Highlights
Recent real-world data confirms that elacestrant, the first-in-class oral selective estrogen receptor degrader (SERD), provides a clinically meaningful median time to next treatment (mTTNT) of 7.9 months in patients with ESR1-mutated metastatic breast cancer (mBC).
The efficacy was particularly pronounced in patients with no prior fulvestrant exposure, reaching a mTTNT of 12.9 months, suggesting a significant advantage in earlier endocrine sequencing.
Elacestrant demonstrated resilience in high-risk subgroups, including those with liver metastases and co-existing PI3K pathway mutations, offering a viable bridge before transitioning to more toxic chemotherapy or antibody-drug conjugates.
Introduction: The Challenge of Endocrine Resistance
In the management of estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC), endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains the cornerstone of first-line treatment. However, the eventual development of resistance is nearly universal. One of the most common and clinically significant mechanisms of acquired resistance is the emergence of mutations in the estrogen receptor 1 (ESR1) gene.
ESR1 mutations typically occur in the ligand-binding domain, leading to constitutive, ligand-independent activation of the estrogen receptor. This renders standard aromatase inhibitors (AIs) ineffective, as they rely on depleting circulating estrogen to inhibit tumor growth. While fulvestrant, an intramuscularly administered SERD, has historically been used to address this, its efficacy is often limited by its pharmacokinetic profile and the increasing complexity of pretreated tumors.
The approval of elacestrant, based on the landmark EMERALD trial, marked a shift in the treatment paradigm. As an oral SERD with higher bioavailability and potent inhibitory effects on both wild-type and mutant ER, elacestrant provided a new option for patients who progressed on prior ET. However, clinical trial populations often differ from the heterogenous patients seen in daily practice. This real-world study by Rugo et al. provides essential evidence on how elacestrant performs in a diverse, real-world clinical setting.
The Biology of ESR1 Mutations and the Role of Elacestrant
Understanding why elacestrant is effective requires a deep dive into the molecular pathology of ESR1 mutations. These mutations, such as Y537S and D538G, allow the receptor to adopt an active conformation without the need for estradiol. In the post-CDK4/6i setting, up to 40% of patients develop these mutations. Elacestrant works by binding to the estrogen receptor, inducing a conformational change that targets the receptor for proteasomal degradation, thereby halting the transcription of estrogen-dependent genes.
Unlike earlier SERDs, elacestrant’s oral formulation allows for consistent therapeutic levels that can overcome the constitutive activity of these mutants. This biological plausibility is the foundation upon which both the EMERALD trial and the current real-world analysis are built.
Study Design and Methodology: A Real-World Perspective
The study utilized a sophisticated data-linking approach, combining claims data from the Komodo Research Dataset with clinical genomic data from Foundation Medicine Inc. This allowed researchers to identify a cohort of 306 patients with ER+/HER2- mBC who possessed a documented ESR1 mutation and had been treated with elacestrant in a clinical practice setting.
The primary outcome measure was Time to Next Treatment (TTNT), which serves as a robust real-world proxy for progression-free survival (PFS). By measuring the interval from the initiation of elacestrant to the start of the subsequent line of therapy or death, the researchers could gauge the duration of clinical benefit in a routine care environment.
The patient population was notably pretreated: 93.8% had received prior ET plus a CDK4/6 inhibitor for at least 12 months, 50.0% had undergone prior chemotherapy, and 72.2% had been treated with fulvestrant. This represents a more heavily pretreated and complex population than that usually seen in registrational trials.
Key Findings: Durable Benefit Across Subgroups
The results of this real-world analysis are encouraging for clinicians navigating the sequencing of therapies in mBC. The median TTNT (mTTNT) for the entire cohort was 7.9 months (95% CI, 7.1-9.8). This finding is particularly striking when considering the high proportion of patients who had already failed multiple lines of therapy.
Impact of Treatment Sequencing
The study highlighted the importance of early intervention with elacestrant. For patients who received elacestrant in the second or third line (1 to 2 prior lines of ET), the mTTNT was 8.2 months. In contrast, for those receiving it in the fourth line or later (3+ prior lines), the mTTNT decreased slightly to 7.5 months. While both groups benefited, the data suggests that elacestrant’s utility is maximized when used earlier in the metastatic setting, potentially delaying the need for more aggressive treatments.
The Fulvestrant and Chemotherapy Factor
One of the most significant findings was the efficacy of elacestrant in patients who had not previously received fulvestrant. In this subgroup, the mTTNT reached 12.9 months. This suggests that elacestrant may be more effective when the estrogen receptor pathway has not been exhausted by prior SERD therapy. Additionally, patients who were chemotherapy-naïve in the metastatic setting showed a mTTNT of 8.4 months, further supporting its role as a bridge before cytotoxic regimens.
Performance in High-Risk Metastatic Sites
Visceral and liver metastases are traditional markers of poor prognosis and potential endocrine resistance. In this study, elacestrant maintained its efficacy in these populations, with a mTTNT of 7.9 months for patients with visceral involvement and 7.2 months for those specifically with liver metastases. This confirms that the drug remains active even in high-burden disease states.
Managing Co-Mutations: The ESR1 and PI3K Interplay
A critical area of investigation in modern breast oncology is the presence of co-occurring mutations. In this cohort, patients with both ESR1 mutations and PI3K pathway mutations (such as PIK3CA, AKT1, or PTEN alterations) were analyzed. These co-mutations often drive aggressive tumor behavior and resistance to standard ET.
The study found that in patients with co-existing ESR1 and PI3K pathway mutations, the mTTNT was 6.3 months. While this is lower than the overall cohort, it remains a clinically meaningful duration of benefit. It suggests that even in the presence of bypass signaling through the PI3K/AKT/mTOR pathway, targeting the ESR1 mutation with elacestrant can still provide disease control, potentially allowing for sequential rather than simultaneous targeted therapy.
Expert Commentary: Re-Evaluating the Sequencing Paradigm
The findings from Rugo et al. underscore a major shift in how we approach the treatment of ER+/HER2- mBC. For years, the move from CDK4/6 inhibitors directly to chemotherapy or antibody-drug conjugates (ADCs) like sacituzumab govitecan was common due to the lack of effective endocrine options. The real-world performance of elacestrant suggests a more nuanced “endocrine-first” sequencing strategy.
By identifying ESR1 mutations through liquid biopsy or tissue testing at the time of progression on first-line therapy, clinicians can select patients who are most likely to respond to elacestrant. This study reinforces that elacestrant is not just a trial-based success but a practical tool that works in patients who have already faced extensive prior treatment, including fulvestrant and chemotherapy.
However, limitations must be noted. As a retrospective claims-based study, TTNT is a proxy and may be influenced by clinician preference or patient logistics rather than just disease progression. Furthermore, while the benefit in PI3K-mutated patients is notable, further research is needed to determine whether combinations of elacestrant with PI3K or AKT inhibitors would yield even greater synergy.
Conclusion: A New Standard for Personalized Sequencing
In conclusion, elacestrant demonstrates durable benefit in real-world clinical practice for patients with ESR1-mutated mBC. Its efficacy is particularly notable in earlier lines of therapy and in those with prolonged exposure to prior endocrine treatments. The ability of elacestrant to provide over 7 months of treatment stability across a broad, pretreated population—including those with visceral disease—validates its role in personalized medicine.
As we continue to refine the sequencing of therapies, the use of elacestrant offers a strategic opportunity to maximize the duration of endocrine-based therapy, preserving quality of life and delaying the onset of chemotherapy-related toxicities. This study serves as a vital bridge between clinical trial efficacy and real-world effectiveness, providing clinicians with the confidence to integrate elacestrant into the management of ESR1-mutated metastatic breast cancer.
References
1. Rugo HS, Kaklamani V, McArthur H, et al. Real-World Outcomes of Elacestrant in ER+, HER2-, ESR1-Mutant Metastatic Breast Cancer. Clin Cancer Res. 2026;32(1):179-187. doi:10.1158/1078-0432.CCR-25-3040.
2. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (ORSERDU) vs standard-of-care endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: outcomes by duration of prior CDK4/6 inhibitor in the phase III EMERALD trial. J Clin Oncol. 2022;40(30):3246-3256.
3. Lloyd MR, et al. Clinical Implications of ESR1 Mutations in Breast Cancer. Clin Cancer Res. 2026;32(1):169.
