Camizestrant Shows PFS Benefit

Positive high-level results from a planned interim analysis of the SERENA-6 Phase III trial showed that AstraZeneca’s camizestrant in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor (palbociclib, ribociclib or abemaciclib) demonstrated a highly statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS). The trial evaluated switching to the camizestrant combination versus continuing standard-of-care treatment with an aromatase inhibitor (AI) (anastrozole or letrozole) in combination with a CDK4/6 inhibitor in the 1st-line treatment of patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer whose tumours have an emergent ESR1 mutation.

The key secondary endpoints of time to second disease progression (PFS2) and overall survival (OS) were immature at the time of this interim analysis. However, the camizestrant combination demonstrated a trend toward improvement in PFS2. The trial will continue as planned to further assess key secondary endpoints.

SERENA-6 is the first global, double-blind, registrational Phase III trial to use a circulating tumour DNA (ctDNA)-guided approach to detect the emergence of endocrine resistance and inform a switch in therapy before disease progression. The novel trial design used ctDNA monitoring at the time of routine tumour scan visits to identify patients for early signs of endocrine resistance and the emergence of ESR1 mutations. Following detection of an ESR1 mutation without disease progression, the endocrine therapy of patients was switched to camizestrant from ongoing treatment with an AI, while continuing combination with the same CDK4/6 inhibitor.

François-Clément Bidard, MD, PhD, Professor of Medical Oncology at Institut Curie & UVSQ/Université Paris-Saclay, France, and co-principal investigator for the trial, said: “Patients have an urgent need for new treatments that delay disease progression on 1st-line endocrine-based therapies. The results from SERENA-6 show that switching from an aromatase inhibitor to camizestrant in combination with any of the three CDK4/6 inhibitors after emergence of an ESR1 mutation delays progression of disease and extends the benefit of 1st-line treatment, representing an important step forward for patients, and a potential shift in clinical practice.”

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "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 one in three patients with HR-positive, HER2-negative advanced breast cancer whose tumours develop ESR1 mutations during treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor. This critical read-out moves us one step closer to realising 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 safety profile of camizestrant in combination with palbociclib, ribociclib or abemaciclib in SERENA-6 was consistent with the known safety profile of each medicine. No new safety concerns were identified and discontinuations were very low and similar in both arms.

Globally, approximately 200,000 patients with HR-positive breast cancer are treated with a medicine in the 1st-line setting; most frequently with endocrine therapies that target estrogen receptor (ER)-driven disease, which are often paired with CDK4/6 inhibitors. However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.

Mutations in the ESR1 gene are a key driver of endocrine resistance and are widely tested for in clinical practice. These mutations develop during treatment of the disease, becoming more prevalent as the disease progresses and are associated with poor outcomes. Approximately 30% of patients with endocrine sensitive HR-positive disease develop ESR1 mutations during 1st-line treatment without disease progression.

Data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

SERENA-6 is a Phase III, double-blind, randomised trial evaluating the efficacy and safety of camizestrant in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib ) versus treatment with an AI (anastrozole or letrozole) in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) in patients with HR-positive, HER2-negative advanced breast cancer (patients with either locally advanced disease, or metastatic disease) whose tumours have an emergent ESR1 mutation.

The global trial enrolled 315 adult patients with histologically confirmed HR-positive, HER2-negative advanced breast cancer, undergoing treatment with an AI in combination with a CDK4/6 inhibitor as 1st-line treatment. The primary endpoint of the SERENA-6 trial is PFS as assessed by investigator, with secondary endpoints including OS, and PFS2 by investigator assessment.