Nubequa (Elacestrant) - Indication and Usage
Nubequa (elacestrant) is FDA-approved specifically for postmenopausal women or adult men with estrogen receptor-positive (ER+), HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have progressed after at least one line of endocrine therapy. 1, 2
Specific Patient Population
- Postmenopausal women or adult men only - not approved for premenopausal women 2
- ER-positive, HER2-negative disease - hormone receptor positivity is mandatory 2
- ESR1 mutation must be documented by an FDA-approved test before initiating treatment 1, 2
- Prior endocrine therapy required - patients must have received ≥1 line of endocrine therapy with documented disease progression 1, 2
Mechanism and Clinical Rationale
Elacestrant is an oral selective estrogen receptor degrader (SERD) that selectively binds to the estrogen receptor in breast cancer cells and inhibits tumor growth. 3 ESR1 mutations represent a critical mechanism of resistance to aromatase inhibitors, making elacestrant particularly valuable in this molecularly-defined subset. 3
Evidence Supporting Approval
The FDA approval was based on the EMERALD trial (Study RAD1901-308), which demonstrated:
- Statistically significant improvement in progression-free survival (PFS) in the ESR1-mutated subgroup (n=228; HR 0.55,95% CI 0.39-0.77; P=0.0005) 2
- No trend toward overall survival detriment (HR 0.90,95% CI 0.63-1.30) in ESR1-mutated patients 2
- Objective response rate of 19.4% in heavily pretreated patients at the recommended dose 4
- Clinical benefit rate of 42.6% overall, with 56.5% in ESR1-mutated patients 4
Critical Restriction: ESR1 Mutation Required
The FDA specifically restricted approval to patients WITH ESR1 mutations because the benefit-risk assessment in patients WITHOUT ESR1 mutations was not favorable. 2 While the intention-to-treat population showed statistical significance for PFS, this was primarily driven by the ESR1-mutated subgroup. 2
Dosing
- Elacestrant 345 mg orally once daily until disease progression or unacceptable toxicity 2
- Taken continuously without breaks 4
Safety Profile
The most common adverse events include:
- Upper gastrointestinal symptoms: nausea (33-69%), vomiting (38%), dyspepsia (44%) 3, 4, 5
- Dyslipidemia (increased triglycerides in 25%) 4
- Fatigue (50%) 5
- Most adverse events are grade 1-2 in severity 4
Clinical Context Within Treatment Algorithm
Based on established guidelines for ER-positive metastatic breast cancer, elacestrant fits into the treatment sequence as follows:
- First-line therapy should be endocrine-based for ER-positive disease unless visceral crisis exists 6
- Sequential endocrine therapies are preferred over immediate chemotherapy to maximize quality of life 6
- Elacestrant represents a later-line option after progression on at least one prior endocrine therapy, specifically for those with ESR1 mutations 2
- CDK4/6 inhibitors plus aromatase inhibitors or fulvestrant remain preferred first-line options for postmenopausal women 6
Key Clinical Pitfall
Do not use elacestrant in patients without documented ESR1 mutations - the FDA explicitly determined that the benefit-risk profile was unfavorable in ESR1 wild-type patients despite statistical significance in the overall trial population. 2 This represents the first oral estrogen receptor antagonist approved specifically for a molecularly-defined subset based on mutation status. 2
Ongoing Development
Clinical trials are evaluating elacestrant in earlier treatment settings and in combination with CDK4/6 inhibitors or everolimus, based on preclinical data suggesting enhanced efficacy with these combinations. 3