Review of Phase 3 Data on Investigational Endocrine Agents: SERENA-6 (ASCO 2025)
Panelists discuss the SERENA-6 trial evaluating camizestrant, which uniquely enrolled patients with molecularly detected ESR1 mutations before clinical progression, showing that early switching to this oral selective estrogen receptor degrader (SERD) improved progression-free survival and quality of life compared with continuing standard therapy, while highlighting ongoing questions about long-term benefits, optimal timing, and the practical challenges of frequent circulating tumor DNA (ctDNA) monitoring in clinical practice.
Camizestrant, another novel oral selective estrogen receptor degrader (SERD)SERD, has entered the treatment landscape with a unique study design compared to with other new endocrine agents. Unlike trials focusing on patients with progressive disease, the SerenaSERENA-6 trial enrolled patients who had not yet progressed but had detectable ESR1 mutations via ctDNA monitoring. The trial randomized randomly assigned these patients to either switch their endocrine backbone to Ccamizestrant or continue their current aromatase inhibitor combined with a CDK4/6 inhibitor. This approach aimed to determine whether an earlier switch, based on molecular progression rather than radiographic evidence, could improve patient outcomes.
The results showed that patients who switched early to Ccamizestrant had a median progression-free survival (PFS) of approximately 16 months, compared to with about 9 months for those who remained on the initial endocrine therapy. This represents a notable improvement in delaying progression. However, questions remain about the long-term benefits since subsequent treatments after progression might affect overall survival and total time on therapy. The trial also showed a quality-of-life advantage for those who switched early, as patients staying on aromatase inhibitors with CDK4/6 inhibitors experienced a more rapid decline in well-being. Still, these findings raise important questions about the optimal timing and practicality of frequent ctDNA monitoring for ESR1 mutations in clinical practice.
While the SerenaSERENA-6 trial offers promising data for a proactive treatment switch, the clinical implications remain to be fully understood. The approach challenges traditional paradigms of waiting for clinical progression before changing therapy. Clinicians will need further evidence to determine if earlier intervention based on molecular markers translates into meaningful long-term benefits for patients. Additionally, implementing such intensive ctDNA surveillance raises logistical and economic considerations. Overall, the trial opens an exciting conversation about personalized treatment strategies and the potential for improving outcomes through earlier detection of resistance mechanisms.
