Giredestrant’s potency, favorable safety profile, and synergy with everolimus (Afinitor) in the phase 3 evERA trial (NCT05306340) underscore its promise as a next-generation oral selective estrogen receptor degrader (SERD) for patients with endocrine-resistant hormone receptor–positive, HER2-negative breast cancer, according to Erica L. Mayer, MD, MPH.
“The evERA study met its 2 primary end points of prolonging progression-free survival [PFS] for both patients with ESR1-mutated disease, as well as the intent-to-treat [ITT] population,” Mayer said in an interview with OncLive® during the 2025 ESMO Congress.
In the interview, Mayer discussed the unique strengths of giredestrant compared with other available agents in hormone receptor–positive, HER2-negative breast cancer, detailed key efficacy and safety findings from the evERA trial, and explained how these data show the potential for oral SERD–containing combination regimens in the post-CDK4/6 inhibitor setting.
Mayer is director of Breast Cancer Clinical Research at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.
OncLive: What distinguishes giredestrant from earlier-generation SERDs? How might its mechanism of action translate into improved outcomes for patients with hormone receptor–positive, HER2-negative metastatic breast cancer?
Mayer: Giredestrant is an oral SERD, and it is a full estrogen receptor [ER] antagonist and degrader. In preclinical studies, it has demonstrated equal, if not more, potency compared with other oral SERDs, and like many SERDs, it has a favorable toxicity profile that allows it to combine well with targeted partners.
What was the rationale for conducting the evERA study?
Patients with metastatic hormone receptor–positive, HER2-negative breast cancer typically receive a CDK4/6 inhibitor–based therapy in the first-line setting. At the time of progression, however, cancers have developed resistance, and there’s an unmet need to identify the best treatment strategies post-CDK4/6 inhibitors. Two of the pathways that create that resistance include the ER pathway and the PI3K/AKT pathway. Thus, there is a rationale to give a combination therapy that targeting both the ER pathway and the PI3K/AKT pathway.
What was the design of the evERA trial?
evERA is a randomized trial that enrolled patients who had progressed after a prior CDK4/6 inhibitor. All the patients had metastatic hormone receptor–positive, HER2-negative disease. They’d received up to 2 prior lines of endocrine therapy with at least exposure to a CDK4/6 inhibitor and had no prior chemotherapy. Patients were randomly assigned to receive the combination of giredestrant with everolimus—the experimental arm, or in the control arm, provider’s choice of endocrine therapy, which could be fulvestrant [Faslodex], exemestane, or tamoxifen plus everolimus. There were coprimary end points for the study of PFS in the population of patients with ESR1-mutated disease and PFS in the ITT population.
What were the key efficacy findings from evERA?
For the coprimary end point of PFS in the population with ESR1-mutant disease, patients receiving giredestrant and everolimus had a statistically significant and clinically meaningful improvement, [with a median PFS of] 9.99 months [95% CI, 8.08-12.94] compared with 5.45 months [95% CI, 3.75-5.62] in the control arm.1 That’s a 62% improvement [HR, 0.38; 95% CI, 0.27-0.54; P <.0001]. Similarly, in the ITT population, there was a statistically significant and clinically meaningful prolongation in PFS as well.
Given the efficacy signal observed in the subgroup of patients with ESR1-mutated disease, how do you see ESR1 mutation status guiding therapy selection?
We currently have approvals for 2 oral SERDs as monotherapy. Those are elacestrant [Orserdu] and imlunestrant [Inluriyo], which are approved to be used in patients [with ER-positive, HER2-negative advanced or metastatic breast cancer] whose tumors have developed an ESR1 mutation [and who have received prior endocrine therapy].2,3 What’s interesting in evERA is that the benefit from the combination was seen not only in the population with ESR1-mutant disease, but also in the ITT population. There was an exploratory subgroup analysis of the non–mutation detected population where there was no difference in PFS, but there were intriguing signals with improvement in response rate and duration of response, as well as a favorable trajectory for overall survival [OS]. The totality of the data suggests and supports that the benefit of this combination is present for the ITT population.
What is the safety profile of giredestrant plus everolimus?
Overall, the toxicities were balanced between the 2 arms and reflected the known safety profiles of the individual study components. Notably, the rates of endocrine-related toxicity were balanced and low [across the arms], which supports the favorable toxicity profile of giredestrant. Most of the toxicities seen—including mucositis, diarrhea, and nausea—were attributed to everolimus. Overall, giredestrant is a well-tolerated drug and mixes well with targeted partners.
What are the next steps for evaluating giredestrant in patients with hormone receptor–positive, HER2-negative breast cancer?
[At ESMO 2025], we presented the primary results from evERA. There’s so much more we need to learn from the study. For example, the OS data that were presented were interim and immature. The curves were trending favorably, but we look forward to having more maturity for OS, which will be presented in the future, as well as [data about] post-progression therapies. Additionally, we want to learn more about the performance of the giredestrant plus everolimus combination in subgroups determined by predictive biomarkers or prior therapies. Look out for those data at a future cancer congress.
What are the potential future clinical implications of the evERA trial findings?
Treating patients post-CDK4/6 inhibitors is challenging. We know from multiple prior studies that the previous standard of care [SOC] of endocrine monotherapy doesn’t work. We see poor PFS if we just give an endocrine therapy by itself. We need combinations. evERA is one of the first studies to evaluate a SERD and targeted partner combination and is the first to compare it with a SOC combination. We feel excited about these data, and this is [a combination] I want to have available for my patients in the future.
References
- 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
- FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed November 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/
- U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 25, 2025. Accessed November 7, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-inluriyo-imlunestrant-adults-er-her2-esr1
