Two separate doses of single-agent camizestrant monotherapy improved progression-free survival vs standard-of-care fulvestrant in patients with estrogen receptor-positive, HER2-negative advanced breast cancer.
Two separate doses of single-agent camizestrant (AZD9833) monotherapy improved progression-free survival (PFS) vs standard-of-care fulvestrant (Faslodex) in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to data from the phase 2 SERENA trial (NCT04214288) presented at the 2022 San Antonio Breast Cancer Symposium.
The study included several treatment arms that comprised several dose levels of camizestrant—300 mg (n = 20), 75 mg (n = 74), and 150 mg (n = 73)—as well as a fulvestrant cohort (n = 173).
Of note, the study authors have not formally analyzed the data from the 300 mg subset as patient enrollment to that treatment arm was ended early.
With a median follow-up of 16.6 months, 16.6 months, and 17.4 months in the 75 mg, 150 mg, and fulvestrant groups, respectively, the median PFS was 7.2 months (95% CI, 3.7-10.9; hazard ratio [HR], 0.58; 95% CI, 0.41-0.81; P = .0124), 7.7 months (95% CI, 5.5-12.9; HR, 0.67; 95% CI, 0.48-0.92; P = .0161), and 3.7 months (95% CI, 2.0-6.0).
The benefit was determined to be both statistically significant and clinically meaningful at both dose levels and further confirmed via blinded independent central review sensitivity analysis.
“The results of SERENA-2 support the further development of camizestrant in ER-positive breast cancer. Currently 2, phase 3 studies of camizestrant in advanced breast cancers, SERENA-4 and SERENA-6 are ongoing,” lead author Mafalda Oliveira, MD, PhD, an attending physician in the Department of Medical Oncology, Breast Cancer Group, at Vall d'Hebron University Hospital Barcelona, Spain, said during a presentation on the findings.
PFS was also assessed in several patient subgroups. Among patients who received a previous CDK4/6 inhibitor, the median PFS was 5.5 months (95% CI, 3.7-10.9; HR, 0.49; 95% CI, 0.31-0.75) and 3.8 months (HR, 0.68; 95% CI, 0.44-1.04) in the 75 mg and 150 mg camizestrant dose cohorts, respectively, vs 2.1 months (95% CI, 1.9-3.7) in the fulvestrant arm.
In those with lung and/or liver metastases, the median PFS was 7.2 months (95% CI, 3.6-11.1; HR, 0.43; 95% CI, 0.28-0.66) in the 75 mg dose group, 5.6 months (95% CI, 3.7-9.1; HR, 0.55; 95% CI, 0.37-0.82) in the 150 mg dose group, and 2.0 months (95% CI, 1.9-3.6) in the fulvestrant group.
Moreover, the median PFS was 6.3 months (95% CI, 3.4-12.9; HR, 0.33; 95% CI, 0.18-0.68), 9.2 months (95% CI, 3.7-12.9; HR, 0.55; 95% CI, 0.33-0.89), and 2.2 months (95% CI, 1.9-3.6) in each respective cohort in a population of patients with ESR1-mutant disease.
In those with evidence of ER-driven disease, the median PFS was 7.4 (95% CI, 4.5-11.1; HR, 0.55; 95% CI, 0.35-0.79), 12.0 (95% CI, 5.6-14.6; HR, 0.55; 95% CI, 0.39-0.86), and 3.2 months, respectively.
The patient population had recurrent or progressive disease following at least 1 line of endocrine therapy. They were not able to have previously received treatment with an oral fulvestrant or a selective estrogen receptor degrader, more than 1 line of endocrine therapy, or chemotherapy for advanced disease.
Patients also needed to have measurable and non-measurable disease. A total of 240 patients (median age, 60 years; ER-positive disease, 100%) were included in the study and were randomly assigned 1:1:1:1 to each respective arm. Stratification factors included prior treatment with a CDK4/6 inhibitor and presence of lung/liver metastases.
More than half of each treatment arm had an ECOG score of 0.
The SERENA-2 trial had a primary end point of PFS, with key secondary end points including clinical benefit rate (CBR) at 24 weeks, overall response rate (ORR), overall survival, and safety. Translational end points included serial circulating tumor DNA analysis.
In terms of other findings, camizestrant was found to reduce ESR1-mutant ctDNA levels to undetectable or close to undetectable at both treatment levels. This was reached by cycle 2, day 1 and was maintained through to cycle 7, day 1. Although fulvestrant also reduced ESR1-mutant ctDNA levels, it was not to the extent that either camizestrant dose did.
Additionally, the ORR was 15.7% in the 75 mg cohort (odds ratio [OR], 1.43; 95% CI, 0.63-3.33; 2-sided P-value = .4789), 20.0% in the 150 mg cohort (OR, 1.96; 95% CI, 0.88-4.51; 2-sided P-value = .1675), and 11.8% in the fulvestrant cohort.
Investigators also reported that the CBR rate at 24-weeks was 47.3% (OR, 1.48; 95% CI, 0.84-2.64), 49.3% (OR, 1.48; 95% CI, 0.84-2.64; 2-sided P-value = .1658), and 39.1% in each group, respectively.
With regard to safety, any treatment-emergent adverse effects (TEAEs) occurred in 77.0% of those in the 75 mg group, 90.4% of those in the 150 mg group, 95.0% in the 300 mg group, and 68.5% in the fulvestrant group, while treatment-related AEs (TRAEs) occurred in 52.7%, 67.1%, 70.0%, and 17.8%, respectively.
Grade 3 or higher TRAEs that led to discontinuation were infrequent in all treatment cohorts. Moreover, dose interruptions due to TRAEs were numerically comparable at both the 75 mg and 150 mg camizestrant groups, generally lasting for a short duration. Investigators reported that all dose levels of camizestrant were well tolerated.
Common grade 3 or higher TEAEs included blood pressure increase (1.4%) in the 75 mg group; fatigue, anemia, arthralgia, alanine transaminase increase, extremity pain, hyponatremia, and blood pressure increase (1.4% each) in the 150 mg group; diarrhea (5.0%) and blood pressure increase (5.0%) in the 300 mg group; and anemia (2.7%) in the fulvestrant group.
Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial. 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas; abstract GS3-02. Accessed December 8, 2022.