AstraZeneca’s Etcamah has won US approval in combination with a CDK4/6 inhibitor for certain patients with advanced HR-positive, HER2-negative breast cancer, opening the door to an earlier treatment switch when an ESR1 mutation signals emerging resistance.

 

The US Food and Drug Administration’s accelerated approval is based on results from the Phase III SERENA-6 trial, in which the Etcamah combination reduced the risk of disease progression or death by 56% compared with standard treatment.

 

The trial found median progression-free survival was 16.0 months with Etcamah versus 9.2 months with an aromatase inhibitor, both given alongside a CDK4/6 inhibitor.

 

The approval covers adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose tumours develop an ESR1 mutation while they are receiving an aromatase inhibitor and a CDK4/6 inhibitor, without evidence of disease progression. The mutation is detected using an FDA-authorised test.

 

Kevin Kalinsky, Division Director of Medical Oncology, Winship Cancer Institute of Emory University and investigator for the trial, said: “This combination provides an important new option for the one in three patients with this form of advanced breast cancer whose tumours develop ESR1 mutations before clinical or radiographic disease progression. Today’s approval will enable clinicians to promptly intervene and change therapeutic strategy at an earlier opportunity ahead of disease progression, rather than waiting until the cancer becomes harder to treat, and patient outcomes and quality of life worsen.”

 

The significance of the approach lies in when treatment is changed. Rather than waiting for scans to show that the cancer has progressed, SERENA-6 used circulating tumour DNA (ctDNA) testing to detect an emerging ESR1 mutation — a key marker of resistance to endocrine therapy — while the disease was still responding to treatment.

 

Patients underwent blood testing alongside routine tumour scans every two to three months. When an ESR1 mutation emerged without disease progression, their endocrine therapy was switched from an aromatase inhibitor to Etcamah while the same CDK4/6 inhibitor was continued.

 

AstraZeneca said the strategy could reshape the first-line treatment paradigm for patients with HR-positive, HER2-negative advanced breast cancer.

 

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “Today’s approval is the tenth granted by the FDA this year across AstraZeneca’s portfolio and our fourth in breast cancer alone. The Etcamah combination reflects AstraZeneca’s leadership in redefining breast cancer care by pioneering a new approach using circulating tumour DNA and is the first and only medicine of its type in the 1st-line setting.”

 

In the planned interim analysis of SERENA-6, the Etcamah combination produced a hazard ratio of 0.44 for disease progression or death, with a 95% confidence interval of 0.31-0.60 and p<0.00001.

 

A subsequent pre-planned analysis also showed a statistically significant improvement in progression-free survival after the next line of treatment, known as PFS2. Median PFS2 was 25.7 months with Etcamah versus 19.1 months with standard treatment, representing a hazard ratio of 0.63.

 

Overall survival data remain immature. The subsequent analysis showed an overall-survival hazard ratio of 0.87, with a 95% confidence interval of 0.57-1.30, and the trial will continue to assess overall survival.

 

The safety profile of Etcamah combined with palbociclib, ribociclib or abemaciclib was consistent with the known safety profiles of the individual medicines. AstraZeneca reported no new safety concerns, while treatment discontinuation rates were low and similar between the two groups.

 

HR-positive breast cancer is the most common subtype of breast cancer, accounting for about 70% of tumours that are HR-positive and HER2-negative.

 

Endocrine therapies, often combined with CDK4/6 inhibitors, are a cornerstone of first-line treatment for advanced disease. But resistance remains a major challenge.

 

ESR1 mutations are a key mechanism of endocrine resistance. AstraZeneca estimates that approximately 30% of patients with endocrine-sensitive HR-positive disease develop an ESR1 mutation during first-line treatment before disease progression.

 

That makes early detection potentially important: the mutation can emerge before conventional scans reveal that the cancer is progressing.

 

SERENA-6 enrolled 315 adults with HR-positive, HER2-negative advanced breast cancer who were receiving an aromatase inhibitor plus a CDK4/6 inhibitor as first-line therapy. The global Phase III trial was randomised and double-blind.

 

It is the first global registrational Phase III trial to use a ctDNA-guided strategy to identify emerging endocrine resistance and trigger a treatment switch before radiographic or clinical progression.

 

Alongside the drug approval, the FDA approved a companion diagnostic designed to detect emerging ESR1 resistance mutations in patients’ circulating tumour DNA.

 

Etcamah is a next-generation oral selective estrogen receptor degrader and complete estrogen receptor antagonist.