Highlights of the CASSANDRA Trial
The PACT-21 CASSANDRA trial represents a significant milestone in the management of pancreatic ductal adenocarcinoma (PDAC). The primary highlights of the first randomization analysis include:
1. Survival Advantage: Preoperative PAXG demonstrated a statistically significant improvement in median event-free survival (EFS) compared to mFOLFIRINOX (16.0 months vs. 10.2 months), representing a 37% reduction in the risk of progression or death.
2. Potent Efficacy: The hazard ratio of 0.63 underscores the superiority of the four-drug cisplatin-based combination over the current standard-of-care triplet, mFOLFIRINOX.
3. Feasibility and Safety: Despite the intensity of both regimens, the safety profiles were manageable, with grade 3 or higher adverse events occurring at similar rates between the two groups.
4. New Comparator Standard: Based on these findings, PAXG is proposed as a new reference standard for future clinical trials involving neoadjuvant therapy for resectable and borderline resectable PDAC.
Background: The Evolution of Neoadjuvant Therapy in PDAC
Pancreatic ductal adenocarcinoma remains one of the most challenging malignancies in clinical oncology, characterized by early systemic dissemination and a high rate of local recurrence even after successful surgical resection. Historically, the treatment paradigm focused on upfront surgery followed by adjuvant chemotherapy. However, the high frequency of positive surgical margins (R1 resections) and the inability of many patients to receive adjuvant therapy due to postoperative complications led to a shift toward preoperative, or neoadjuvant, strategies.
Neoadjuvant chemotherapy aims to downstage the primary tumor, increase the rate of R0 resections, and address micrometastatic disease earlier in the treatment course. For years, modified FOLFIRINOX (mFOLFIRINOX) has been considered the gold standard in this setting based on its efficacy in the metastatic and adjuvant landscapes. Despite its widespread use, the search for more effective regimens continues. The PAXG regimen—a combination of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine—was developed to leverage the synergistic mechanisms of platinum agents, taxanes, and antimetabolites to overcome the dense stroma and chemoresistance characteristic of PDAC.
CASSANDRA Study Design and Methodology
The CASSANDRA trial (PACT-21) is a randomized, open-label, 2×2 factorial phase 3 trial conducted across 17 academic hospitals in Italy. The study targeted a specific and high-risk population: patients aged 18 to 75 years with pathologically confirmed resectable or borderline resectable PDAC (Stages I-III).
Patient Randomization and Stratification
Patients were randomized 1:1 using a central web-based system. Stratification factors included the participating center and baseline carbohydrate antigen 19-9 (CA 19-9) levels. The trial utilized a unique factorial design. In the first randomization, patients received either four months of PAXG or four months of mFOLFIRINOX. A second randomization subsequently determined whether patients received an additional two months of chemotherapy before or after surgery.
Dosing and Administration
The PAXG regimen consisted of intravenous cisplatin (30 mg/m2), nab-paclitaxel (150 mg/m2), and gemcitabine (800 mg/m2) administered every 14 days, combined with oral capecitabine (1250 mg/m2 daily, divided into two doses). The mFOLFIRINOX regimen followed the standard protocol: intravenous fluorouracil (2400 mg/m2 continuous infusion), leucovorin (400 mg/m2), irinotecan (150 mg/m2), and oxaliplatin (85 mg/m2) every 14 days.
Study Endpoints
The primary endpoint for this first randomization analysis was event-free survival (EFS) in the intention-to-treat population. EFS was defined as the time from randomization to disease progression (preventing surgery), local or distant recurrence after surgery, or death from any cause.
Key Findings: A Paradigm Shift in Efficacy
The analysis included 260 eligible patients randomized between late 2020 and early 2024. The baseline characteristics, including age (median 63-65 years) and sex distribution, were well-balanced between the two arms.
Superior Event-Free Survival
The results of the CASSANDRA trial provide compelling evidence for the superiority of PAXG. The median EFS was 16.0 months (95% CI 12.4–19.8) in the PAXG group, compared to 10.2 months (95% CI 8.6–13.5) in the mFOLFIRINOX group. This absolute difference of nearly six months is clinically profound in the context of pancreatic cancer. The calculated hazard ratio (HR) was 0.63 (95% CI 0.47–0.84), with a highly significant p-value of 0.0018.
Impact on Surgical Outcomes
While the full analysis of surgical resection rates and R0 margins is integrated into the long-term trial results, the significant extension in EFS suggests that the PAXG regimen is more effective at maintaining disease control during the critical preoperative period. This allows a higher proportion of patients to proceed to surgery without the early progression often seen with less intensive regimens.
Secondary Outcomes and Ongoing Analysis
The trial reached its necessary events for the primary EFS analysis. However, follow-up for overall survival (OS) is still ongoing. Given the strong correlation between EFS and OS in pancreatic cancer, there is high anticipation that the OS data will mirror the EFS benefit observed here.
Safety and Tolerability Profiles
The use of four-drug chemotherapy combinations naturally raises concerns regarding toxicity. The CASSANDRA trial monitored adverse events (AEs) closely in all patients who received at least one dose of therapy.
At least one grade 3 or worse adverse event was observed in 66% of patients in the PAXG group and 61% in the mFOLFIRINOX group. The slightly higher incidence in the PAXG group was not statistically significant, suggesting that the four-drug combination does not disproportionately increase the safety burden compared to the three-drug mFOLFIRINOX triplet. Common high-grade toxicities included hematological events (neutropenia, anemia) and gastrointestinal disturbances, which are typical for these regimens and were managed through standard supportive care and dose modifications. One fatal event was reported in the mFOLFIRINOX group, highlighting the inherent risks of intensive chemotherapy in this patient population.
Expert Commentary and Clinical Interpretation
The CASSANDRA trial results are poised to disrupt the current treatment landscape for resectable PDAC. For years, mFOLFIRINOX has been the undisputed leader in neoadjuvant and adjuvant therapy. However, the 5.8-month improvement in median EFS provided by PAXG cannot be ignored. The biological plausibility of PAXG’s success likely lies in its multi-pathway inhibition. By combining the DNA-damaging effects of cisplatin with the stroma-disrupting properties of nab-paclitaxel and the antimetabolite actions of gemcitabine and capecitabine, PAXG addresses the heterogeneity of pancreatic tumors more effectively than fluorouracil-based triplets.
Clinicians must, however, consider the generalizability of these results. The study was conducted in Italian academic centers with high expertise in managing complex chemotherapy protocols. In community settings, the intensive monitoring required for a four-drug regimen like PAXG may be more challenging. Furthermore, the 2×2 factorial design means that the final interpretation will depend on the results of the second randomization (timing of additional chemotherapy), though the EFS benefit of the initial PAXG induction is robust.
Current guidelines may soon reflect these findings, potentially recommending PAXG as a preferred neoadjuvant option for patients with good performance status. Additionally, PAXG should now be considered the benchmark against which new investigative agents or immunotherapy combinations are compared in future phase 3 trials.
Summary and Conclusion
In conclusion, the CASSANDRA trial demonstrates that preoperative PAXG is superior to mFOLFIRINOX in extending event-free survival for patients with stage I-III resectable or borderline resectable pancreatic ductal adenocarcinoma. With a median EFS of 16.0 months and a manageable safety profile, PAXG offers a significant advancement in neoadjuvant care. These findings suggest that the clinical community should consider PAXG as a new standard preoperative option, providing a stronger foundation for curative-intent surgery and long-term survival in one of medicine’s most difficult-to-treat cancers.
Funding and Clinical Registry
The PACT-21 CASSANDRA trial was funded by MyEverest and Codice Viola. The trial is registered on ClinicalTrials.gov (NCT04793932) and EudraCT (2020-003080-26 and 2024-519031-42-00).
References
1. Reni M, Macchini M, Orsi G, et al. Preoperative mFOLFIRINOX versus PAXG for stage I-III resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results of the first randomisation analysis of a randomised, open-label, 2×2 factorial phase 3 trial. Lancet. 2026;406(10522):2945-2956. doi:10.1016/S0140-6736(25)01685-X.
2. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Chemotherapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-2406.
3. Versteijne E, Vogel JA, Besselink MG, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763-1773.
