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The phase III evERA trial found that the all-oral combination of giredestrant and everolimus extended median progression-free survival to 10.0 months versus 5.5 months with standard endocrine therapy in patients with ESR1-mutated advanced ER-positive breast cancer that progressed on CDK4/6 inhibitors. Safety profiles were similar between groups; overall survival data remain immature.
An all-oral combination of the selective estrogen receptor degrader (SERD) giredestrant and the mTOR inhibitor everolimus nearly doubled median progression-free survival (PFS) compared with standard endocrine therapy in patients with advanced ER-positive breast cancer whose disease progressed after CDK4/6 inhibitor treatment, according to phase III evERA trial results published in the New England Journal of Medicine. Among patients with ESR1-mutated tumors, median PFS rose from 5.5 months on standard endocrine therapy to 10.0 months with the experimental combination.
The international phase III trial enrolled 373 patients from 13 countries with ER-positive/HER2-negative unresectable or metastatic breast cancer. ESR1-mutated tumors accounted for 55% of the overall population. Patients were randomized to giredestrant plus everolimus (Afinitor) or investigator’s choice of endocrine therapy plus everolimus; pre- or perimenopausal women and men also received a luteinizing hormone-releasing hormone agonist.
In the primary analysis of the ESR1-mutant group, the combination produced a hazard ratio of 0.38 for progression or death (95% CI 0.27-0.54, P<0.001). In the overall population, median PFS increased to 8.8 months with giredestrant-everolimus, a 44% reduction in the PFS hazard (95% CI 0.44-0.71, P<0.001). The benefit persisted across most prespecified subgroups, including patients with detectable PIK3CA, AKT1, or PTEN alterations and regardless of duration of prior CDK4/6 inhibitor therapy.
Adverse-event rates were similar between the two arms. Any-grade AEs occurred in 97-99% of all patients. The most common AEs in the experimental versus control arms were stomatitis (47.3% vs 48.9%), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%). The rate of fatal AEs was 2.7% in both arms.
A New Option After CDK4/6 Failure
For patients with advanced ER-positive/HER2-negative breast cancer, a CDK4/6 inhibitor plus endocrine therapy is the worldwide first-line standard, but few options exist after progression. The trial addressed this unmet need with a regimen that targets two distinct resistance mechanisms: ESR1 mutations and aberrations in PI3K/AKT/mTOR signaling.
“The giredestrant-everolimus combination has the advantage of targeting two distinct signaling pathways, providing improved efficacy,” wrote Erica J. Mayer, MD, MPH, of Dana-Farber Cancer Institute and colleagues. “Moreover, this all-oral regimen could reduce the treatment burden by eliminating injections and reducing hospital visits.”
Aditya Bardia, MD, MPH, of UCLA Health said the findings “provide another novel therapeutic option for patients with ESR1-mutant breast cancer and may support endocrine therapy-based sequencing strategies that could delay the need for chemotherapy until later lines of treatment.”
Why Endocrine Resistance Prompted the Trial
Resistance to CDK4/6 inhibition plus endocrine therapy commonly involves aberrations in PI3K/AKT/mTOR signaling and ESR1 mutations, the study authors noted. This biology provided the rationale for pairing giredestrant, an oral SERD that degrades the estrogen receptor, with everolimus, an mTOR inhibitor. The trial’s primary endpoint was investigator-assessed PFS, evaluated first in the ESR1-mutant subgroup and then in the overall population. Bardia noted that, together with other positive trials of oral SERDs such as lidERA in the adjuvant setting, the results point to oral SERDs “becoming an important endocrine therapy backbone in ER-positive breast cancer.”
“Patients in the clinical trial achieved a median progression-free survival of 10 months, which is clinically meaningful in this treatment setting.”
— Aditya Bardia, MD, MPH, UCLA Health
Survival Data Still Immature
Overall survival (OS) data remain immature, according to the report. Estimated 18-month OS among patients with ESR1-mutated tumors was 71.5% with giredestrant-everolimus versus 50.9% in the control group; in the overall population, estimates were 75.1% and 62.0%, respectively. These are estimates, not final OS results, and OS was a key secondary endpoint evaluated only if PFS results were statistically significant. Whether the PFS advantage will translate into a confirmed survival benefit is not yet known. In addition, with any-grade AEs occurring in 97-99% of patients in both arms, tolerability in real-world practice outside a clinical trial remains to be seen.
Regulatory Decisions and Longer Follow-Up
Longer follow-up of the evERA trial is expected to mature the overall survival data. The results, published in a peer-reviewed journal, position the giredestrant-everolimus combination as a candidate for regulatory review in the post-CDK4/6 setting, though any approval decisions and timing have not been announced in the source material. Researchers and clinicians will also be watching how this regimen fits into evolving endocrine-based sequencing strategies alongside other oral SERDs, and whether combinations can continue delaying chemotherapy for patients with ER-positive advanced breast cancer. Patients should discuss treatment options with their oncologist.
Key Questions
What did the evERA trial find?
In patients with advanced ER-positive breast cancer that progressed on CDK4/6 inhibitors, giredestrant plus everolimus increased median PFS from 5.5 to 10.0 months in ESR1-mutated disease and to 8.8 months in the overall population, both statistically significant.
What is giredestrant?
Giredestrant is an oral selective estrogen receptor degrader (SERD), a drug designed to degrade the estrogen receptor that drives ER-positive breast cancer growth.
Was the combination safe?
Adverse-event rates were similar between the experimental and control groups. The most common side effects were stomatitis, diarrhea, and anemia; fatal adverse events occurred in 2.7% of patients in both arms.
Did the treatment improve overall survival?
Overall survival data remain immature. Estimated 18-month survival favored the combination, but final OS results are not yet available.
Who could benefit from this treatment?
The trial enrolled patients with ER-positive/HER2-negative unresectable or metastatic breast cancer whose disease progressed after CDK4/6 inhibitor therapy, with the strongest benefit seen in the ESR1-mutant subgroup. Availability depends on regulatory decisions.
Source: rss
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