Endocrine therapy is a primary treatment approach for Estrogen Receptor-positive (ER+), Human Epidermal Growth Factor Receptor 2-negative (HER2-) metastatic breast cancer (MBC). The growth of these tumors is often driven by estrogen, which binds to and activates the estrogen receptor (ER) protein within the cancer cells. Both Elacestrant and Fulvestrant are Selective Estrogen Receptor Degraders (SERDs). These medications work by targeting the ER to block its activity and prevent the proliferation of hormone-sensitive cancer.
Mechanisms of Estrogen Receptor Degradation
Both Elacestrant and Fulvestrant function by binding to the estrogen receptor (ER) and initiating its degradation. This process is a defining characteristic of SERDs, setting them apart from older hormonal therapies like Tamoxifen, which only block the receptor. SERDs promote the destruction of the receptor protein, achieving a more complete disruption of the estrogen signaling pathway.
Fulvestrant, an injectable SERD, was the first drug in this class approved and has been a standard treatment for endocrine-resistant breast cancer. It binds to the ER, changing its shape, which prevents the receptor from entering the cell nucleus and marks it for destruction. Elacestrant, a newer, orally available SERD, works through a similar dual mechanism of receptor antagonism and degradation. Its chemical structure allows it to maintain activity even against mutated forms of the estrogen receptor.
A significant difference lies in the drugs’ effectiveness against mutations in the ESR1 gene, which codes for the ER. These mutations frequently develop as resistance mechanisms to prior endocrine therapies, causing the receptor to become constantly active. Elacestrant has demonstrated strong anti-tumor activity against these mutated receptors, which are often less responsive to Fulvestrant. This ability to overcome ESR1 mutation-driven resistance provides a therapeutic advantage in this patient population.
Practical Differences in Drug Administration
The administration method represents a major difference for patients. Elacestrant is designed for daily oral administration. This oral route offers convenience that can improve a patient’s quality of life and adherence to the treatment schedule.
In contrast, Fulvestrant must be administered through an intramuscular injection, typically 500 mg monthly, following an initial loading schedule. This requires the patient to visit a clinic or infusion center for the procedure. The injection is often deep into the muscle and can be large, sometimes involving two separate injections. This process can cause localized injection site pain and discomfort.
Comparative Efficacy in Metastatic Disease
Elacestrant’s efficacy was established in the Phase III EMERALD trial, comparing it to standard-of-care (SOC) endocrine therapy, including Fulvestrant or an aromatase inhibitor. The trial focused on patients whose cancer progressed after one or two previous lines of endocrine therapy and who had all received a prior CDK4/6 inhibitor. In the overall population, Elacestrant significantly prolonged median Progression-Free Survival (PFS) compared to SOC, showing a 30% reduction in the risk of progression or death.
The greatest benefit of Elacestrant was observed in the subgroup of patients whose tumors harbored an ESR1 mutation, accounting for nearly half of the trial population. In this specific group, Elacestrant reduced the risk of progression or death by 45%. The median PFS for patients with ESR1 mutations was 3.8 months with Elacestrant, compared to only 1.9 months with SOC.
Fulvestrant’s efficacy has been demonstrated in various settings, such as the FALCON trial, where it showed a longer median PFS (16.6 months) compared to anastrozole (13.8 months) in endocrine-therapy-naïve patients. However, in the post-CDK4/6 inhibitor setting, the efficacy of standard single-agent endocrine therapies like Fulvestrant is limited, with historical median PFS often around two months.
While Fulvestrant was a component of the SOC arm in the EMERALD trial, the significant improvement seen with Elacestrant positions it as a more effective option in this later-line setting. For patients with ESR1 mutations who had a longer response to prior CDK4/6 inhibitor therapy (over 12 months), Elacestrant showed a median PFS of 8.6 months, significantly higher than the 1.9 months seen with SOC.
Safety and Tolerability Profiles
The safety profile of Elacestrant is manageable and consistent with other endocrine therapies, though its oral nature introduces a different spectrum of common side effects. The most frequently reported adverse events are gastrointestinal issues, with nausea occurring in about 35% of patients and vomiting in approximately 19%. Other common side effects include musculoskeletal pain, fatigue, and elevations in cholesterol and liver enzymes.
Fulvestrant is well-tolerated systemically, but its administration route is associated with specific adverse events. The most common side effect is pain at the injection site, which occurs in a notable percentage of patients due to the volume and intramuscular nature of the shot. Other frequent side effects include arthralgia (joint pain), hot flashes, and nausea.
Patients on Fulvestrant may experience monthly injection site pain, but systemic side effects are typically less severe, with a lower incidence of high-grade nausea and vomiting compared to Elacestrant. The convenience of oral Elacestrant is balanced against managing its more common gastrointestinal side effects. Monitoring of the lipid profile is also necessary with Elacestrant due to potential increases in cholesterol and triglycerides.