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.

LBA1006 Background: The combination of endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the current standard of care (SOC) for 1L treatment of pts with ER+, HER2– LA/mBC. GIRE, a next-generation oral selective full ER antagonist and degrader, has shown superior efficacy vs SOC ET in the adjuvant setting (lidERA BC; Bardia SABCS 2025) and in combination with everolimus vs SOC ET + everolimus in the post-CDK4/6i LA/mBC setting (evERA BC; Mayer ESMO 2025). Primary analysis results of persevERA BC (NCT04546009) are presented. Methods: Pts with de novo mBC or recurrent LA/mBC, measurable disease/evaluable bone disease, and no prior systemic LA/mBC therapy were randomized 1:1 to GIRE (30 mg daily QD) + LET placebo (QD) + PALBO (125 mg QD on Days 1–21) or LET (2.5 mg QD) + GIRE placebo (QD) + PALBO on each 28-day cycle (with a luteinizing hormone-releasing hormone agonist in pre-/peri-menopausal women, and men). The primary endpoint was investigator-assessed progression-free survival (INV-PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and safety. Results: 992 pts were randomized (495 to GIRE; 497 to LET). Median age was 63.0 years; 80.1% were post-menopausal; 19.1% had de novo mBC; 69.3% had recurrent disease with treatment-free interval (TFI) >12 months (mo); 60.4% had visceral disease. At data cutoff (01/30/26), median follow-up was 52.2 mo and 623 INV-PFS events were observed. The hazard ratio (HR) for INV-PFS was 0.89 (95% confidence interval CI = 0.76, 1.05; p = 0.1553); median INV-PFS was 33.1 mo with GIRE + PALBO vs 28.2 mo with LET + PALBO (Δ 4.9 mo) (Table). The most common grade 3–4 adverse events (AEs) in the GIRE arm were hematologic abnormalities associated with PALBO. ET discontinuations due to AEs were similar (6.5% with GIRE vs 5.5% with LET). Conclusion: 1L GIRE + PALBO resulted in a numerical improvement in INV-PFS vs LET + PALBO in ER+, HER2– LA/mBC, though it did not meet pre-defined statistical significance. The safety profile was tolerable, consistent with individual agents, with no unexpected findings. The ongoing 1L pionERA BC study (NCT06065748) is exploring GIRE vs fulvestrant, in combination with physician’s choice of CDK4/6i in pts who have relapsed on adjuvant ET or with <12 mo TFI. Clinical trial information: NCT04546009 . GIRE + PALBO(n = 495) LET + PALBO(n = 497) Median PFS, mo (95% CI) 33.1 (30.2, 38.3) 28.2 (25.0, 33.1) HR* (95% CI); p-value † 0.89 (0.76, 1.05); 0.1553 Median OS, mo (95% CI) NE (NE) NE (61.3, NE) HR* (95% CI); p-value † 1.03 (0.83, 1.28); 0.777 ORR, % 60.2 58.8 Median DoR, mo (95% CI) 38.5 (30.4, 48.7) 30.4 (25.3, 36.1) HR* (95% CI); p-value † 0.80 (0.63, 1.01); 0.056 CBR, % 82.6 82.1 *Stratified. † Stratified log-rank. NE, not evaluable.