Giredestrant Plus Palbociclib Shows Numerical PFS Gain in ER+, HER2– LA/mBC

Primary findings from the phase 3 persevERA BC trial (NCT04546009) evaluating first-line giredestrant plus palbociclib vs letrozole plus palbociclib in patients with estrogen receptor–positive (ER+), HER2-negative locally advanced or metastatic breast cancer (LA/mBC), showed a numerical imporvement in investigator-assessed progression-free survival (INC-PFS).¹’

At the primary analysis, presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, with a median follow-up of 52.2 months in the giredestrant arm and 52.1 months in the letrozole arm, giredestrant plus palbociclib produced a numerical improvement in INV-PFS that did not reach pre-specified statistical significance. Median INV-PFS was 33.1 months (95% CI, 30.2-38.3) with giredestrant plus palbociclib vs 28.2 months (95% CI, 25.0–33.1) with letrozole plus palbociclib, yielding a stratified hazard ratio of 0.89 (95% CI, 0.76–1.05; P = .1553). The trial was designed to detect a hazard ratio of 0.77 with 89% power, and the statistical significance boundary after the interim analysis was set at a hazard ratio of 0.85.

Secondary efficacy results showed no difference in overall survival (OS) at an immature analysis: 172 OS events (34.7%) occurred in the giredestrant arm vs 166 (33.4%) in the letrozole arm, with median OS not reached in either group (stratified HR, 1.03; 95% CI, 0.83–1.28; P = .7767). Objective response rate (ORR) and clinical benefit rate (CBR) were similar between arms—ORR 60.2% vs 59.9% and CBR 82.6% vs 82.1%, respectively, while duration of response (DOR) was numerically longer with giredestrant plus palbociclib (median 38.5 months; 95% CI, 30.4–48.7) than with letrozole plus palbociclib (median 30.4 months; 95% CI, 25.3–36.1). Results across key subgroups were generally consistent with the overall population. Giredestrant has shown efficacy across breast cancer settings in prior studies, including a 35% reduction in risk of invasive disease or death as adjuvant monotherapy in ER+, HER2– early breast cancer in the phase 3 lidERA BC trial.²

persevERA BC was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 992 patients with first-line ER+, HER2– LA/mBC in a 1:1 ratio. Patients in the experimental arm received giredestrant 30 mg orally once daily plus palbociclib 125 mg orally once daily on days 1 through 21 of each 28-day cycle; the control arm received letrozole 2.5 mg orally once daily plus matched placebo and palbociclib on the same schedule. Eligibility required no prior selective estrogen receptor degrader (SERD) therapy and disease recurrence at least 12 months from completing prior (neo)adjuvant endocrine treatment. The primary end point was INV-PFS per RECIST v1.1.

The safety profile of giredestrant plus palbociclib was manageable, with no unexpected findings. Any-grade adverse events (AEs) occurred in 99.8% of patients in the giredestrant arm vs 98.0% in the letrozole arm, and grade 3/4 AEs were reported in 85.5% vs 80.8%, respectively. AEs leading to treatment discontinuation were low and similar between arms (9.5% vs 8.3% for any agent). Bradycardia occurred more frequently with giredestrant plus palbociclib (11.7%) than with letrozole plus palbociclib (1.8%); however, the majority of events were grade 1 and asymptomatic (11.3% versus 1.8%), and no grade 3/4 bradycardia events were reported in either arm.¹

Turner noted that further exploration is needed to identify which patients may benefit most from giredestrant in the first-line setting. The ongoing phase 3 pionERA BC trial (NCT06065748) is evaluating giredestrant vs fulvestrant in combination with physician’s choice of CDK4/6 inhibitor in patients with estrogen receptor–positive, HER2– breast cancer who relapsed on adjuvant endocrine therapy or had a treatment-free interval of less than 12 months. Results of that study are anticipated to further define the role of giredestrant among patients with hormone receptor–positive metastatic breast cancer.

References

1. Turner NC, Jhaveri KL, Bardia A, et al. Giredestrant (GIRE) + palbociclib (PALBO) vs letrozole (LET) + PALBO as first-line (1L) therapy in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer (ER+, HER2– LA/mBC): Primary analysis of the Phase III persevERA BC trial. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 30–June 3, 2026; Chicago, IL.
2. Schmid P, Geyer CE Jr, Martín M, et al. Efficacy and safety of giredestrant (GIRE) in patients (pts) with estrogen receptor-positive, HER2-negative early breast cancer (ER+, HER2- eBC) in the phase III lidERA BC clinical trial: results by menopausal status. J Clin Oncol. 2026;44(suppl 16):502. doi:10.1200/JCO.2026.44.16_suppl.502