Switching to Camizestrant/CDK4/6i Improved PFS in HR+/HER2– Breast Cancer

After treatment with an aromatase inhibitor plus a CDK4/6 inhibitor, switching to camizestrant plus a CDK4/6 inhibitor showed a PFS benefit over remaining on the aromatase inhibitor.

Camizestrant plus a CDK4/6 inhibitor—either palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)—elicited a clinically meaningful and statistically significant increase in progression-free survival (PFS) when compared with standard of care in the first line for patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer with an emergent ESR1 mutation, according to planned interim results from the phase 3 SERENA-6 trial (NCT04964934) shared in a press release from the developer, AstraZeneca.1

At the time of analysis, the secondary end points of time to second disease progression (PFS2) and overall survival (OS) were immature, though a trend for improved PFS2 was noted with the camizestrant combination.

Previously, in November 2024, results from the SERENA-2 trial (NCT03616587) demonstrated that camizestrant with ribociclib yielded increased PFS and better responses in estrogen receptor–positive, HER2-negative advanced breast cancer.2

The developer plans for data to be presented an upcoming medical conference, as well as shared with global regulatory authorities.

“Patients have an urgent need for new treatments that delay disease progression on first-line endocrine-based therapies,” François-Clément Bidard, MD, PhD, a professor of Medical Oncology at Institut Curie and UVSQ/Université Paris-Saclay, France, and co-principal investigator for the trial, wrote in the press release.1 “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 the emergence of an ESR1 mutation delays the progression of the disease and extends the benefit of first-line treatment, representing an important step forward for patients, and a potential shift in clinical practice.”

SERENA-6 is a randomized, double-blind study evaluating switching to camizestrant plus a CDK4/6 inhibitor after treatment with an aromatase inhibitor—either letrozole (Femara) or anastrozole (Arimidex)—plus a CDK4/6 inhibitor compared with remaining on the aromatase treatment.

Trial treatment was administered over 28-day cycles, and a placebo with camizestrant or an aromatase inhibitor was taken orally once daily all 28 days. Abemaciclib was taken orally twice daily for all 28 days, and palbociclib or ribociclib was taken orally once daily for 21 days, then stopped for the final 7 days of the cycle. Treatment was repeated in 28-day cycles for the duration of trial participation.

A total of 315 patients 18 years or older with histologically confirmed HR–positive, HER2-negative advanced breast cancer received an aromatase inhibitor with a CDK4/6 inhibitor in the first line of treatment for at least 6 months without having their cancer get worse.

Additional eligibility criteria include a proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy, an ECOG performance status of 0 or 1, an ESR1 mutation detected by central testing of ctDNA, adequate organ and marrow function, and a willingness and ability to comply with all required study procedures.3

Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complications; known active uncontrolled or symptomatic central nervous system metastases, carcinomatous meningitis, or leptomeningeal disease;evidence of severe or uncontrolled systemic diseases which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study; known or family history of severe heart disease; previous treatment with camizestrant, investigational selective estrogen receptor degraders, or fulvestrant (Faslodex); and persistent non-hematological toxicities caused by a CDK4/6 inhibitor or aromatase inhibitor treatment.

The primary trial end point was PFS assessed by the investigator. Secondary end points include PFS2, OS, chemotherapy-free survival, objective response rate, clinical benefit rate, quality of life, and plasma concentration of camizestrant at specified time points.

Regarding safety, treatment discontinuations were “very low” in both arms and no new safety signals were identified; the safety profiles of the trial agents were all consistent with known profiles.1

“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,” concluded Susan Galbraith, executive vice president of Oncology Hematology Research and Development at AstraZeneca.1

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://tinyurl.com/322nhnks
2. Ruiz-Borrego M, Ruiz IV, Vaklavas C, et al., Results from SERENA-1 Parts K/L: A Phase 1 study of the next-generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) in combination with ribociclib in women with ER-positive, HER2 negative advanced breast cancer, presented at the San Antonio Breast Cancer Symposium, December 10-13, 2024, San Antonio, Texas. PS7-08.
3. 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://tinyurl.com/k3nszukh