Clinical Summary:

• Design/Population: The phase 3 persevERA trial randomized patients with previously untreated HR-positive, HER2-negative locally advanced or metastatic breast cancer to giredestrant plus palbociclib or letrozole plus palbociclib.
• Key Outcomes: Median progression-free survival was 33 months with giredestrant plus palbociclib versus 28 months with letrozole plus palbociclib, failing to meet the prespecified threshold for statistical significance. Overall response rates were similar, while duration of response was numerically longer with giredestrant.
• Clinical Relevance: Although the trial did not meet its primary end point, the results provide important insights into the activity and tolerability of next-generation oral SERDs in the frontline metastatic setting.

Mabel Mardones, MD, Rocky Mountain Cancer Centers, Denver, Colorado, and Sarah Cannon Research Institute, Nashville, Tennessee, discusses results from the phase 3 persevERA trial evaluating giredestrant, a next-generation oral selective estrogen receptor degrader, in combination with palbociclib for patients with HR-positive, HER2-negative metastatic breast cancer. The study sought to determine whether giredestrant could improve outcomes compared with standard endocrine therapy in the frontline setting.

While the combination demonstrated a numerical progression-free survival advantage and longer duration of response, the study did not achieve its primary efficacy end point. Safety profiles were generally comparable between treatment arms, with low discontinuation rates and no unexpected toxicities, supporting continued investigation of giredestrant in ongoing studies of endocrine-sensitive and endocrine-resistant disease.

Dr Mardones presented these results at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript: 

My name is Dr Mabel Mardones, I’m a breast medical oncologist with Rocky Mountain Cancer Centers in Denver, Colorado, and an Executive Committee member for breast cancer research with Sarah Cannon Research Institute.

Today we’re going to be talking about the persevERA study, which is evaluating giredestrant, a potent next-generation SERD and full estrogen receptor antagonist. 

There have been 2 other trials that have shown efficacy with giredestrant: one in the adjuvant setting, called lidERA, and another in the metastatic setting evaluating giredestrant in combination with everolimus. This is the primary analysis of persevERA, evaluating the efficacy and safety of frontline giredestrant plus palbociclib in ER-positive, HER2-negative metastatic breast cancer.

This was a phase 3 randomized, double-blind, placebo-controlled, multicenter trial in the frontline setting for patients with locally advanced or metastatic breast cancer. Eligible patients had ER-positive disease and had received no prior treatment in the metastatic setting and no prior SERD therapy. The study included patients with disease recurrence more than 1 year after prior adjuvant therapy, as well as patients with disease recurrence within 1 year of completing adjuvant tamoxifen. Patients with de novo metastatic breast cancer were included, although enrollment in that subgroup was capped at 20%.

A total of 992 patients were randomized to receive either giredestrant plus palbociclib or letrozole plus palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, duration of response, safety, and patient-reported outcomes. The predefined hazard ratio boundary for efficacy was 0.85.

Baseline demographics included a median age of approximately 63 years. About 59% of patients were White and 28% were Asian. Eighty percent of patients were postmenopausal, 68% had treatment-free intervals greater than one year, and 60% had visceral metastases.

Looking at the results, investigator-assessed progression-free survival was 33 months in the giredestrant plus palbociclib arm versus 28 months in the letrozole plus palbociclib arm.This corresponded to a hazard ratio of 0.89, representing a numerical improvement, but it did not meet statistical significance. The absolute difference was approximately five months. No meaningful differences were observed across the predefined subgroups.

Overall survival remains immature, and no differences have been observed at this time. Overall response rates were similar between the two groups, at approximately 60%. Duration of response was numerically longer with giredestrant plus palbociclib, at 38 months versus 30 months in the comparator arm. Median time on therapy was approximately 29 months.

The adverse event profile was similar between the two treatment arms. Discontinuation rates were low, around 5% to 6%.

Importantly, key adverse events such as musculoskeletal pain occurred at similar rates in both groups. Hepatobiliary toxicity occurred in approximately 25% of patients in both arms. One notable finding was bradycardia, which occurred in 11% of patients receiving giredestrant compared with 1.8% in the comparator arm. Almost all of these events were grade 1.

There are additional ongoing studies, including PIONEER, which is evaluating giredestrant versus fulvestrant in an endocrine-resistant population, and SERENA-4, which is studying a similar patient population. We anticipate additional data from these trials in the near future.

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.