Nicholas C. Turner, MD, PhD, on Treating Emergent ESR1 Mutations in Advanced Breast Cancer

Here at ASCO, we're presenting the results of the SERENA-6 study in the plenary session. SERENA-6 is a study for patients who've got metastatic advanced breast cancer that's hormone receptor-positive, HER2-negative on their first-line aromatase inhibitor and CDK4/6. We know in this setting, up to 40% of patients can acquire ESR1 mutations in their cancer as the key mechanism of resistance. We also know we can use liquid biopsies to detect these ESR1 mutations emerging long before disease progression. In SERENA-6, we recruited over 3,000 patients into surveillance with sequential liquid biopsies every two to three months to detect those ESR1 mutations at the earliest stages. 315 patients were then randomized to the standard of care, which was to continue AI and CDK4/6 inhibitor or to switch from AI to camizestrant and CDK4/6. Camizestrant is a next-generation oral SERD. It’s been designed specifically to target these estrogen receptor mutations as well as the wild-type ER. It completely inhibits ER signaling as well as degrades the mutant receptor. And what we then showed is that by switching to camizestrant, we over doubled progression-free survival in the study. And very importantly, 24 months after randomization, only 5% of patients in the control arm were without progression, whereas those who switched over to camizestrant when we detect an ESR1 mutation, 30% of them were without progression. And we're starting to see a real tail on the curve emerge. Also, we looked at quality of life and time to deterioration of quality of life in the study, and we saw a very substantial prolongation in the time to deterioration in quality of life—almost out to two years in the camizestrant group by switching ahead of disease progression. So in SERENA-6, we're trying to bring forward a new way of treating people with advanced hormone receptor-positive breast cancer to prolong first-line therapy. Currently, we don't know the optimal time to change therapy. We have to wait until disease progression. The tumor starts to grow on the scan again. But this can cause symptoms and it's often a real psychological blow for patients. And so what we are doing here is identifying much earlier exactly when the tumor is beginning to develop resistance to therapy and then switching to an effective therapy that targets those ESR1 mutations and keeps the patient well on first-line therapy for longer.