Dr Mayer on Efficacy Findings With Giredestrant Plus Everolimus in ER+/HER2– Advanced Breast Cancer

"evERA was a positive trial. Both coprimary end points were met, and in patients whose tumors harbored an ESR1 mutation, progression-free survival improved from approximately 5.5 months to nearly 10 months with giredestrant plus everolimus.”

Erica L. Mayer, MD, MPH, a medical oncologist and director of Clinical Research in Breast Oncology at Dana-Farber Cancer Institute, discussed efficacy and safety findings from the phase 3 evERA trial (NCT05306340), a randomized study evaluating giredestrant plus everolimus (Afinitor) vs physician’s choice of endocrine therapy plus everolimus in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer.

The evERA trial met both coprimary end points, Mayer explained, demonstrating a clinically meaningful improvement in progression-free survival (PFS) with the combination of the oral selective estrogen receptor degrader (SERD) giredestrant and the mTOR inhibitor everolimus. Among patients with ESR1-mutant disease, median PFS was 9.99 months (95% CI, 8.08-12.94) with giredestrant plus everolimus (n = 102) vs 5.45 months (95% CI, 3.75-5.62) with the control regimen (n = 105; HR, 0.38; 95% CI, 0.27-0.54; P < .0001). A benefit was also observed in the intention-to-treat population, with a median PFS of 8.77 months (95% CI, 6.60-9.59) with the giredestrant-based regimen (n = 183) vs 5.49 months (95% CI, 4.01-5.59) in the endocrine therapy arm (n = 190; HR, 0.56; 95% CI, 0.44-0.17; P < .0001). Importantly, this benefit was consistent regardless of the endocrine comparator selected in the control arm, supporting the robustness of the treatment effect.

Mayer emphasized that the efficacy signal extended across multiple clinically relevant subgroups. Consistent with prior data presented at the 2025 ESMO Congress, subgroup analyses showed that benefit with giredestrant plus everolimus was maintained across key clinicopathologic factors, including PIK3CA mutation status, ESR1 mutation status, and duration of prior CDK4/6 inhibitor therapy. Patients with co-occurring ESR1 and PIK3CA mutations derived substantial benefit, as did patients with either shorter or longer prior exposure to CDK4/6 inhibitors,.

From a tolerability standpoint, the combination was described as well tolerated, with no increase in endocrine-related toxicity attributable to giredestrant compared with standard endocrine therapy. The safety profile was largely driven by adverse effects classically associated with everolimus, including stomatitis, diarrhea, and fatigue. Mayer noted that these toxicities were manageable with established mitigation strategies, such as prophylactic steroid mouthwash, which has become standard in clinical practice when using mTOR inhibition.

Mayer highlighted that the combination of an oral SERD with a targeted partner offers a rational, chemotherapy-sparing strategy that may represent a new standard of care for a broad population of patients in this setting.