AstraZeneca's Next-Gen Oral SERD Shows Promising Results in Breast Cancer Trial

On February 26, 2025, AstraZeneca announced positive mid-term results from the Phase III SERENA-6 trial for its oral selective estrogen receptor degrader (SERD) camizestrant. The study demonstrated statistically and clinically significant improvements in progression-free survival (PFS) when combined with CDK4/6 inhibitors such as palbociclib, ribociclib, or abemaciclib. This marks camizestrant as the first and only oral SERD proven to provide first-line treatment benefits when used with approved CDK4/6 inhibitors.

The SERENA-6 trial assessed the efficacy and safety of switching to camizestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer harboring ESR1 mutations. The study compared the camizestrant combination therapy to the standard care of continuing with aromatase inhibitors like anastrozole or letrozole alongside CDK4/6 inhibitors.

While key secondary endpoints such as PFS2 and overall survival (OS) remain immature at this stage, there is a noted trend towards improved PFS2 in the camizestrant group. The trial will continue as planned to further evaluate these critical secondary endpoints.

Notably, SERENA-6 is the first global, double-blind Phase III trial utilizing circulating tumor DNA (ctDNA) to guide the detection of endocrine resistance. This innovative approach allows for early identification of endocrine resistance signs and the emergence of ESR1 mutations during routine tumor scans. Upon detection of ESR1 mutations without disease progression, patients transitioned from aromatase inhibitor therapy to camizestrant while maintaining treatment with the same CDK4/6 inhibitor.

François-Clément Bidard, a professor of medical oncology at Université Versailles-Saint-Quentin, who is also the principal investigator of the trial, stated, “Patients urgently need new therapies to delay disease progression during first-line endocrine therapy. The SERENA-6 trial shows that transitioning to camizestrant after the emergence of ESR1 mutations can delay disease progression and extend the benefits of first-line treatment, representing a significant step forward for patients and a potential shift in clinical practice.”

Susan Galbraith, Executive Vice President of Oncology Research and Development at AstraZeneca, noted that these impressive results indicate camizestrant’s versatility in combination with approved CDK4/6 inhibitors, offering a promising new treatment option for one-third of HR+ HER2-negative advanced breast cancer patients who develop ESR1 mutations while receiving aromatase inhibitors with CDK4/6 inhibitors. This pivotal outcome brings AstraZeneca closer to establishing camizestrant as a new standard of care, aiming to transform treatment paradigms in HR+ breast cancer.

Globally, approximately 200,000 HR+ breast cancer patients receive first-line drug treatment, typically involving endocrine therapy targeting estrogen receptor-driven disease, often in conjunction with CDK4/6 inhibitors. However, many advanced patients develop resistance to these treatments. ESR1 mutations are key drivers of this resistance and are widely tested in clinical practice, becoming more prevalent as the disease progresses and associated with poor outcomes. About 30% of endocrine-sensitive HR+ patients experience ESR1 mutations during first-line treatment without disease progression.