Clinical Summary: 

• Design/Population: In the phase 3 persevERA BC trial, patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had not received prior systemic therapy for advanced disease were randomly assigned to receive giredestrant plus palbociclib or letrozole plus palbociclib. 
• Key Outcomes: Giredestrant plus palbociclib numerically improved progression-free survival compared with letrozole plus palbociclib but did not achieve statistical significance.
• Clinical Relevance: These findings do not support replacing standard first-line endocrine therapy with giredestrant in combination with palbociclib, although additional studies of giredestrant-based strategies remain ongoing.

Results from the phase 3 persevERA BC trial demonstrated that giredestrant plus palbociclib did not significantly improve progression-free survival (PFS) compared with letrozole plus palbociclib among patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.

These results were presented by Nicholas Turner, MD, PhD, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom, at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In this study, researchers enrolled 992 patients with de novo metastatic breast cancer or recurrent locally advanced or metastatic breast cancer who had not received prior systemic therapy for advanced disease. Patients were randomized 1:1 to receive either 30 mg of once daily giredestrant plus letrozole placebo and 125 mg of once daily palbociclib on days 1 through 21 or 2.5 mg of once daily letrozole plus 125 mg of once daily palbociclib on days 1 through 21 in 28-day cycles. Pre- and perimenopausal patients received a luteinizing hormone-releasing hormone agonist. 

The primary end point was investigator-assessed PFS. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of response, clinical benefit rate, and safety. 

At a median follow-up of 52.2 months, 623 PFS events were reported. Median PFS was 33.1 months in the giredestrant plus palbociclib arm and 28.2 months in the letrozole plus palbociclib arm (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.76 to 1.05; P = .1553). Median OS was not reached in either treatment arm (HR, 1.03; 95% CI, 0.83 to 1.28; P = .777). The ORR was 60.2% in the giredestrant plus palbociclib arm and 30.4% in the letrozole plus palbociclib arm. Median duration of response was 38.5 months and 30.4 months, respectively (HR, 0.80; 95% CI, 0.63 to 1.01; P = .056). The clinical benefit rate was 82.6% in the giredestrant plus palbociclib arm and 82.1% in the letrozole plus palbociclib arm. 

The most common grade 3/4 adverse events were hematologic in nature. Treatment discontinuations were reported in 6.5% of patients in the giredestrant plus palbociclib arm and 5.5% in the letrozole plus palbociclib arm. 

First-line giredestrant plus palbociclib “resulted in a numerical improvement in [investigator-assessed] PFS vs [letrozole plus palbociclib]... though it did not meet pre-defined statistical significance,” concluded Dr Turner. “The ongoing [first-line] pionERA BC study is exploring [giredestrant] vs fulvestrant, in combination with physician’s choice of CDK4/6i in pts who have relapsed on adjuvant [endocrine therapy] or with <12 mo [treatment-free interval].”

Source: 

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 the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA1006.