Background
Phase 3, open-label, randomized (1:1) trial; N=373. ER+/HER2- locally advanced or metastatic breast cancer with progression or recurrence after a CDK4/6 inhibitor plus endocrine therapy. Giredestrant (oral SERD) + everolimus targets ER and PI3K-AKT-mTOR pathways. Stratified by ESR1 status, disease site, prior fulvestrant. ESR1-mutated: 207 pts (102 vs 105).
Results
Interventions and follow up: Arm A: Giredestrant + everolimus (n=183)
Arm B: Standard endocrine therapy (exemestane n=141, fulvestrant n=39, tamoxifen n=6) + everolimus (n=190)
Primary endpoint: Investigator-assessed PFS, tested first in ESR1-mutated, then in overall population
mFollow up: NR
Results: PFS (ESR1-mutated): 10.0 vs 5.5 mo, HR 0.38 (95% CI 0.27–0.54), P<.001
PFS (ITT): 8.8 vs 5.5 mo, HR 0.56 (95% CI 0.44–0.71), P<.001
12-mo PFS (ESR1-mutated): 40.5% vs 15.2%
12-mo PFS (ITT): 34.1% vs 18.1%
OS (ESR1-mutated, interim): NR vs 21.0 mo, HR 0.62, P=.0566
OS (ITT, interim): NR vs 26.9 mo, HR 0.69, P=.0473
ORR: ESR1-mutated 26.6% vs 13.8%; ITT 23.8% vs 11.7%
mDoR: ESR1-mutated 14.9 vs 7.3 mo; ITT 12.7 vs 7.7 mo
Arm B: Standard endocrine therapy (exemestane n=141, fulvestrant n=39, tamoxifen n=6) + everolimus (n=190)
Primary endpoint: Investigator-assessed PFS, tested first in ESR1-mutated, then in overall population
mFollow up: NR
Results: PFS (ESR1-mutated): 10.0 vs 5.5 mo, HR 0.38 (95% CI 0.27–0.54), P<.001
PFS (ITT): 8.8 vs 5.5 mo, HR 0.56 (95% CI 0.44–0.71), P<.001
12-mo PFS (ESR1-mutated): 40.5% vs 15.2%
12-mo PFS (ITT): 34.1% vs 18.1%
OS (ESR1-mutated, interim): NR vs 21.0 mo, HR 0.62, P=.0566
OS (ITT, interim): NR vs 26.9 mo, HR 0.69, P=.0473
ORR: ESR1-mutated 26.6% vs 13.8%; ITT 23.8% vs 11.7%
mDoR: ESR1-mutated 14.9 vs 7.3 mo; ITT 12.7 vs 7.7 mo
Adverse events
Any-grade AE: 98.9% vs 96.8%
Stomatitis: 47.3% vs 48.9%
Diarrhea: 26.9% vs 22.6%
Anemia: 23.6% vs 21.0%
Bradycardia (G1–2): 3.8% vs 0.5%
Grade ≥3 (any): NR
Discontinuation due to AE: 17.0% vs 11.8%
Stomatitis: 47.3% vs 48.9%
Diarrhea: 26.9% vs 22.6%
Anemia: 23.6% vs 21.0%
Bradycardia (G1–2): 3.8% vs 0.5%
Grade ≥3 (any): NR
Discontinuation due to AE: 17.0% vs 11.8%
Conclusions
All-oral giredestrant + everolimus significantly prolonged PFS vs standard endocrine therapy + everolimus after prior CDK4/6 inhibitor, with the largest benefit in ESR1-mutated tumors (HR 0.38). Safety was broadly similar between arms, with more AE-related discontinuations on the giredestrant arm.
Key Limitations
Open-label with investigator-assessed PFS. Comparator was mainly exemestane + everolimus (141/190), not a contemporary oral SERD or PI3K/AKT-pathway-based regimen. ITT benefit is driven largely by ESR1-mutated subgroup. OS is interim and immature, with P values not formally significant in ESR1-mutated cohort. Everolimus toxicity (stomatitis) remains substantial; median treatment duration was short (about 7 mo).
Clinical Context
Positions an all-oral SERD + mTOR inhibitor as an option after CDK4/6 inhibitor progression, particularly for ESR1-mutated disease, alongside existing options (oral SERD monotherapy, fulvestrant + capivasertib or alpelisib, everolimus-based endocrine therapy). The FDA has accepted Roche/Genentech's NDA for giredestrant + everolimus in ER+/HER2- ESR1-mutated advanced breast cancer, PDUFA date 18 December 2026; not yet approved. Data support other global filings.