Breast cancer is the second leading cause of death among women worldwide, impacting approximately 260,000 individuals and resulting in 40,000 deaths annually [1]. Over two-thirds of these cases are classified as hormone receptor-positive breast cancer [2]. Affecting about one in eight women during their lifetime, breast cancer is one of the most prevalent cancers diagnosed in women. Although rarer in men, the incidence of breast cancer in males is increasing, with contributing factors including Klinefelter syndrome, high body mass index, testicular and liver diseases, radiation exposure, and alcohol consumption [3]. Additionally, about 10–15% of breast cancer patients develop brain metastases, typically appearing 2–3 years after the initial diagnosis [1].

In patients with estrogen receptor-positive (ER+) metastatic breast cancer, hormone therapy remains the primary treatment option to delay the need for chemotherapy [4]. The current standard of care (SOC) for ER+ metastatic breast cancer involves a combination of hormone therapy and CDK4/6 inhibitors [5]. However, resistance often arises due to mutations in the ESR1 gene, which encodes the estrogen receptor [6]. For patients who progress despite hormone therapy and CDK4/6 inhibitors, sequential endocrine monotherapy is typically recommended. Fulvestrant, approved by the U.S. Food and Drug Administration (FDA) in 2002, is administered via intramuscular injection and has shown better efficacy than tamoxifen and aromatase inhibitors (AIs). It is commonly used as a second- or third-line treatment [7]. Despite its effectiveness, fulvestrant is associated with a relatively low median progression-free survival (PFS) of just 2 months. Additionally, most patients eventually develop resistance to the drug, although the precise mechanisms behind this resistance are not yet fully understood [8]. Furthermore, fulvestrant’s limited bioavailability has prompted the development of oral selective estrogen receptor degraders (SERDs), which offer the potential for improved bioavailability and effectiveness [9].

SERDs are antiestrogens designed to destabilize the H12 region of the estrogen receptor, working by binding to the receptor and promoting the degradation of the ER signaling pathway [10]. Several SERDs are currently in clinical development [7], with elacestrant (RAD-1901) being one of the notable non-steroidal small molecules that acts as an estrogen receptor antagonist [11]. On January 27, 2023, the U.S. FDA approved elacestrant for the treatment of advanced or metastatic breast cancer in patients with ER+, ESR1-mutated, and HER2-negative (HER2–) profiles, following progression after at least one line of endocrine therapy [12]. This approval marked elacestrant as the first oral estrogen receptor antagonist approved for patients with ESR1 mutations [13]. Two phase I clinical trials (NCT02650817, NCT02338349) evaluated elacestrant in patients with hormone receptor-positive breast cancer that had metastasized to the brain [1]. With elacestrant now approved, patients with PIK3CA mutations and metastatic ER+ breast cancer may need to consider the benefits and risks of combining alpelisib and fulvestrant vs. using elacestrant as a single agent [7]. As elacestrant is integrated into standard care, molecular profiling will become increasingly important in treatment decisions, underscoring the critical role of precision medicine in managing breast cancer [14].

This post-hoc analysis aims to systematically evaluate the effectiveness of elacestrant as a therapeutic option in the management of breast cancer. By aggregating and analyzing data from clinical trials, we intend to provide a comprehensive understanding of the drug’s efficacy, safety, and potential advantages over existing treatments.

The current evidence supporting the use of elacestrant in patients with advanced breast cancer has led to the initiation of several other clinical trials. These trials are exploring the use of elacestrant in early-stage breast cancer and its combination with other therapies for metastatic cases, including drugs like alpelisib, everolimus, and CDK4/6 inhibitors [19]. The research includes two phase I trials and one phase III trial (EMERALD), which revealed significant insights into disease progression and patient survival, though no conclusive results were achieved. The phase I trials specifically targeted ER+, HER2– breast cancer, with the objective of evaluating elacestrant’s safety, tolerability, and preliminary efficacy. However, the small sample sizes may limit the broader applicability of the findings. A post-hoc analysis of PFS outcomes across these trials showed no statistically significant benefit for the intervention group. While the uniformity across the studies suggests methodological consistency and similar patient populations, this does not confirm the efficacy of elacestrant. The ORR was estimated at 0.07, with a 95% confidence interval ranging from 0.02 to 0.18, pointing to a relatively low response rate. Nevertheless, due to the variability and limited scope of the available data, it remains difficult to draw a definitive conclusion regarding the effectiveness of elacestrant in treating breast cancer.

The phase III EMERALD trial highlighted encouraging outcomes for elacestrant in the management of ER+/HER2– metastatic breast cancer [20]. The study showed a significantly extended PFS for patients receiving oral elacestrant compared to those on standard care, particularly in individuals whose disease had progressed after prior endocrine therapy and CDK4/6 inhibitor treatment [21]. However, its efficacy in patients who have not received fulvestrant remains unclear, emphasizing the need for further research. Elacestrant’s pharmacological profile is complex, exhibiting dose-dependent ER antagonist and agonist effects, along with the ability to penetrate the blood-brain barrier (BBB) [20]. This feature could be significant in treating breast cancer patients with CNS involvement.

In the phase III EMERALD trial, patients with mESR1-mutant tumors experienced a 45% reduction in the risk of disease progression or death when treated with elacestrant compared to standard endocrine therapy. In this group, the median PFS was 3.79 months with elacestrant, compared to 1.87 months for those receiving standard treatment (HR, 0.54; P < 0.001) [22]. Elacestrant also showed higher PFS rates at both 6 months (34.3% vs. 20.4%) and 12 months (22.3% vs. 9.4%), indicating sustained benefits from this oral SERD therapy. The improved PFS was notably consistent among patients with mESR1 mutations. Specifically, in this subgroup, the PFS rates at 6 months were 40.8% for elacestrant compared to 19.1% for standard therapy, and at 12 months, they were 26.8% vs. 8.2% [22]. Additionally, subgroup analysis from the EMERALD trial revealed that elacestrant provided clinical benefits for patients who had previously received fulvestrant, regardless of their ESR1 mutational status, highlighting its potential as a treatment option for refractory HR+ breast cancer [23].

Elacestrant, a nonsteroidal SERD, exhibits dose-dependent ER antagonist and agonist activities, positioning it as a leading candidate for treating HR-positive breast cancer [24]. Studies have shown that elacestrant can act as an ER agonist within the CNS and readily crosses the BBB [25]. Laboratory research with doses ranging from 0.3 mg/kg to 100 mg/kg has indicated no significant effects on uterine wet weight or epithelial thickness [26]. However, at a low dose of 0.3 mg/kg, a notable increase in uterine weight was observed, whereas no such effect occurred at doses of 1 mg/kg or higher [25]. This suggests that elacestrant’s activity may shift towards antagonism at higher doses [25]. In both single-ascending dose and multiple-ascending dose trials, doses up to 1,000 mg daily were found to be safe and well tolerated, with no maximum tolerated dose identified. Elacestrant’s oral bioavailability was approximately 10%, with a half-life ranging from 27 h to 47 h, reaching steady-state levels after 5–6 days of administration. After seven days of treatment, the mean ER occupancy in the uterus was 83% at 200 mg and 92% at 500 mg daily. The median ratio of elacestrant in cerebrospinal fluid compared to plasma was 0.126% for the 500 mg dose and 0.205% for the 200 mg dose [27]. These complex pharmacological properties may influence how elacestrant is used in the treatment of breast cancer in the future.

Reported side effects of elacestrant include hypercholesterolemia and hypertriglyceridemia, occurring in 30% and 27% of patients, respectively. The rates of severe (Grade 3 and 4) hypercholesterolemia and hypertriglyceridemia were relatively low, at 0.9% and 2.2%, respectively [28]. Other more frequently observed side effects include musculoskeletal pain, nausea, and various gastrointestinal issues [29]. Patients taking elacestrant are also advised against breastfeeding due to potential risks [29]. However, due to the limited ability of elacestrant and other SERDs to effectively cross the BBB, breast cancer patients with brain metastases are still unable to fully benefit from SERD treatments [30].

The findings from this post-hoc analysis suggest a relationship between the effectiveness of ER-targeting therapies and the levels of ER and PR expression in tumor cells. High ER expression enhances the interaction with SERDs, while PR expression indicates a reliance on ER signaling for tumor growth and survival [11]. This is significant because current oncology guidelines recommend endocrine therapy for ER+ tumors, even when ER is expressed in as few as 1% of tumor cells [31]. Upcoming clinical trials that will compare elacestrant with fulvestrant as the foundational endocrine therapy, in combination with treatments like CDK4/6 inhibitors, alpelisib, and everolimus, are expected to provide valuable insights into the best SERD for second-line treatment [32]. Based on this information, the effectiveness of endocrine therapies in breast cancer treatment appears to be closely tied to the expression of ER and PR within tumors [33]. However, to determine the most suitable endocrine therapy, whether SERD or another type, further research and clinical trials are required to assess their efficacy and safety fully [34]. Ultimately, the selection of treatment should be individualized, taking into consideration the tumor’s characteristics and the patient’s overall health, with input from a multidisciplinary team of healthcare professionals [35].