Camizestrant Combo Misses PFS End Point in First-Line ER+/HER2– Breast Cancer

Camizestrant (Etcamah) plus palbociclib (Ibrance) did not meet the primary end point of a statistically significant improvement in progression-free survival (PFS) compared with anastrozole plus palbociclib as first-line treatment for patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer in the phase 3 SERENA-4 trial (NCT04711252), according to a news release from AstraZeneca.¹

Investigators observed a numerical PFS improvement with the camizestrant combination in patients who had not received any prior systemic therapy for advanced disease, but the difference did not reach statistical significance. The safety profile of camizestrant plus palbociclib was consistent with the known profiles of each agent, and no new safety concerns emerged. The developers stated that detailed data will be shared in due course.

Susan Galbraith, executive vice president of oncology hematology research and development at AstraZeneca, said in the release that although the outcome was disappointing, it “reinforces the importance of ESR1 testing for patients on first-line therapy.” She added that the company remains confident in the long-term potential of camizestrant in the early breast cancer setting and will continue to advance its broader development program.

What is the background of the SERENA-4 trial?

SERENA-4 was a global, double-blind, randomized phase 3 trial that enrolled 1371 adults with ER-positive, HER2-negative locally advanced or metastatic breast cancer. Eligible patients had de novo stage IV disease or recurrent disease and had not received any systemic treatment for metastatic disease. Those with recurrence after early-stage disease must have received at least 24 months of standard adjuvant endocrine therapy with an aromatase inhibitor (AI) or tamoxifen, with at least 12 months elapsed since the last dose of adjuvant AI therapy and no disease progression while on treatment.

Patients were randomly assigned 1:1 to receive oral camizestrant at 75 mg once daily plus palbociclib at 125 mg once daily for 21 consecutive days followed by 7 days off treatment, along with a matching anastrozole placebo; or anastrozole at 1 mg once daily plus the same palbociclib schedule and a matching camizestrant placebo.² Men, when medically applicable, and pre- or perimenopausal women were required to receive a monthly luteinizing hormone-releasing hormone agonist. The trial began in January 2021, with an estimated primary completion date of August 2026 and an estimated study completion date of February 2029.

The primary end point was investigator-assessed PFS. Secondary end points included overall survival (OS), PFS2, and health-related quality of life.¹

Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist administered once daily; the recommended dose in combination with a CDK4/6 inhibitor is 75 mg. The agent is approved in the US, EU, Japan, and several other countries in combination with palbociclib, ribociclib (Kisqali), or abemaciclib (Verzenio) for adults with hormone receptor (HR)–positive, HER2-negative locally advanced or metastatic breast cancer upon detection or emergence of an ESR1 mutation during first-line endocrine-based therapy.¹

In what setting did the FDA approve camizestrant?

The SERENA-4 readout follows the FDA’s September 4, 2026, approval of camizestrant in that ESR1-mutated population, which was supported by data from the phase 3 SERENA-6 trial (NCT04964934).³ The approval defied an April 2026 vote by the FDA’s Oncologic Drugs Advisory Committee, which had voted 6 to 3 against the new drug application after concluding that the data available at the time did not demonstrate a clinically meaningful benefit for patients whose ESR1 mutations were detected via circulating tumor DNA (ctDNA) before radiographic progression.⁴ The agency subsequently delayed its decision in May 2026 to review supplemental ctDNA clearance analyses ahead of updated survival data presented at the 2026 American Society of Clinical Oncology Annual Meeting.

In SERENA-6, switching to camizestrant plus a CDK4/6 inhibitor upon detection of an emergent ESR1 mutation reduced the risk of disease progression or death by 55% compared with continuing AI plus CDK4/6 inhibitor therapy (HR, 0.45; 95% CI, 0.34-0.59; P <.00001) at a median follow-up of 23 months. The median PFS was 16.8 months vs 9.2 months, respectively, and 34.9% vs 14.2% of patients remained progression free at 24 months. The median PFS2 was 25.7 months vs 19.1 months (HR, 0.63; 95% CI, 0.46-0.86; P = .00373), and the early-switch strategy delayed the need for chemotherapy or antibody-drug conjugate therapy by a median of 3.9 months.³

SERENA-6 enrolled 315 patients who had received an AI plus a CDK4/6 inhibitor as initial endocrine-based therapy for at least 6 months, had an ESR1 mutation detected in ctDNA without evidence of disease progression, and had received no more than 1 prior line of chemotherapy for advanced disease. Grade 3 or higher adverse effects occurred in 60% of patients in the camizestrant arm vs 46% in the AI-continuation arm, with neutropenia (45% vs 34%) and leukopenia (10% vs 3%) among the most common. Photopsia was reversible and brief in reported cases.³

Beyond the advanced setting, the developers are evaluating camizestrant in the adjuvant setting through the phase 3 CAMBRIA-1 (NCT05774951) and CAMBRIA-2 (NCT05952557) trials, which together encompass approximately 10,000 patients at intermediate and high risk of recurrence. The trials are assessing camizestrant as monotherapy, in combination with CDK4/6 inhibitors, and following CDK4/6 inhibitor treatment in HR-positive, HER2-negative breast cancer.

References

1. Update on SERENA-4 phase III trial of Etcamah in combination with palbociclib in upfront 1st-line advanced ER-positive breast cancer. News release. AstraZeneca. September 11, 2026. Accessed September 14, 2026. https://tinyurl.com/2s5yhp6m

2. A comparative study of AZD9833 plus palbociclib versus anastrozole plus palbociclib in patients with ER-positive HER2 negative breast cancer who have not received any systemic treatment for advanced disease (SERENA-4). ClinicalTrials.gov. Accessed September 14, 2026. https://tinyurl.com/2rpt6wjs

3. FDA grants accelerated approval to a new breast cancer treatment. News release. FDA. September 4, 2026. Accessed September 14, 2026. https://tinyurl.com/ym8hw67u

4. April 30, 2026 meeting of the Oncologic Drug Advisory Committee (ODAC). YouTube. Accessed September 14, 2026. https://tinyurl.com/5cry64pu