The next-generation selective estrogen receptor degrader (SERD) camizestrant improved progression-free survival compared to fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer, according to results from the phase II SERENA-2 trial presented by Mafalda Oliveira, MD, PhD, at the 2022 San Antonio Breast Cancer Symposium (Abstract GS3-02).
Hormone receptor–positive, HER2-negative breast cancer is often treated with drugs that inhibit the activity of the estrogen receptor, which drives the growth of these tumors. Common forms of treatment include selective estrogen receptor modulators (SERMs), which inhibit the estrogen receptor in breast tissue; aromatase inhibitors, which prevent the production of estrogen; and SERDs, which antagonize and destabilize the estrogen receptor, leading to its inhibition and degradation.
However, most tumors eventually develop resistance to available endocrine therapies and commonly acquire a mutation in the estrogen receptor gene, ESR1. SERDs, such as fulvestrant, can block estrogen receptor activity in such cases.
Mafalda Oliveira, MD, PhD
“These ESR1-mutated tumors have constitutive activation of the [estrogen receptor] and worse prognosis, and they are in need of novel therapeutic options,” said Dr. Oliveira, an attending physician in the Medical Oncology Department at the Vall d’Hebron University Hospital and in the Breast Cancer Group at the Vall d’Hebron Institute of Oncology in Barcelona. “Next-generation oral SERDs have the potential to shut down the growth signaling derived from a constitutively activated [estrogen receptor], which is especially important in the setting of tumors with ESR1 mutations.”
As fulvestrant is currently the only SERD approved by the U.S. Food and Drug Administration for breast cancer—and it must be given via injection in a physician’s office—researchers are working to develop newer, more accessible, and more effective SERDs. Camizestrant, for example, is taken as a daily pill.
SERENA-2
Dr. Oliveira and colleagues conducted the phase II SERENA-2 trial to determine whether patients with estrogen receptor–positive breast cancer would benefit more from therapy with camizestrant or fulvestrant. Patients who were previously treated with no more than one prior endocrine therapy regimen and no more than one prior chemotherapy regimen were randomly assigned to receive fulvestrant or one of three dose levels of daily camizestrant: 75 mg, 150 mg, or 300 mg. The 300-mg arm was discontinued early due to strategic reasons, in the absence of toxicity concerns.
The 75-mg camizestrant arm, the 150-mg camizestrant arm, and the fulvestrant arms included 74, 73, and 73 patients, respectively. In the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% at 75 mg and 33% at 150 mg compared to fulvestrant. Patients treated with 75 mg of camizestrant and 150 mg of camizestrant had a median progression-free survival of 7.2 months and 7.7 months, respectively, compared with 3.7 months for patients treated with fulvestrant.
Among patients with an ESR1 mutation, camizestrant reduced the risk of disease progression or death by 67% at the 75 mg dose (median progression-free survival of 6.3 vs 2.2 months) and by 45% at 150 mg (median progression-free survival of 9.2 vs 2.2 months). A reduction in the risk of disease progression or death was also observed in patients without a detectable ESR1 mutation, with a 22% reduction in risk at the 75 mg dose and a 24% reduction in risk at the 150 mg dose.
Camizestrant also demonstrated improved efficacy compared to fulvestrant in other high-risk patient subgroups; those with lung and/or liver metastases experienced a reduction in the risk of disease progression or death of 57% with the 75-mg dose and 45% for the 150-mg dose compared to fulvestrant. Patients who had been previously treated with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors experienced a reduction in the risk of disease progression or death of 51% at the 75-mg dose and 32% at the 150-mg dose.
Adverse events of grade 3 or higher in the 75 mg/day, 150 mg/day, and fulvestrant arms occurred in 12.2%, 21.9%, and 13.7% of patients, respectively.
KEY POINTS
- In the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% at 75 mg and 33% at 150 mg compared to fulvestrant.
- Patients treated with 75 mg of camizestrant and 150 mg of camizestrant had a median progression-free survival of 7.2 months and 7.7 months, respectively, compared with 3.7 months for patients treated with fulvestrant.
- Among patients with an ESR1 mutation, camizestrant reduced the risk of disease progression or death by 67% at the 75 mg dose (median progression-free survival of 6.3 vs 2.2 months) and by 45% at 150 mg (median progression-free survival of 9.2 vs 2.2 months). A reduction in the risk of disease progression or death was also observed in patients without a detectable ESR1 mutation, with a 22% reduction in risk at the 75 mg dose and a 24% reduction in risk at the 150 mg dose.
Next Steps
Dr. Oliveira and colleagues are following up on these data with two phase III clinical trials, both both examining camizestrant in combination with a CDK4/6 inhibitor: one evaluating the efficacy of camizestrant vs an aromatase inhibitor in first-line therapy, and the other examining the benefit of treatment acceleration to camizestrant when ESR1 mutations are detected in circulating tumor DNA.
“The results of this study support further development of camizestrant in [hormone receptor]-positive breast cancer,” Dr. Oliveira said. “These results are noteworthy and may relaunch the enthusiasm for the development of oral SERDs in breast cancer.”
Limitations of this study include a relatively small sample size characteristic of phase II studies.
Disclosure: This study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead.
