Oral SERD Elacestrant Shifts Treatment Landscape for ESR1-Mutated Metastatic Breast Cancer
核心洞察
Elacestrant (Orserdu) was approved by the FDA in early 2023 for ER-positive, HER2-negative, ESR1 (搜索)-mutated advanced or metastatic breast cancer (搜索) after endocrine therapy progression.
The approval was based on the phase 3 EMERALD trial, which demonstrated significantly improved progression-free survival (PFS) in patients with ESR1 (搜索) mutations.
Elacestrant offers an oral alternative to fulvestrant injections, potentially improving patient quality of life and convenience.
The FDA's approval of elacestrant (Orserdu) in early 2023 marks a significant advancement in the treatment of estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (搜索), particularly for patients with ESR1 (搜索) mutations. This oral selective ER degrader (SERD) offers a new endocrine-based option for patients who have progressed on prior lines of endocrine therapy. The approval was based on the Phase 3 EMERALD trial (NCT03778931), which demonstrated a statistically significant improvement in progression-free survival (PFS) in patients with ESR1 mutations treated with elacestrant compared to those treated with fulvestrant or aromatase inhibitors.
Clinical Efficacy in ESR1-Mutated Breast Cancer
The EMERALD trial, a randomized, open-label, active-controlled, multicenter study, enrolled 478 participants with advanced or metastatic breast cancer (搜索), including 228 with ESR1 (搜索) mutations. Patients had progressed on one or two prior lines of endocrine therapy, including a CDK4/6 inhibitor. The results showed that in the ESR1-mutated population, the median PFS was 3.8 months (95% CI, 2.2-7.3) with elacestrant compared to 1.9 months (95% CI, 1.9-2.1) with fulvestrant/aromatase inhibitors (HR, 0.55; 95% CI, 0.39-0.77; P < .0005). This improvement highlights the clinical benefit of elacestrant in this specific patient subgroup.
The Role of ESR1 Mutations in Endocrine Resistance
ESR1 (搜索) mutations are acquired somatic mutations that enable the estrogen receptor to function even in the presence of aromatase inhibitors, leading to endocrine resistance. Sarah Donahue, MPH, NP, UCSF Helen Diller Family Comprehensive Cancer Center (搜索), emphasizes that ESR1 testing should be conducted at the time of disease progression after aromatase inhibitor therapy, as these mutations are not present at baseline. Testing can be performed using either tissue or liquid biopsy to detect circulating tumor DNA.
Elacestrant: An Oral SERD with a Manageable Safety Profile
Elacestrant is a nonsteroidal oral SERD that degrades the ERα in a dose-dependent manner and inhibits estradiol-dependent ER-directed gene transcription and tumor growth. The recommended dose is one 345-mg tablet daily, with or without food. While the most common adverse events (AEs) include musculoskeletal pain (41%), nausea (35%), and increased cholesterol levels (30%), these are generally manageable. Donahue notes that patients generally tolerate the agent well, with low-grade nausea and fatigue being the most commonly reported AEs.
Shifting Towards Oral Therapies and Future Directions
The availability of an oral SERD like elacestrant represents a significant shift in the treatment landscape, offering patients an alternative to intramuscular fulvestrant injections, which can be painful and cause scarring over time. Furthermore, ongoing studies are evaluating the efficacy of elacestrant in combination with targeted therapies, which could further expand its use in clinical practice. Several other oral SERDs, including camizestrant, amcenestrant, and giredestrant, are also in development, suggesting a promising future for this class of drugs in the treatment of ER-positive breast cancer (搜索).