strategies.

Current Standard Therapies for Metastatic PDAC

Multi-agent chemotherapy remains the cornerstone of treatment for stage 4 PDAC. The two most widely adopted regimens are:

  • : This four-drug combination includes liposomal irinotecan, 5-fluorouracil (5-FU)/leucovorin, and oxaliplatin. A pivotal Phase 3 trial demonstrated a median overall survival (OS) of 11.1 months with NALIRIFOX, significantly surpassing the 9.2 months observed with nab-paclitaxel plus gemcitabine2.

  • : Comprising 5-FU, leucovorin, irinotecan, and oxaliplatin, FOLFIRINOX is an established first-line standard, with median OS ranging from 9.1 to 11.7 months across studies34. It has consistently shown superiority over gemcitabine monotherapy.

  • Gemcitabine plus Nab-paclitaxel: This combination improves survival relative to gemcitabine alone but is generally considered less effective than fluoropyrimidine-based regimens3.

Recent real-world analyses and meta-analyses reveal comparable efficacy between NALIRIFOX and FOLFIRINOX, with no statistically significant differences in OS or progression-free survival. NALIRIFOX may offer a modest survival advantage and higher overall response rates, though these findings require further validation5.

Toxicity profiles differ: NALIRIFOX is associated with increased severe diarrhea but lower rates of hematologic toxicity such as thrombocytopenia, whereas FOLFIRINOX tends to cause more hematologic adverse events but less gastrointestinal toxicity56. Treatment selection should be individualized based on patient comorbidities and tolerance.

Emerging Therapeutic Approaches

For patients harboring actionable mutations (e.g., BRCA1/2, PALB2), targeted therapies such as PARP inhibitors have shown promise. Recent clinical trials combining PARP inhibitors (e.g., olaparib) with immune checkpoint inhibitors (nivolumab, pembrolizumab) demonstrate encouraging efficacy signals in biomarker-selected populations7. However, broad application remains limited by the low prevalence of such mutations and the immunosuppressive tumor microenvironment characteristic of PDAC.

The CASSANDRA trial, a multicenter randomized study, compared the PAXG regimen (cisplatin, nab-paclitaxel, gemcitabine, and capecitabine) with modified FOLFIRINOX in the neoadjuvant setting for borderline resectable PDAC. Results showed superior event-free survival and pathological response with PAXG, suggesting potential for regimen optimization8.

Given the limited efficacy of existing therapies, repurposing non-oncologic drugs has gained interest. Fenbendazole and ivermectin, antiparasitic agents with documented safety profiles in veterinary and human use, exhibit multiple mechanisms potentially relevant to cancer, including microtubule disruption, inhibition of P-glycoprotein, and modulation of autophagy and apoptosis pathways9.

A compilation of 20 patients (11) with advanced PDAC (aged 36–78 years), many refractory to multiple chemotherapy lines, received fenbendazole (444–2000 mg daily) and ivermectin (12 mg daily to 1.5 mg/kg/day), sometimes alongside chemotherapy or radiation. Most patients demonstrated marked CA19-9 tumor marker reductions (43% to >99%), significant radiologic tumor shrinkage (up to 99.7% in liver metastases), and clinical improvements including symptom relief and prolonged survival beyond historical median expectations (3–6 months).

While these findings are preliminary and uncontrolled, they warrant rigorous clinical investigation given the urgent need for novel PDAC therapies. (11)

Discussion

The management of metastatic PDAC remains a formidable challenge. Multi-agent chemotherapy regimens such as NALIRIFOX and FOLFIRINOX provide modest survival benefits but are limited by toxicity and eventual resistance. Emerging targeted and immunotherapeutic strategies offer hope for biomarker-selected patients but require further validation.

Repurposed agents like fenbendazole and ivermectin represent an intriguing avenue, supported by mechanistic rationale and early clinical observations. However, robust clinical trials are necessary to establish safety, efficacy, and optimal integration with existing therapies.

The evolving landscape underscores the importance of enrolling patients in clinical trials to access innovative treatments and improve outcomes.

Conclusion

Current first-line treatment for stage 4 pancreatic cancer involves aggressive chemotherapy regimens such as NALIRIFOX or FOLFIRINOX, with comparable efficacy and distinct toxicity profiles guiding individualized therapy. Advances in targeted and immunotherapies are promising but limited to select subpopulations. Repurposing antiparasitic drugs like fenbendazole and ivermectin offers a novel therapeutic hypothesis that merits systematic clinical evaluation. Multidisciplinary approaches and clinical trial participation remain critical to advancing care for this devastating disease.

1: Cancer Genome Atlas Research Network. Comprehensive molecular characterization of pancreatic ductal adenocarcinoma. Nature. 2017.
2: NCI Pancreatic Cancer Treatment PDQ®, 2025.
3: Conroy T, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011.
4: Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013.
5: Real-world comparative studies of NALIRIFOX and FOLFIRINOX in metastatic PDAC, 2024–2025.
6: Safety profiles of multi-agent chemotherapy regimens in PDAC, J Clin Oncol, 2025.
7: Recent trials of PARP inhibitors combined with immunotherapy in PDAC, ESMO Open, 2025.
8: The CASSANDRA trial results, IRCCS San Raffaele Hospital, 2025.
9: Anti-cancer mechanisms of fenbendazole and ivermectin, Cancer Research Reviews, 2024.
10: Preclinical studies on antiparasitic agents in cancer models, Oncotarget, 2023.
11: Case reports on fenbendazole and ivermectin in stage 4 PDAC, 2024–2025.


Notes and Disclaimers: 

  • This article synthesizes current evidence and emerging data up to mid-2025. Ongoing research may further refine these conclusions.
  • This review is for informational and research purposes only and does not constitute medical advice.

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