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Giredestrant plus palbociclib improved PFS numerically just shy of 5 months in the persevERA trial, but was deemed negative due to lack of statistical significance.
The addition of giredestrant to palbociclib (Ibrance) failed to demonstrate a statistically significant improvement in investigator-assessed progression-free survival (PFS) vs letrozole plus palbociclib in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer, according to data from the primary analysis of the phase 3 persevERA BC trial (NCT04546009) that were presented at the
The median investigator-assessed PFS was 33.1 months (95% CI, 30.2-38.2) in the giredestrant arm (n = 495) vs 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). The 12-, 24-, and 36-month PFS rates in the giredestrant arm were 77.8%, 59.7%, and 45.8%, respectively. The respective rates in the letrozole arm were 77.3%, 57.3%, and 41.9%. Results were also largely consistent across key subgroups.
“First-line giredestrant plus palbociclib resulted in a numerical improvement in investigator-assessed PFS vs letrozole plus palbociclib in ER-positive, HER2-negative locally advanced or metastatic breast cancer, though it did not meet predefined statistical significance,” 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, said in a presentation of the data.
CDK4/6 inhibitor–based therapy is the cornerstone of first-line treatment for women with ER-positive, HER2-negative locally advanced or metastatic breast cancer. Giredestrant is a potent next-generation oral selective ER degrader (SERD) and full ER antagonist designed to elicit deep and sustained inhibition of ER signaling.
In the prior phase 3 lidERA BC (NCT04961996) and evERA BC (NCT05306340) trials, giredestrant proved superior to standard endocrine therapy as monotherapy in the adjuvant setting and in combination with everolimus (Afinitor) in post CDK4/6 inhibition in the locally advanced or metastatic setting.2,3
Building on this foundation, investigators evaluated the combination of frontline giredestrant and palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.
persevERA is a randomized, double-blind, placebo-controlled, multicenter study that enrolled 992 patients. Patients were randomly assigned 1:1 to oral giredestrant at 30 mg plus oral palbociclib at 125 mg and placebo once daily on days 1 through 21 of each 28-day cycle; or oral letrozole at 2.5 mg plus the same dose of palbociclib and placebo on days 1 through 21 of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity, at which point patients were followed for survival.
Patients were eligible for the study if they had a locally confirmed histologic and cytologic diagnosis of untreated ER-positive, HER2-negative locally advanced or metastatic breast cancer. Patients could not have received prior therapy for advanced disease or with a SERD and must have had disease recurrence after 12 months of completing prior neo(adjuvant) tamoxifen/aromatase inhibition. However, Turner noted that disease recurrence within 12 months of receiving tamoxifen was allowed in version 1 of the protocol prior to amendment. Additionally, patients with de novo metastatic disease were capped at 20%, Turner said.
The primary end point was investigated-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.
Per the statistical plan of the study, a 2-sided stratified log-rank test was employed, with the HR estimated using a stratified Cox proportional hazards model. The primary analysis was planned to occur after approximately 620 investigator-assessed PFS events occurred. The study was designed to detect an HR of 0.77 with 89% power, and the statistical significance boundary for efficacy was defined as an HR of 0.85.
Following an interim analysis, the P-value boundary for the primary analysis was 0.0456.
The data cutoff was January 30, 2026, at which point the 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.
Turner remarked that baseline characteristics were balanced between arms.
No difference in OS was seen with giredestrant vs letrozole. The median OS was not evaluable (NE) in either the giredestrant (95% CI, NE-NE) or letrozole (95% CI, 61.3 months-NE) arms (HR, 1.03; 95% CI, 0.83-1.28; P = .7767). The 24- and 36-month OS rates in the giredestrant arm were 84.9% and 74.1%, respectively. These respective rates in the letrozole arm were 84.2% and 74.1%.
The ORR was 60.2% with giredestrant (n = 465) vs 58.8% with letrozole (n = 469). Within the giredestrant arm, the 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 NE and 16 (3.4%) had missing data. In the letrozole arm, the rates of CR, PR, SD, and PD were 4.5%, 54.4%, 30.9%, and 6.2%, respectively; 2 patients (0.4%) were NE and 17 (3.6%) had missing data.
The clinical benefit rates were 82.6% and 82.1% with giredestrant and letrozole, respectively.
The median DOR was 38.5 months (95% CI, 30.4-48.7) in the giredestrant arm (n = 280) vs 30.4 months (95% CI, 25.3-36.1) in the letrozole arm (n = 276).
“AEs [adverse effects], serious AEs, grade 3 to 4 AEs, related AEs, and AEs leading to treatment discontinuation were similar between treatment arms,” Turner said. “Giredestrant plus palbociclib was well tolerated, with a manageable safety profile and no unexpected findings.”
The mean dose intensity in the investigational arm was 98.2% (SD, 4.1) with giredestrant and 81.3% (SD, 16.9) with palbociclib. In the control arm, the mean dose intensity was 98.9% (SD, 6.2) with letrozole and 81.8% (SD, 16.9) with palbociclib.
The most common treatment-emergent AEs that occurred in at least 15% of patients in both arms, in order of frequency were neutropenia, anemia, decreased white blood cell count, arthralgia, nausea, fatigue, diarrhea, COVID-19, constipation, decreased platelet count, leukopenia, increased aspartate aminotransferase levels, back pain, alopecia, increased alanine aminotransferase levels, decreased appetite, headache, cough, and hot flush.
The median treatment duration was 29.8 months (range, 0-63.4) with giredestrant and 28.3 months (range, 0-63.4) with palbociclib in the investigational arm. In the control arm, the median treatment duration was 25.2 months (range, 0.2-62.6) with letrozole and 24.2 months (range, 0.2-62.6) with palbociclib.
Musculoskeletal pain (38.9%; 38.0%), hepatotoxicity (25.7%; 28.5%), and bradycardia (11.7%; 1.8%) were evaluated as selected AEs and were present in both the giredestrant and letrozole arms, respectively.
Giredestrant will be evaluated vs fulvestrant (Faslodex) in combination with physician’s choice of CDK4/6 inhibitor in the frontline setting in the ongoing pionERA BC trial (NCT06065748) in patients whose disease has relapsed on adjuvant endocrine therapy or those who have a treatment-free interval of less than 12 months.
“Further exploration is needed to assess which patients may benefit from giredestrant in the first-line setting,” Turner concluded.
Disclosures: Turner disclosed 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 research funding from AstraZeneca (Inst), Guardant Health (Inst), Inivata (Inst), InVitae (Inst), Merck Sharpe and Dohme (Inst), Natera (Inst), Personalis (Inst), Pfizer (Inst), and Roche (Inst).
