Giredestrant plus everolimus improves progression-free survival in treatment-resistant breast cancer
1. In this randomized controlled trial involving patients with disease progression during first-line treatment for breast cancer, giredestrant plus everolimus prolonged progression-free survival compared with standard endocrine therapy plus everolimus.
2. Overall survival improvement was not established, and serious adverse events were numerically more frequent with giredestrant.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Endocrine therapy combined with a CDK4/6 inhibitor is standard initial treatment for estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Once resistance emerges, subsequent endocrine-based treatment often provides only brief disease control. Acquired ESR1 mutations and altered mTOR signaling both contribute to resistance, providing a rationale for targeting both pathways simultaneously. In this international randomized controlled trial, the all-oral estrogen receptor degrader giredestrant plus everolimus was compared with investigator-selected endocrine therapy plus everolimus in patients whose cancer had progressed or recurred after initial treatment. The primary outcome was progression-free survival, evaluated first in patients with ESR1-mutated tumors and then across the entire trial population. It was found that giredestrant plus everolimus significantly prolonged progression-free survival in both populations, with the clearest benefit in ESR1-mutated disease. An exploratory analysis did not establish a benefit in patients without detectable ESR1 mutations. Tumor responses appeared more frequent and durable with giredestrant. However, overall survival results were equivocal, and serious events as well as everolimus discontinuation were numerically more frequent in the group that received giredestrant. Limitations of this study include the open-label design, enrichment for ESR1-mutated tumors, predominant use of exemestane in the control group, and exclusion of patients with rapid progression on prior CDK4/6 therapy. In summary, giredestrant plus everolimus improved disease control after CDK4/6 inhibitor treatment, particularly in ESR1-mutated advanced breast cancer.
Click to read the study in NEJM
Relevant Reading: Metastatic breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
In-Depth [randomized controlled trial]: This phase III trial enrolled 373 patients at 133 sites in 13 countries. Patients were randomized to giredestrant 30 mg daily plus everolimus 10 mg daily (n=183) or investigator-selected exemestane, fulvestrant, or tamoxifen plus everolimus (n=190). Randomization was stratified by previous fulvestrant treatment, ESR1 mutation status, and visceral disease. The primary endpoint was investigator-assessed progression-free survival, tested hierarchically in the ESR1-mutated population and then the overall population. Among patients with ESR1 mutations, progression free survival was 10.0 months in the giredestrant group versus 5.5 months in the control group (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.27 to 0.54; P<0.001). In the overall trial population, those who received giredestrant also had longer progression-free survival as compared to control (8.8 months versus 5.5 months; HR, 0.56; 95% CI, 0.44 to 0.71; P<0.001). Among patients with measurable disease in the overall population, confirmed objective response occurred in 23.8% versus 11.7%, with median response durations of 12.7 versus 7.7 months. Overall survival remained immature: the hazard ratio for death was 0.62 (95% CI, 0.38 to 1.02) in the ESR1-mutated population and 0.69 (95% CI, 0.47 to 1.00) overall. Any-grade adverse events occurred in 98.9% versus 96.8%; stomatitis, diarrhea, and anemia were most common. Serious adverse events occurred in 29.1% versus 23.1%, and everolimus discontinuation because of adverse events occurred in 17.0% versus 11.8%. Overall, these results suggest that giredestrant-everolimus may serve as a viable second-line treatment option for ER–positive, HER2–negative advanced breast cancer.
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