Giredestrant (oral SERD) + everolimus improves PFS after CDK4/6 inhibition, with the strongest benefit in ESR1-mutated breast cancer

Giredestrant is an oral selective estrogen receptor degrader (SERD) designed to overcome ER-driven endocrine resistance, and everolimus is an oral mTOR inhibitor targeting the PI3K–AKT–mTOR pathway; the all-oral combo was tested in the Phase 3, open-label evERA trial (NCT05306340) in ER+/HER2− locally advanced/metastatic breast cancer progressing after CDK4/6 inhibitor + endocrine therapy (n=373; 183 vs 190). Investigator-assessed median PFS improved in the primary ESR1-mutant subgroup (n=207): 10.0 vs 5.5 months (HR 0.38, 95% CI 0.27–0.54; P<0.001), and in the overall population: 8.8 vs 5.5 months (HR 0.56, 95% CI 0.44–0.71; P<0.001). The randomized comparison within evERA is the relevant estimate of benefit; historical BOLERO-2 results come from a different treatment era and population. Any-grade AEs were near-universal and similar (98.9% vs 96.8%); common AEs were stomatitis (47.3% vs 48.9%), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%), consistent with an everolimus-driven toxicity profile.