Armando Orlandi, Medical Director at the Agostino Gemelli University Hospital Foundation IRCCS, shared a post on LinkedIn about his recent article:
“An Evolving Landscape in Oncology Evidence Standards.
January 2025 marked a notable milestone: both the FDA and EMA approved datopotamab-deruxtecan for metastatic breast cancer with unique regulatory considerations around its dual primary endpoints.
The Trial Results:
- PFS: 6.9 vs 4.9 months (HR 0.63) – POSITIVE
- OS: 18.6 vs 18.3 months (HR 1.01) – NEGATIVE
This represents a unique breast cancer approval where one of two primary endpoints (OS) did not meet statistical significance – raising fascinating questions about evolving regulatory frameworks.
FDA’s August 2025 Guidance: Looking Forward
The FDA then published comprehensive guidance emphasizing that Overall Survival:
- ‘Is considered a gold standard endpoint in oncology’
- ‘Should be prioritized as the primary endpoint when feasible’
- Must be assessed ‘to adequately evaluate the potential for harm’
- Is critical because ‘prolongation of life…is of clear inherent value’
This guidance represents thoughtful forward-looking regulatory science, providing clearer frameworks for future trial design and OS assessment.
Important Clinical Considerations:
Cases like this raise meaningful questions about how we balance different types of evidence in patient care. When considering a therapy with significant clinical activity but without demonstrated survival benefit, how do we best serve our patients?
Questions Worth Exploring:
- How should dual primary endpoint trials be interpreted when results diverge?
- What role should early efficacy signals play in regulatory decisions for life-threatening diseases?
- How do we optimize treatment sequencing with expanding therapeutic options?
- How can the new FDA guidance help standardize future trial designs?
The FDA’s August guidance provides valuable clarity for future oncology development, emphasizing robust OS assessment and pre-specified statistical plans. This forward-looking approach should help sponsors design better trials and provide clearer evidence for clinical decision-making.
As I explore in my recent commentary in The Breast, this case highlights the evolving nature of evidence standards in our rapidly advancing therapeutic landscape.
The datopotamab-deruxtecan approval represents an interesting case study in regulatory flexibility, while the subsequent FDA guidance demonstrates continued commitment to rigorous evidence standards.
Together, they illustrate how regulatory science continues to evolve alongside therapeutic innovation – balancing patient access to promising therapies with robust evidence requirements.
This presents an opportunity for our community to engage in thoughtful discussion about evidence standards, trial design, and optimal patient care.”
Title: FDA and EMA approval of datopotamab-deruxtecan: A paradigm shift in breast cancer drug evaluation?
Author: Armando Orlandi
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