Phase 3 Trial of Giredestrant Misses Primary PFS End Point

The phase 3 persevERA Breast Cancer trial (NCT04546009) evaluating giredestrant (GDC-9545) plus palbociclib (Ibrance) as first-line therapy for estrogen receptor (ER)-positive, human HER2-negative locally advanced or metastatic breast cancer did not meet its primary end point of a statistically significant improvement in investigator-assessed progression-free survival (PFS) compared with letrozole (Femara) plus palbociclib.¹ A numerical PFS improvement was observed, and the safety profile was consistent with that of each individual agent. Full data will be presented at an upcoming medical meeting.

The randomized, double-blind, placebo-controlled, multicenter study enrolled 992 patients globally. The intent-to-treat population served as the basis for the primary PFS analysis. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety.

Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, noted that despite the persevERA outcome, the company remains confident in giredestrant’s potential based on efficacy signals observed across other trials in the program. “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,” Garraway said in a news release.

Context Within the Giredestrant Development Program

Giredestrant is an investigational oral, next-generation selective estrogen receptor degrader (SERD) and full antagonist designed to block estrogen binding to the estrogen receptor, triggering receptor degradation and inhibiting tumor cell proliferation. It is currently under investigation in 5 company-sponsored phase 3 trials spanning adjuvant, first-line, and later-line treatment settings across both ER-positive/HER2-negative and ER-positive/HER2-positive metastatic breast cancer.

The persevERA result follows 2 positive phase 3 readouts for giredestrant. The evERA Breast Cancer trial (NCT05306340) demonstrated a statistically significant improvement in PFS when giredestrant was combined with everolimus vs standard-of-care endocrine therapy (SOC ET) plus everolimus in patients with ER-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. Results were presented at the European Society for Medical Oncology (ESMO) Annual Meeting in October 2025.²

The lidERA Breast Cancer trial (NCT04961996) subsequently demonstrated superiority of adjuvant giredestrant over SOC ET in patients with ER-positive, HER2-negative early-stage breast cancer. Those results were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2025.³ Roche has indicated it will submit the lidERA phase 3 data to the US FDA in the coming weeks.¹ Separately, the FDA recently accepted a new drug application for giredestrant based on the evERA data.⁴

Scientific rationale for the adjuvant program was previously supported by the phase 2 coopERA trial (NCT04436744), which showed that neoadjuvant giredestrant was superior to an aromatase inhibitor in reducing Ki-67 levels, a marker of malignant cell proliferation, in patients with ER-positive, HER2-negative early breast cancer.

Remaining First-Line Data Expected in 2027

The persevERA trial is the first of 2 distinct phase 3 studies evaluating giredestrant in the first-line metastatic setting. The ongoing pionERA Breast Cancer trial (NCT06065748) is examining giredestrant in combination with physician’s choice of CDK4/6 inhibitor vs fulvestrant (Faslodex) plus physician’s choice of CDK4/6 inhibitor in patients with ER-positive, HER2-negative advanced breast cancer who are resistant to adjuvant endocrine therapy. That trial is expected to yield results in 2027.

The persevERA and pionERA studies target biologically distinct patient populations: persevERA enrolled endocrine-sensitive patients receiving palbociclib as the CDK4/6 inhibitor backbone, whereas pionERA focuses on endocrine-resistant patients and allows for multiple CDK4/6 inhibitor options. This distinction may be relevant to interpreting the persevERA outcome, given that endocrine sensitivity can influence the degree of differential benefit from next-generation SERDs versus aromatase inhibitors in the frontline setting.

Disease Burden and Unmet Need

ER-positive breast cancer accounts for approximately 70% of all breast cancer diagnoses. Globally, an estimated 2.3 million women are diagnosed with breast cancer annually, and approximately 670,000 die from the disease each year, according to the World Health Organization. In the US and EU combined, an estimated 273,000 patients are diagnosed in the early-stage setting each year, with approximately 88,000 in the first-line metastatic setting and 106,000 in the second- and third-line combined.

Despite therapeutic advances, ER-positive breast cancer presents ongoing clinical challenges. Up to one-third of patients with early-stage disease experience disease recurrence during or after adjuvant endocrine therapy, and adherence is limited by tolerability issues that lead many patients to interrupt or discontinue treatment prematurely, an outcome associated with increased mortality risk. In the advanced setting, resistance to endocrine therapy—particularly following CDK4/6 inhibitor exposure—is common and portends worse outcomes.

The persevERA findings underscore the complexity of the first-line endocrine-sensitive metastatic setting and the difficulty of demonstrating added benefit over an established CDK4/6 inhibitor-based backbone.

REFERENCES

1. Roche provides update on phase III persevERA study in ER-positive advanced breast cancer. News release. Roche. March 8, 2026. Accessed March 9, 2026. https://tinyurl.com/5d46urx4

2. 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.

3. 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

4. FDA accepts new drug application for Genentech’s giredestrant in ESR1-mutated, ER-positive advanced breast cancer. News release. Genentech. February 19, 2026. Accessed March 9, 2026. https://tinyurl.com/ytf5t36m