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Even without formal trial data on sequencing, clinicians are beginning to prescribe one oral SERD after progression on another (e.g., vepdegestrant after imlunestrant). This practice is driven by a belief in targeting the driving ESR1 mutation and by patient-specific factors like toxicity aversion, highlighting a real-world clinical need.
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The Lidara study showed SERD benefit in patients without pre-existing ESR1 mutations. Success is likely multifactorial: SERDs are more effective and better tolerated than AIs. Critically, they also prevent the most common resistance mechanism—the acquisition of ESR1 mutations—from developing in the first place, altering the disease's future trajectory.
The LIDERA trial's early, robust success with the oral SERD giredestrant in adjuvant therapy is surprising. In the metastatic setting, these drugs primarily benefit tumors with ESR1 mutations, which are acquired after therapy and rare at diagnosis. This paradoxical result suggests a different mechanism of action in early-stage disease and necessitates longer follow-up to confirm the finding.
The SERENA-6 strategy of switching to an oral SERD upon detecting an ESR1 mutation in ctDNA—before clinical progression—is a novel concept. It forces oncologists to grapple with the idea of 'molecular progression' and whether this biomarker-led switch truly alters the disease's natural history.
Despite showing a progression-free survival (PFS) benefit, oncologists advise against the SERENA-6 strategy of switching therapy upon detecting an ESR1 mutation before clinical progression. The lack of overall survival data, flawed trial comparison (PFS vs PFS2), and significant cost burdens make this approach premature for clinical practice.
The SERINA-6 trial suggests a paradigm shift: proactively switching from an AI to an oral SERD upon detecting an ESR1 mutation in ctDNA—before clinical or radiographic progression—significantly improves progression-free survival and patient quality of life.
With several new oral endocrine agents showing similar efficacy for ESR1-mutated breast cancer, clinicians' choices are driven by practical factors. Treatment selection hinges on tolerability (e.g., vepdegestrant's QT prolongation risk) and familiarity with an agent's real-world performance, rather than marginal differences in trial data.
The SERENA-6 trial demonstrated that using ctDNA to detect ESR1 mutations and switching from an AI to an oral SERD before clinical progression significantly improves progression-free survival and quality of life. This proactive approach, while debated by the FDA, highlights a potential paradigm shift from reactive to preemptive treatment changes.
A significant, immediate use for adjuvant oral SERDs like gerodestrant will be for patients who cannot tolerate the arthralgias and other side effects of standard aromatase inhibitors (AIs). This addresses a large and challenging clinical problem, positioning SERDs as a key alternative for maintaining long-term adherence to endocrine therapy.
The success of oral SERD clinical trials hinges on study design. Trials like AMIRA-3 and Axilera failed in their overall populations but showed benefit in ESR1-mutant subgroups. EMERALD succeeded by making this subgroup a co-primary endpoint, proving the importance of targeting the right population from the outset.
Experts are divided on switching to an oral SERD based on detecting an ESR1 mutation before radiologic progression. A key counterargument is that this is not the patient's only chance to receive the drug, and the strategy may offer less progression-free survival than waiting for clinical progression.
