The Unmet Need in Hormone-Positive Breast Cancer
For decades, estrogen receptor-positive (ER+) breast cancer – representing approximately 70-80% of all breast cancers – has been treated with therapies designed to block estrogen's tumor-fueling effects. While aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) like tamoxifen have been cornerstones of treatment, resistance inevitably develops.
The SERD Evolution
SERDs represent a powerful class of endocrine therapy. Unlike AIs (which reduce estrogen production) or SERMs (which block estrogen binding but can have partial agonist effects in some tissues), SERDs like fulvestrant and elacestrant bind to the estrogen receptor (ER), block its function, and tag it for destruction by the cell's protein degradation machinery 2 7 .
The Groundbreaking Phase I Trial: RAD1901-005
The phase I RAD1901-005 trial (NCT02338349) was designed to answer critical initial questions: What is the safe and recommended dose of elacestrant? How well is it tolerated? Does it show signs of clinical activity in heavily pretreated patients?
Trial Design and Patient Population
Part A
Standard "3+3" dose-escalation design exploring doses from 200mg to 1000mg daily using capsules.
Parts B & C
Evaluated the 400mg capsule and then a new 400mg tablet formulation.
Part D
Focused on heavily pretreated population (prior CDK4/6i, fulvestrant, ≥2 prior lines).
| Characteristic | Value (n=50 at RP2D) | Significance |
|---|---|---|
| Median Age | 63 years | Representative of typical advanced breast cancer population |
| Median Prior Lines of Therapy | 3 (Systemic, any) | Heavily pretreated population |
| Prior CDK4/6 Inhibitor (%) | 52% (26/50) | High prevalence, indicating target population with emerging resistance needs |
| Prior Fulvestrant (%) | 52% (26/50) | Tested against existing SERD |
| Baseline ESR1 Mutation (ctDNA, %) | 50% (25/50) | Key biomarker population with known resistance mechanism |
Key Findings: Efficacy Signals in Tough Terrain
Recommended Dose
400 mg once daily (tablet) with manageable toxicity profile
Objective Response Rate
19.4% overall, 33.3% in ESR1-mutant patients
Clinical Benefit Rate (24 weeks)
42.6% overall, 56.5% in ESR1-mutant patients
| Outcome Measure | Overall (RP2D) | Prior CDK4/6i | Prior Fulvestrant | ESR1 Mutation (ctDNA) |
|---|---|---|---|---|
| Objective Response Rate (ORR) (Confirmed, Measurable Disease) | 19.4% (6/31) | 16.7% | 15.0% | 33.3% (5/15) |
| Clinical Benefit Rate (24 weeks) (CBR24) | 42.6% (20/47) | 30.4% (7/23) | Data not explicitly stated | 56.5% (13/23) |
| Median Progression-Free Survival (PFS) | ~4.5 months | Data not explicitly stated | Data not explicitly stated | Data not explicitly stated |
The FES-PET Substudy: Visualizing Target Engagement
A critical companion study, RAD1901-106 (NCT02650817), provided visual proof of elacestrant's mechanism of action in patients using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT).
Methodology
- 16 postmenopausal women with ER+ ABC
- Received either 200mg (escalating to 400mg) or 400mg elacestrant daily
- FES-PET/CT scans before treatment and on Day 14
- Primary endpoint: percentage change in FES uptake in tumor lesions
Results
- Median reduction in tumor FES uptake: 89.1%
- Consistent across dose cohorts (89.1% for 200/400mg; 88.7% for 400mg)
- Only 25% showed residual ER availability (>25% persistence of FES uptake)
- Clinical Benefit Rate: 30.8% (4/13 evaluable patients)
| Parameter | Result | Interpretation |
|---|---|---|
| Median Reduction in FES Uptake (SUV) at Day 14 | 89.1% (Q1:75.1%, Q3:94.1%) | Profound reduction in available ER in tumors |
| Reduction in 200mg->400mg Cohort | 89.1% (Q1:67.4%, Q3:94.2%) | Consistent effect starting at 200mg |
| Reduction in 400mg Cohort | 88.7% (Q1:79.5%, Q3:94.1%) | Maximal effect achieved at 400mg |
| Patients with Residual ER Availability (>25% FES Uptake Persistence) | 25% (4/16) | Majority had near-complete ER blockade |
| Clinical Benefit Rate (CBR) | 30.8% (4/13) | Clinical activity observed alongside target engagement |
The Scientist's Toolkit: Key Reagents Unlocking Elacestrant's Potential
Beyond Phase I: The Path to Approval and Future Directions
EMERALD Phase III Trial (NCT03778931)
- Global, randomized, open-label trial comparing elacestrant (400mg daily) vs standard endocrine monotherapy
- ER+/HER2- advanced breast cancer patients progressed after 1-2 lines of endocrine therapy, including a CDK4/6 inhibitor
- Prospectively stratified by ESR1 mutation status
- Met primary endpoints with statistically significant improvement in PFS
- Led to U.S. FDA approval in January 2023 for postmenopausal women or adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer 6
Future Research Directions
Conclusion: A New Pillar of Endocrine Therapy
The phase I study of elacestrant revealed that this novel oral SERD could effectively degrade the ER, induce objective tumor responses, and provide clinically meaningful benefit in heavily pretreated patients with advanced ER+/HER2- breast cancer. The significant activity in patients with ESR1 mutations was particularly encouraging and foreshadowed its eventual biomarker-driven approval. The FES-PET substudy showed dramatic reductions in available ER within tumors. With an acceptable safety profile, these results supported further development through the successful EMERALD phase III trial, culminating in FDA approval and establishing elacestrant as a vital new oral option for ESR1-mutated advanced breast cancer.