Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5.

Purpose: AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC).

Materials And Methods: In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety.

Results: Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively.

Conclusion: The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.