What is the recommended use and dosage of Elacestrant (Oral Selective Estrogen Receptor Degrader) for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer?

Elacestrant Use and Dosage for HR-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

Elacestrant (Orserdu) is recommended at a dose of 345 mg orally once daily with food for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. 1

Patient Selection and Testing

• Patient selection requires confirmation of ESR1 mutations before starting treatment
• Testing should be performed using:
  • Next-generation sequencing in tumor tissue OR
  • Cell-free DNA in plasma (if negative in plasma, testing in tumor tissue is recommended to detect additional mutations) 2
• ESR1 mutations must be in the ligand binding domain (between codons 310 to 547) 1

Dosing and Administration

• Dosage: 345 mg tablet taken orally once daily with food 1
• Continue until disease progression or unacceptable toxicity
• Dose modifications:
  • Dose interruption, reduction, or discontinuation may be required for adverse reactions
  • For patients with moderate hepatic impairment (Child-Pugh B): Reduce dosage
  • For patients with severe hepatic impairment (Child-Pugh C): Avoid use 1

Clinical Efficacy

Elacestrant demonstrated superior efficacy compared to standard endocrine therapy in:

• ESR1-mutated patients: Median PFS 3.8 months vs 1.9 months (HR 0.55,95% CI 0.39-0.77, p=0.0005) 1, 3
• The benefit in the overall population was primarily driven by the ESR1-mutated subgroup 3
• Efficacy was demonstrated even in patients previously treated with fulvestrant 4

Place in Treatment Algorithm

For patients with HR-positive, HER2-negative, ESR1-mutated advanced/metastatic breast cancer:

1. First-line therapy: Nonsteroidal aromatase inhibitor + CDK4/6 inhibitor 2
2. After progression on first-line therapy:
   • If ESR1-mutated: Elacestrant 345 mg daily 1, 3
   • For patients with PIK3CA mutations: Consider alpelisib + endocrine therapy 2
3. Alternative options after progression on endocrine therapy:
   • Fulvestrant + CDK4/6 inhibitor (if no prior CDK4/6 inhibitor exposure) 2
   • For BRCA1/2 mutation carriers: Olaparib or talazoparib in 1st-3rd line setting 2

Adverse Effects and Monitoring

• Most common adverse reactions (≥10%):

  • Musculoskeletal pain (41%)
  • Nausea (35%)
  • Increased cholesterol (30%)
  • Increased AST (29%)
  • Increased triglycerides (27%)
  • Fatigue (26%) 1

• Monitoring requirements:

  • Lipid profile before starting treatment and periodically thereafter (dyslipidemia is a significant concern) 1
  • Liver function tests (increased AST/ALT are common)
  • Complete blood count (decreased hemoglobin may occur)

Drug Interactions

• Avoid concomitant use with:

  • Strong and moderate CYP3A4 inhibitors (e.g., itraconazole, fluconazole)
  • Strong and moderate CYP3A4 inducers (e.g., rifampin, efavirenz) 1, 5

• Dose adjustments needed when used with:

  • P-gp substrates (e.g., digoxin)
  • BCRP substrates (e.g., rosuvastatin) 1

Special Considerations

• Pregnancy: Can cause fetal harm; advise on effective contraception 1
• Lactation: Not recommended during treatment 1
• Hepatic impairment: Dose reduction for moderate impairment; avoid in severe impairment 1
• Male patients: Elacestrant is approved for use in men with HR-positive, HER2-negative, ESR1-mutated advanced breast cancer 1

Clinical Pearls and Pitfalls

• Elacestrant is the first FDA-approved oral selective estrogen receptor degrader 3, 5
• Unlike other endocrine therapies, elacestrant maintains efficacy in tumors with ESR1 mutations, which are a common mechanism of resistance to aromatase inhibitors 3, 6
• Elacestrant shows activity even in patients who have progressed on fulvestrant (another SERD) 4
• Nausea management is important as it occurs in 35% of patients (vs 19% with standard endocrine therapy) 1
• The benefit of elacestrant is primarily in ESR1-mutated disease; patients without ESR1 mutations may not derive significant benefit 3