First-Line Camizestrant Plus CDK4/6 Inhibition Boosts PFS in ERS1+, HR+/HER2-Negative Advanced Breast Cancer

The investigational selective estrogen receptor degrader (SERD) camizestrant plus either palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio), displayed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs a standard-of-care aromatase inhibitor plus a CDK4/6 inhibitor for the frontline treatment of patients with hormone receptor (HR)–positive/HER2-negative advanced breast cancer harboring an emergent ESR1 mutation, according to topline data from a planned interim analysis in the phase 3 SERENA-6 trial (NCT04964934).1

PFS was the primary end point of the study; key secondary end points were time to second disease progression (PFS2) and overall survival (OS), of which were immature at the time of the analysis. Other secondary end points included chemotherapy-free survival, objective response rate per RECIST 1.1 criteria, and clinical benefit rate at 24 weeks. A trend towards an improvement in PFS2 was reported with the camizestrant combination. The study will continue as planned to further evaluate the key secondary end points.

"Patients have an urgent need for new treatments that delay disease progression on first-line endocrine-based therapies,” François-Clément Bidard, MD, PhD, stated in a news release. “The results from SERENA-6 show that switching from an aromatase inhibitor to camizestrant in combination with any of the 3 CDK4/6 inhibitors after emergence of an ESR1 mutation delays progression of disease and extends the benefit of first-line treatment, representing an important step forward for patients, and a potential shift in clinical practice."

Bidard is the head of the Translational Research Group and a professor of medicine in the Department of Medical Oncology at Institut Curie & UVSQ/Université Paris-Saclay in France. He is the co-principal investigator for SERENA-6.

Camizestrant is a potent, next-generation SERD and complete estrogen receptor (ER) antagonist. Data from a range of preclinical models has shown that the agent has anti-cancer activity, including in models with ER-activating mutations. Findings from the phase 1 SERENA-1 trial (NCT03616587) demonstrated that camizestrant was well tolerated and had anti-tumor activity as monotherapy or in combination with palbociclib, ribociclib, or abemaciclib in patients with advanced breast cancer. Additionally, in the phase 2 SERENA-2 study (NCT04214288) camizestrant monotherapy displayed a PFS benefit compared with fulvestrant (Faslodex) regardless of ESR1 mutation status or previous treatment with endocrine therapy in patients with ER-positive locally advanced or metastatic breast cancer.

SERENA-6 was a global double-blind, randomized study that enrolled 315 patients with HR-positive/HER2-negative metastatic breast cancer with a detectable ESR1 mutation.1,2 Eligible patients needed to have an ECOG performance status of 0 or 1, adequate organ and bone marrow function, and needed to be receiving letrozole or anastrozole in combination with either palbociclib, abemaciclib, or ribociclib, with or without luteinizing hormone-releasing hormone, as initial endocrine therapy for advanced disease.2

Patients in the investigational group received oral camizestrant at a dose of 75 mg once daily in combination with either oral abemaciclib given at 50, 100, or 150 mg twice daily, oral palbociclib at 75, 100, or 125 mg once daily, or oral ribociclib once daily for 21 days on, 7 days off. These patients also received anastrozole or letrozole placebo once daily.

In the active comparator arm, patients received oral anastrozole at 1 mg once daily or oral letrozole at 2.5 mg once daily, in combination with palbociclib, abemaciclib, or ribociclib at the same dose ranges as the investigational arm.

Additional findings from SERENA-6 showed that the safety profile of camizestrant plus palbociclib, ribociclib, or abemaciclib was consistent with the known profiles of each agent.1 There were no new safety concerns and treatment discontinuation rates were low and similar between the investigational and control arms.

"These impressive results demonstrate the versatility of camizestrant in combination with all the widely approved CDK4/6 inhibitors to provide a well-tolerated new potential treatment option in the first-line setting for the 1 in 3 patients with HR-positive/HER2-negative advanced breast cancer whose tumors develop ESR1 mutations during treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor,” Susan Galbraith, PhD, executive vice president, Oncology Hematology R&D at AstraZeneca added in the news release. “This critical read-out moves us one step closer to realizing the potential of camizestrant to become a new standard-of-care as we look to shift the treatment paradigm and establish this new endocrine therapy backbone in HR-positive breast cancer.”

The data from SERENA-6 will be presented at an upcoming medical meeting and shared with global regulatory authorities.

References

1. Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 Phase III trial. News release. AstraZeneca. February 26, 2025. Accessed February 26, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html
2. Phase III study to assess AZD9833+ CDK4/​6 inhibitor in HR+/​HER2-MBC with detectable ESR1m before progression (SERENA-6) (SERENA-6). ClinicalTrials.gov. Updated January 10, 2025. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT04964934