SERD Combination Slows Breast Cancer After CDK4/6 Inhibitor Progression

An all-oral treatment regimen for advanced estrogen receptor (ER)-positive breast cancer almost doubled progression-free survival (PFS) versus standard endocrine therapy in a study of post-CDK4/6 progression disease.

Among patients with ESR1-mutated cancers, median PFS increased from 5.5 months with standard endocrine therapy to 10.0 months with the selective estrogen receptor degrader (SERD) giredestrant and everolimus (Afinitor). In the overall population, giredestrant and everolimus increased median PFS to 8.8 months, also statistically significant. Adverse-event (AE) rates were similar in the two treatment groups, as were the most frequently reported AEs,

“The giredestrant-everolimus combination has the advantage of targeting two distinct signaling pathways, providing improved efficacy,” reported Erica J. Mayer, MD, MPH, of Dana-Farber Cancer Institute in Boston, and colleagues in the New England Journal of Medicine. “Moreover, this all-oral regimen could reduce the treatment burden by eliminating injections and reducing hospital visits.”

Results of the evERA trial occurred within the context of an ongoing unmet need for more effective endocrine-based regimens for patients whose disease has progressed after treatment with a CDK4/6 inhibitor, said Aditya Bardia, MD, MPH, of UCLA Health in Los Angeles.

“This is an important study, as it builds on the previous success of oral SERDs in combination therapy,” Bardia told MedPage Today. “Patients in the clinical trial achieved a median progression-free survival of 10 months, which is clinically meaningful in this treatment setting. These 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.”

“Along with other positive clinical trials, including lidERA in the adjuvant setting, these results highlight the growing potential of oral SERDs to become an important endocrine therapy backbone in ER-positive breast cancer,” he said.

For patients with advanced ER-positive/HER2-negative breast cancer, a CDK4/6 inhibitor plus endocrine therapy has become the worldwide first-line standard, Mayer and colleagues noted in their introduction. However, few options exist after disease progression.

Mechanisms of resistance to CDK4/6 inhibition plus endocrine therapy include aberrations in PI3K/AKT/mTOR signaling and ESR1 mutations, the authors continued. The recognition provided a biologic/molecular rationale for combination treatment with giredestrant and the mTOR inhibitor everolimus.

Women of any menopausal status and men with ER-positive/HER2-negative unresectable or metastatic breast cancer were eligible for the international phase III evERA trial. Investigators randomized patients to the giredestrant-everolimus combination or investigator’s choice of endocrine therapy plus everolimus. Pre- or perimenopausal women, as well as men, also received a luteinizing hormone-releasing hormone agonist.

The primary endpoint was investigator-assessed PFS, evaluated first in patients with ESR1-mutated disease and then in the overall trial population. OS was a key secondary endpoint, also evaluated first in the ESR1-mutant subgroup, if the PFS analysis yielded statistically significant results in the subgroup and overall population.

The study involved 373 patients from 13 countries. ESR1-mutated tumors accounted for 55% of the overall population.

The primary analysis in the ESR1-mutant group yielded a hazard ratio of 0.38 in favor of giredestrant-everolimus (95% CI 0.27-0.54, P<0.001). The analysis of the overall population showed a 44% reduction in the PFS hazard (95% CI 0.44-0.71, P<0.001). The advantage for giredestrant-everolimus persisted across most prespecified subgroups, including patients with detectable PIK3CA, AKT1, or PTEN alteration and regardless of duration of prior CDK4/6 inhibitor therapy.

Data for OS remain immature, but an estimation of 18-month OS among patients with ESR1-mutated tumors showed 71.5% for giredestrant-everolimus and 50.9% in the control group. In the overall population, the 18-month OS estimates were 75.1% and 62.0%, respectively.

Any-grade adverse events (AEs) occurred in 97-99% of all patients. The most common AEs in the experimental and control arms were stomatitis (47.3% vs 48.9%, respectively), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%). The rate of fatal AE was 2.7% in both arms.