Background
Phase III, open-label RCT. N=477 ER+ HER2- advanced breast cancer with 1–2 prior lines of ET including a mandatory CDK4/6 inhibitor. ESR1 mutations assessed prospectively in plasma ctDNA. Elacestrant is an oral selective estrogen receptor degrader (SERD) — the first oral SERD approved for ER+ mBC.
Interventions and follow up
Arm A: Elacestrant 345mg oral daily
Arm B: Investigator's choice standard-of-care endocrine monotherapy (fulvestrant or aromatase inhibitor)
Primary endpoint: PFS in all patients and ESR1-mutated subgroup
mFollow up: 14.0 months
Arm B: Investigator's choice standard-of-care endocrine monotherapy (fulvestrant or aromatase inhibitor)
Primary endpoint: PFS in all patients and ESR1-mutated subgroup
mFollow up: 14.0 months
Results
PFS (all patients): 2.79 vs 1.91mo, HR 0.70, 95% CI 0.55–0.88, P=.002
PFS (ESR1-mutated): 3.78 vs 1.87mo, HR 0.55, 95% CI 0.39–0.77, P<.001
12-mo PFS rate (ESR1-mut): 22.3% vs 9.4%
PFS (ESR1-mutated): 3.78 vs 1.87mo, HR 0.55, 95% CI 0.39–0.77, P<.001
12-mo PFS rate (ESR1-mut): 22.3% vs 9.4%
Adverse events
GI: Grade ≥3 nausea 2.9% vs 1.9%; grade ≥3 vomiting 1.7%
Musculoskeletal: Grade ≥3 musculoskeletal pain 1.3%
Other: No significant myelosuppression, cardiac, or hepatotoxicity signals; overall tolerable
Tolerability: Discontinuation 4.6% vs 3.8%
Musculoskeletal: Grade ≥3 musculoskeletal pain 1.3%
Other: No significant myelosuppression, cardiac, or hepatotoxicity signals; overall tolerable
Tolerability: Discontinuation 4.6% vs 3.8%
Conclusions
Elacestrant significantly improved PFS vs standard ET in ER+ HER2- mBC after CDK4/6 inhibitor, with greatest benefit in the ESR1-mutated subgroup. Oral dosing and favorable tolerability are practical advantages over injectable fulvestrant.
Key Limitations
Modest absolute PFS gains (~1.9mo overall; ~2mo ESR1-mutated) — 12-month landmark differences are more interpretable. OS not reported at primary analysis. Heterogeneous SOC comparator (fulvestrant vs AI) may underestimate benefit vs optimal comparator. mPFS ~3.8mo even in ESR1-mutated highlights difficulty of post-CDK4/6i ET. Oral SERD class rapidly evolving (camizestrant and others).
Clinical Context
Elacestrant (Orserdu): FDA approved 2023 for ER+ HER2- ESR1-mutated advanced BC after ≥1 line of ET including a CDK4/6 inhibitor. ESR1 testing (ctDNA) required per label. First oral SERD to market in BC; convenient oral dosing is a major advantage over IM fulvestrant. ESMO-MCBS 2. Emerging oral SERDs with larger effect sizes are in development.
References