Giredestrant Plus Palbociclib Misses PFS End Point in ER+/HER2– Advanced Breast Cancer

Treatment with the combination of giredestrant and palbociclib generated a numerical but not statistically significant improvement in progression-free survival (PFS) compared with letrozole plus palbociclib (Ibrance) in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer, missing the primary end point of the phase 3 persevERA trial (NCT04546009).¹

In the experimental arm, adverse effects were manageable and consistent with the known safety profiles of the individual agents. Full data will be shared at an upcoming medical meeting.

Although persevERA missed its PFS end point, giredestrant in combination with everolimus (Afinitor) generated a PFS improvement vs standard-of-care (SOC) endocrine therapy plus everolimus (HR, 0.38; 95% CI, 0.27-0.54; P < .0001) in patients with ESR1-mutated, ER-positive/HER2-negative locally advanced or metastatic in the phase 3 evERA trial (NCT05306340).² Based on the evERA data, the FDA accepted a new drug application seeking the approval of giredestrant plus everolimus for the treatment of patients with ESR1-mutated, ER-positive/HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on a prior endocrine therapy.³

“[Although] persevERA didn’t meet its primary objective, we are confident in the potential of giredestrant to become a new SOC endocrine therapy in early and advanced ER-positive breast cancer," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, stated in a news release.¹ “We believe there is a path forward for combining giredestrant with a CDK4/6 inhibitor in the adjuvant setting, and we are conducting further studies. The efficacy demonstrated in evERA and [the phase 3] lidERA [trial (NCT04961996)] provides clear validation of the clinical activity of giredestrant and reinforces the strength of our expanding clinical development program.”

How was persevERA designed?

The persevERA trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter study that enrolled patients at least 18 years of age with ER-positive, HER2-negative locally advanced or metastatic breast cancer not amenable to curative-intent therapy.⁴ No prior systemic therapy in the locally advanced or metastatic settings was permitted. Patients who experienced disease recurrence after early-stage breast cancer were allowed to enroll if they received at least 24 months of treatment without disease progression during treatment and had a disease-free interval of at least 12 months following the completion of therapy. Other key inclusion criteria comprised measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients were randomly assigned 1:1 to receive oral giredestrant once per day, a letrozole-matched placebo once per day, and palbociclib at 125 mg on days 1 to 21 of each 28-day cycle; or a giredestrant-matched placebo once per day, oral letrozole once per day, and palbociclib at 125 mg on days 1 to 21 of each 28-day cycle. In both arms, premenopausal/perimenopausal patients and male participants also received a luteinizing hormone-releasing hormone agonist on day 1 of each cycle.

Along with the primary end point of PFS per RECIST 1.1 criteria, secondary end points included overall survival, objective response rate, duration of response, clinical benefit rate, quality of life, and safety.

References

1. Genentech provides update on phase III persevErA study in ER-positive advanced breast cancer. News release. Genentech. March 8, 2026. Accessed March 9, 2026. https://www.gene.com/media/press-releases/15106/2026-03-08/genentech-provides-update-on-phase-iii-p
2. Rugo HS, Tolaney SM, Jhaveri KL, et al. Clinical and biomarker subgroup analysis of evERA Breast Cancer: a phase III trial of giredestrant plus everolimus in patients with estrogen receptor-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS3-09.
3. FDA accepts new drug application for Roche’s giredestrant in ESR1-mutated, ER-positive advanced breast cancer. News release. Roche. February 19, 2026. Accessed March 9, 2026. https://www.roche.com/media/releases/med-cor-2026-02-20
4. A study evaluating the efficacy and safety of giredestrant combined with palbociclib compared with letrozole combined with palbociclib in participants with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer (persevERA Breast Cancer). ClinicalTrials.gov. Updated February 20, 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04546009