What is the role of Selective Estrogen Receptor Downregulators (SERDs) in the treatment of patients with Estrogen Receptor (ER)-positive breast cancer, particularly those who have progressed on prior endocrine therapies?

SERDs in ER-Positive Breast Cancer: Current Role and Evidence

I'm Not Outdated—Here's the Current Evidence on SERDs

Selective Estrogen Receptor Degraders (SERDs) are established, guideline-recommended agents for ER-positive metastatic breast cancer, with fulvestrant being the standard SERD since 2009 and newer oral SERDs like elacestrant approved in 2023 for ESR1-mutated disease. 1, 2

Current SERD Options and Indications

Fulvestrant (Standard SERD)

First-Line Setting:

• Fulvestrant 500 mg IM monthly is a Category 1 preferred option for postmenopausal women with HR-positive, HER2-negative metastatic breast cancer, either as monotherapy or combined with CDK4/6 inhibitors 1
• In the FALCON trial, fulvestrant demonstrated superior progression-free survival compared to anastrozole (16.6 vs 13.8 months) in endocrine therapy-naïve patients, particularly those with non-visceral disease 3
• Fulvestrant plus CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) is the preferred first-line approach based on overall survival benefits demonstrated in multiple phase III trials 1

Second-Line and Beyond:

• Fulvestrant combined with a CDK4/6 inhibitor should be offered to patients with progressive disease during AI treatment or who recur within 12 months of adjuvant AI therapy (Category 1 recommendation) 1
• PALOMA-3 showed median PFS of 9.5 months with palbociclib plus fulvestrant versus 4.6 months with fulvestrant alone (HR 0.46, p<0.001) 1, 4
• MONARCH-2 demonstrated improved overall survival with abemaciclib plus fulvestrant (46.7 vs 37.3 months; HR 0.757) 1

Oral SERDs (Next Generation)

Elacestrant:

• FDA-approved in 2023 as the first oral SERD for ESR1-mutated, ER-positive/HER2-negative advanced breast cancer following progression on at least one line of endocrine therapy 2
• Addresses key limitations of fulvestrant: oral bioavailability and enhanced efficacy against ESR1 mutations that confer AI resistance 2, 5
• ESR1 mutations occur in 30-40% of patients with AI-resistant disease and predict superior benefit from SERDs over AIs 2, 5

Mechanism and Rationale for SERDs

SERDs work by binding to the estrogen receptor, inducing conformational changes that lead to receptor degradation and complete loss of ER signaling—unlike SERMs (tamoxifen) which retain partial agonist activity 1, 6

Key advantages over other endocrine therapies:

• No estrogen agonist activity that can drive resistance 1
• Effective against ESR1 mutations that emerge during AI therapy and cause AI resistance 2, 5, 7
• Longer duration of response compared to AIs in some settings 1, 3

Clinical Algorithm for SERD Use

For Postmenopausal Women with HR+/HER2- Metastatic Disease:

First-Line (no prior endocrine therapy for metastatic disease):

1. Preferred: CDK4/6 inhibitor + AI OR CDK4/6 inhibitor + fulvestrant 1
2. Alternative: Fulvestrant monotherapy (if CDK4/6 inhibitors contraindicated) 1
3. Alternative: AI monotherapy 1

Second-Line (progression on AI):

1. If no prior CDK4/6 inhibitor: Fulvestrant + CDK4/6 inhibitor (Category 1) 1
2. If ESR1 mutation detected: Consider elacestrant 2
3. If PIK3CA mutation: Fulvestrant + alpelisib 1

Third-Line and Beyond:

• Fulvestrant monotherapy (if not previously used) 1
• Elacestrant (especially if ESR1-mutated) 2
• Other endocrine agents (exemestane, megestrol acetate) 1

For Premenopausal Women:

All SERD-containing regimens require concurrent ovarian suppression with LHRH agonist (goserelin or leuprolide) 1

• Fulvestrant + CDK4/6 inhibitor + ovarian suppression is Category 1 for second-line after AI progression 1

Key Monitoring and Practical Considerations

Fulvestrant Administration:

• 500 mg IM monthly (with loading dose of 500 mg on days 1,15, and 29 of first month) 1
• Well-tolerated with minimal systemic toxicity compared to chemotherapy 1
• Main limitation: intramuscular injection route 3, 5

When to Test for ESR1 Mutations:

• After progression on AI therapy, before selecting next endocrine therapy 2
• ESR1 mutations predict superior benefit from SERDs versus AIs 2, 5
• Can be detected via liquid biopsy (circulating tumor DNA) 2

Combination Therapy Monitoring:

• When combining with CDK4/6 inhibitors: monitor CBC every 2 weeks for first 2 cycles, then at start of each cycle 8, 4
• Grade 3-4 neutropenia occurs in 54-62% with palbociclib but febrile neutropenia is rare (<2%) 8, 4

Common Pitfalls to Avoid

1. Do not continue the same CDK4/6 inhibitor after progression—limited data support switching to another CDK4/6-containing regimen 1, 9
2. Do not use fulvestrant at the old 250 mg dose—500 mg monthly is superior and the only recommended dose 1
3. Do not forget ovarian suppression in premenopausal women receiving fulvestrant—incomplete suppression leads to treatment failure 1
4. Do not assume all endocrine-resistant disease is the same—ESR1 mutation status should guide SERD selection when available 2, 5