AstraZeneca has announced that the Phase III SERENA-4 trial evaluating camizestrant in combination with palbociclib did not meet its primary endpoint of a statistically significant improvement in progression-free survival (PFS) in the upfront first-line treatment of patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer.
According to the company, a numerical improvement in PFS was observed with camizestrant plus palbociclib compared with anastrozole plus palbociclib, but the difference did not reach statistical significance. Detailed efficacy results, including the magnitude of the PFS difference, have not yet been disclosed and are expected to be presented at a later date.
The safety profile of camizestrant plus palbociclib was consistent with the established safety profiles of the individual therapies, with AstraZeneca reporting no new safety concerns.
About the SERENA-4 Trial
SERENA-4 (NCT04711252) is a global, randomized, multicenter, double-blind Phase III trial comparing camizestrant plus palbociclib with anastrozole plus palbociclib as initial systemic treatment for ER-positive, HER2-negative advanced breast cancer.
The study enrolled 1,371 adults with newly diagnosed Stage IV de novo or recurrent advanced disease who had not previously received systemic therapy for advanced breast cancer. For patients whose disease recurred after early-stage breast cancer, eligibility required at least 24 months of prior standard adjuvant endocrine therapy and an appropriate treatment-free interval following aromatase inhibitor therapy.
The primary endpoint was investigator-assessed PFS. Secondary endpoints include overall survival, second progression-free survival and health-related quality of life.
Susan Galbraith, Executive Vice President of Oncology Haematology R&D at AstraZeneca, commented on the result:
“Whilst we are disappointed by the SERENA-4 outcome, it sharpens our focus on maximising the number of patients who can benefit from Etcamah today.”
AstraZeneca said the result reinforces its focus on ESR1 testing during first-line treatment and its ongoing development of camizestrant in earlier stages of breast cancer.
SERENA-4 and SERENA-6 Tested Different Treatment Strategies
The negative primary endpoint in SERENA-4 is distinct from the positive findings of the SERENA-6 Phase III trial, which established the clinical benefit of camizestrant in a biomarker-selected first-line setting.
SERENA-4 investigated whether replacing an aromatase inhibitor with camizestrant from the beginning of first-line treatment, in combination with palbociclib, could improve outcomes in a broad ER-positive, HER2-negative advanced breast cancer population.
SERENA-6, by contrast, used circulating tumor DNA monitoring to identify patients who developed an ESR1 mutation while receiving first-line aromatase inhibitor plus CDK4/6 inhibitor therapy but before radiographic disease progression. Those patients were then randomized to switch endocrine therapy to camizestrant while continuing their CDK4/6 inhibitor or to remain on their aromatase inhibitor-based regimen.
In the initial SERENA-6 analysis, median PFS was 16.0 months with camizestrant versus 9.2 months with continued aromatase inhibitor therapy, corresponding to a hazard ratio for progression or death of 0.44.
With longer follow-up, median PFS was reported at 16.8 versus 9.2 months, respectively, while the benefit extended to second progression-free survival.
Camizestrant Recently Received FDA Accelerated Approval
The SERENA-4 announcement comes only one week after the US Food and Drug Administration granted accelerated approval to camizestrant (Etcamah) in combination with a CDK4/6 inhibitor, abemaciclib, palbociclib or ribociclib, for adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer following detection of an ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor treatment.
The approval, announced on September 4, 2026, was based on the SERENA-6 results. The FDA also approved Guardant360 CDx as a companion diagnostic for identifying eligible patients with ESR1 mutations.
FDA Grants Accelerated Approval to Camizestrant for ESR1-Mutated Advanced Breast Cancer
The different outcomes of SERENA-4 and SERENA-6 therefore highlight an important distinction in the development of camizestrant: while replacing an aromatase inhibitor with camizestrant universally at the start of first-line therapy did not produce a statistically significant PFS advantage in SERENA-4, biomarker-guided switching after the emergence of an ESR1 mutation has demonstrated significant clinical benefit.
What Is Camizestrant?
Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) and complete estrogen receptor antagonist designed to inhibit ER-driven tumor growth.
ESR1 mutations are an important mechanism of acquired resistance to endocrine therapy in HR-positive breast cancer. They can emerge during aromatase inhibitor treatment and may be detected in circulating tumor DNA before conventional clinical or radiological disease progression.
The SERENA development program is investigating camizestrant across several stages and treatment settings in ER-positive breast cancer.
Camizestrant Development Continues in Early Breast Cancer
Despite the SERENA-4 result, AstraZeneca is continuing the development of camizestrant in early-stage breast cancer.
The Phase III CAMBRIA-1 and CAMBRIA-2 trials are evaluating camizestrant across adjuvant treatment settings in patients at intermediate or high risk of recurrence. Together, the company’s early breast cancer camizestrant program involves approximately 10,000 patients and includes evaluation of the drug as monotherapy, in combination with CDK4/6 inhibitors and following CDK4/6 inhibitor therapy.
Full results from SERENA-4 will be important for understanding the extent of the numerical PFS difference, outcomes across clinically relevant patient subgroups and the implications of the findings for the broader development of oral SERDs in first-line advanced breast cancer.
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