Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, making up more than 80% of cases. DelveInsight estimates that there were around 56,000 PDAC cases in the United States. CASSANDRA trial (NCT04793932) was initially designed as a phase II study to identify the better neoadjuvant regimen but was upgraded to a phase III trial after the PREOPANC-1 and -2 studies established neoadjuvant therapy, specifically mFOLFIRINOX, as a standard of care in resectable and borderline resectable PDAC. This made CASSANDRA’s comparison both timely and clinically relevant. The use of event-free survival (EFS) as the primary endpoint aligns with Food and Drug Administration’s (FDA) standards for neoadjuvant trials, similar to disease-free survival in adjuvant studies like PRODIGE-24 and CONKO-001. 

At data cutoff of March 1, 2025 in the CASSANDRA trial, with a median follow-up of 24.5 months, PAXG (cisplatin, nab-paclitaxel [ABRAXANE], gemcitabine, and capecitabine) showed a statistically significant improvement in EFS. The 3-year EFS rate was 31% in the PAXG group versus 13% in the mFOLFIRINOX group, yielding a hazard ratio (HR) of 0.64. Median EFS was 16.0 months with PAXG compared to 10.2 months with mFOLFIRINOX.

Secondary endpoints further supported PAXG’s advantage, including a significantly higher disease control rate (DCR) of 98% and a greater proportion of patients with a CA19-9 reduction of over 50%. Resection rates not statistically different between groups (75% vs 67%; p = 0.165), PAXG led to more favorable pathological results, such as a higher proportion of patients with stage <II diseases (35% vs 23%; p= 0.03) and more node-negative (R0/N0) resections.

Although overall survival (OS) data are still immature, early findings reflect the EFS trend and indicate possible OS benefit. Median OS was 37.3 months in the PAXG group versus 26.0 months in the mFOLFIRINOX group, with an HR of 0.70.

KOL insights

“PAXG significantly improved the median event-free survival by almost 6 months, with an increase in the 3-year event-free survival rate from 13% to 31%, PAXG appears to be the most suitable option for neoadjuvant therapy in patients with resectable or borderline resectable PDAC” – Expert Opinion

“Regarding the other secondary endpoints—assessed in the intention-to-treat population—PAXG significantly improved the disease control rate, the CA19-9 response rate, the pathological complete response rate, the N0 resection rate, and consistently reduced the detection of intraoperative and postoperative metastases” – Expert Opinion

“Although the improvement in EFS with PAXG is “promising,” the median follow-up remains relatively short at approximately 25 months.  Before determining that this is the preferred neoadjuvant chemotherapy for patients with localized and borderline resectable PDAC, it would be helpful to see longer survival follow-up and the potential for improvement in overall survival – Expert Opinion

Conclusion

The first phase III trial to focus on "PDAC optimal preoperative chemotherapy duration" is CASSANDRA study.  At ASCO 2025, CASSANDRA Phase III study delivered compelling evidence that PAXG should be considered the preferred neoadjuvant regimen for patients with resectable or borderline resectable PDAC. The significant improvement in 3-year EFS, along with the favorable biological and clinical surrogate endpoints, including a greater CA19.9 response (>50% drop in 88% vs 64%), higher disease control (98% vs 91%), and more frequent downstaging to pathologic stage II or lower (35% vs 23%), positioned PAXG as a strong alternative to mFOLFIRINOX. While R0 resection rates were numerically higher with PAXG (75% vs 67%), this was not statistically significant. Toxicity profile was somewhat concerning with more neutropenia observed in the PAXG arm, though overall toxicity was considered manageable. Key limitations include the absence of OS and quality of life (QoL) data, and the inclusion of CA19.9 rise as part of the EFS definition, which may not be universally accepted. These findings, if corroborated by maturing OS data, could reshape neoadjuvant standard treatment algorithms  for patients with PDAC.

Further research is needed to determine which treatments should be considered after surgery. An optimal perioperative strategy for PDAC patients will be clarified with the help of studies like CASSANDRA and other ongoing clinical trials.