Giredestrant Plus Palbociclib Falls Short of Statistical Significance in Phase 3 Breast Cancer Trial

Data from the primary analysis of the phase 3 persevERA BC trial (NCT04546009), presented at the 2026 ASCO Annual Meeting, showed that adding giredestrant to palbociclib (Ibrance) did not produce a statistically significant improvement in investigator-assessed progression-free survival (PFS) compared with letrozole plus palbociclib in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer.

The giredestrant arm (n = 495) achieved a median investigator-assessed PFS of 33.1 months (95% CI, 30.2–38.2), compared with 28.2 months (95% CI, 25.0–33.1) in the letrozole arm (n = 497; HR, 0.89; 95% CI, 0.76–1.05; P =.1553). PFS rates at 12, 24, and 36 months in the giredestrant group were 77.8%, 59.7%, and 45.8%, respectively, vs 77.3%, 57.3%, and 41.9% in the letrozole group. Findings were broadly consistent across major subgroups.

"First-line giredestrant plus palbociclib produced a numerical improvement in investigator-assessed PFS over letrozole plus palbociclib in ER-positive, HER2-negative locally advanced or metastatic breast cancer, though it did not reach the predefined threshold for statistical significance," said Nicholas C. Turner, MD, PhD, director of clinical research and development at the Royal Marsden Hospital and Institute of Cancer Research in London, United Kingdom, during his presentation.

Background and Rationale

CDK4/6 inhibitor–based regimens represent the standard of care in the first-line treatment of women with ER-positive, HER2-negative locally advanced or metastatic breast cancer. Giredestrant is a potent, next-generation oral selective ER degrader (SERD) and complete ER antagonist developed to produce deep and sustained suppression of ER signaling.

In the earlier phase 3 lidERA BC (NCT04961996) and evERA BC (NCT05306340) trials, giredestrant demonstrated superiority over standard endocrine therapy as a single agent in the adjuvant setting and in combination with everolimus (Afinitor) following CDK4/6 inhibition in the locally advanced or metastatic setting. These results provided the foundation for evaluating frontline giredestrant combined with palbociclib in the same patient population.

Trial Design

persevERA is a randomized, double-blind, placebo-controlled, multicenter study that enrolled 992 patients, who were assigned 1:1 to one of two treatment arms. The experimental arm received oral giredestrant 30 mg plus oral palbociclib 125 mg and placebo once daily on days 1 through 21 of a 28-day cycle. The control arm received oral letrozole 2.5 mg plus the same palbociclib dose and placebo on the same schedule. Treatment continued until disease progression or unacceptable toxicity, after which patients entered survival follow-up.

Eligible patients had a locally confirmed histologic and cytologic diagnosis of untreated ER-positive, HER2-negative locally advanced or metastatic breast cancer. Prior therapy for advanced disease or with a SERD was not permitted, and patients were required to have experienced disease recurrence at least 12 months after completing prior neo(adjuvant) tamoxifen or aromatase inhibitor therapy. Turner noted, however, that an earlier version of the protocol allowed recurrence within 12 months of tamoxifen before a subsequent amendment. Patients with de novo metastatic disease were capped at 20% of enrollment.

The primary end point was investigator-assessed PFS per RECIST 1.1 criteria. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes.

The statistical plan used a 2-sided stratified log-rank test, with the hazard ratio estimated via a stratified Cox proportional hazards model. The primary analysis was triggered after approximately 620 investigator-assessed PFS events. The trial was powered at 89% to detect an HR of 0.77, and the threshold for statistical significance was set at an HR of 0.85. Following an interim analysis, the P-value boundary for the primary analysis was established at 0.0456.

The data cutoff was January 30, 2026. At that point, median follow-up was 52.2 months (range, 0.4–63.5) in the giredestrant arm and 52.1 months (range, 0.3–62.6) in the letrozole arm. Baseline characteristics were well balanced across both groups.

Additional Efficacy Results

OS did not differ between arms. The median OS was not yet evaluable in either the giredestrant group (95% CI, NE–NE) or the letrozole group (95% CI, 61.3 months–NE; HR, 1.03; 95% CI, 0.83–1.28; P =.7767). OS rates at 24 and 36 months were 84.9% and 74.1% in the giredestrant arm, and 84.2% and 74.1% in the letrozole arm.

ORR was 60.2% in the giredestrant arm (n = 465) and 58.8% in the letrozole arm (n = 469). In the giredestrant group, rates of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were 4.1%, 56.1%, 31.4%, and 4.5%, respectively; 2 patients (0.4%) were not evaluable and 16 (3.4%) had missing data. Corresponding rates in the letrozole arm were 4.5%, 54.4%, 30.9%, and 6.2%, with 2 patients (0.4%) not evaluable and 17 (3.6%) with missing data.

Clinical benefit rates were 82.6% and 82.1% in the giredestrant and letrozole arms, respectively. Median DOR was 38.5 months (95% CI, 30.4–48.7) with giredestrant (n = 280) versus 30.4 months (95% CI, 25.3–36.1) with letrozole (n = 276).

Safety Profile

"Adverse effects, serious adverse effects, grade 3 to 4 adverse effects, treatment-related adverse effects, and adverse effects resulting in treatment discontinuation were similar across both arms," Turner noted. "Giredestrant plus palbociclib was well tolerated, with a manageable safety profile and no unexpected findings."

Mean dose intensity in the investigational arm was 98.2% (SD, 4.1) for giredestrant and 81.3% (SD, 16.9) for palbociclib. In the control arm, mean dose intensity was 98.9% (SD, 6.2) for letrozole and 81.8% (SD, 16.9) for palbociclib.

Treatment-emergent adverse effects occurring in at least 15% of patients in both arms included, in descending order of frequency: neutropenia, anemia, decreased white blood cell count, arthralgia, nausea, fatigue, diarrhea, COVID-19, constipation, decreased platelet count, leukopenia, elevated aspartate aminotransferase, back pain, alopecia, elevated alanine aminotransferase, decreased appetite, headache, cough, and hot flush.

Median treatment duration in the investigational arm was 29.8 months (range, 0–63.4) for giredestrant and 28.3 months (range, 0–63.4) for palbociclib. In the control arm, median treatment duration was 25.2 months (range, 0.2–62.6) for letrozole and 24.2 months (range, 0.2–62.6) for palbociclib.

Selected adverse effects of interest—musculoskeletal pain, hepatotoxicity, and bradycardia—were reported in 38.9%, 25.7%, and 11.7% of patients in the giredestrant arm, compared with 38.0%, 28.5%, and 1.8% in the letrozole arm, respectively.

Looking Ahead

Giredestrant will be further assessed against fulvestrant (Faslodex) in combination with a physician's choice of CDK4/6 inhibitor in the first-line setting through the ongoing pionERA BC trial (NCT06065748), which is enrolling patients whose disease has relapsed on adjuvant endocrine therapy or who have a treatment-free interval of fewer than 12 months.

"Further investigation is needed to identify which patients are most likely to benefit from giredestrant in the first-line setting," Turner concluded.

DISCLOSURES: Turner reported consulting or advisory roles with AstraZeneca, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Health, Inivata, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics, and Roche; and institutional research funding from AstraZeneca, Guardant Health, Inivata, InVitae, Merck Sharp and Dohme, Natera, Personalis, Pfizer, and Roche.

REFERENCES

1. (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. J Clin Oncol. 2026;44(suppl 17):LBA1006. doi:10.1200/JCO.2026.44.17_suppl.LBA1006

2. Bardia A, Schmid P, Martín M, et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global phase III lidERA Breast Cancer trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS1-10.

3. Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): primary results of the phase III evERA BC trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA16.