Advanced Breast Cancer, New Hormone Therapy Reduces Risk of Progression by 56%

With over 55,000 new cases diagnosed each year and 52,000 Italian women living with metastatic cancer, breast cancer is the most common cancer not only among women, but in the entire population of our country. Despite the many advances made, it remains the leading cause of cancer death worldwide among women. However, good news comes from Asco 2025 where today the positive results of the phase 3 Serena-6 study were presented. The results of the study showed that AstraZeneca's camizestrant in combination with a cyclin-dependent kinase (Cdk) 4/6 inhibitor (palbociclib, ribociclib or abemaciclib) demonstrated a statistically significant and clinically relevant improvement in progression-free survival (PFS). The study evaluated switching to the camizestrant combination versus continuing standard treatment with an aromatase inhibitor (AI) (anastrozole or letrozole) in combination with a CDK4/6 inhibitor in the first-line treatment of patients with hormone receptor (Hr)-positive, Her2-negative advanced breast cancer whose tumors harbor an emerging Esr1 mutation. These results, presented at the plenary session of the American Society of Clinical Oncology Annual Meeting in Chicago (abstract #LBA4), will be published simultaneously in The New England Journal of Medicine.

Results showed that the camizestrant combination reduced the risk of investigator-assessed disease progression or death by 56% compared with standard treatment. The median PFS was 16.0 months for patients who switched to the camizestrant combination versus 9.2 months for the comparator arm. Importantly, consistent PFS benefit was observed with all CDK4/6 inhibitors and across clinically relevant subgroups in the study, including analysis by age, race, geographic region, time to Esr1 mutation detection, and Esr1 mutation type.

The camizestrant combination was also associated with a significant delay in the time to deterioration in quality of life: in an exploratory endpoint, the camizestrant combination reduced the risk of deterioration in global health status and quality of life by 47% compared with the aromatase inhibitor (Ai) combination. The median time to deterioration in global health status was 23.0 months in patients treated with the camizestrant combination, compared with 6.4 months in patients who continued treatment with the aromatase inhibitor (Ai) combination (Eortc Qlq-C30). The camizestrant combination also delayed the time to worsening of pain compared with the Ai combination.

Data for the key secondary endpoints, time to second progression of disease (PFS2) and overall survival (OS), were not yet mature at the time of this interim analysis. However, a trend toward a sustained benefit of camizestrant treatment, based on PFS2, was observed (HR 0.52; 95% CI). The study will continue to evaluate OS, PFS2, and other key secondary endpoints.

"In Italy, there are approximately 52,000 women with metastatic breast cancer - says Giampaolo Bianchini, associate professor and head of the Breast Group at the IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University in Milan -. Approximately 70% of these patients have a tumor with expression of the estrogen receptor (called Er or Esr1) and are negative for the expression of the Her2 protein. The first line of treatment in the case of 'endocrine sensitive' tumors, approximately 60% of these patients, is extremely effective and well tolerated, allowing a median survival of over 5 years to be achieved, with many patients exceeding 10 years. Unfortunately, however, after an initial response, the tumor finds a way to grow again. The most frequent resistance mechanism, in approximately 45% of cases, is a mutation affecting the estrogen receptor Esr1. Camizestrant is a new generation hormone therapy, belonging to the class of drugs called Serd, which leads to the potent selective degradation of the estrogen receptor".

The "drug - adds Bianchini - which has excellent tolerability, has already demonstrated in the Serena-2 study to be extremely effective in regressing tumors that, upon clinical progression, demonstrate having acquired this molecular alteration. The Serena-6 study aimed to demonstrate that the oncological paradigm adopted in the last 40 years, that is, changing therapy when a drug clinically no longer works, is not the best way to treat patients, testing the revolutionary hypothesis that the change in therapy should instead be anticipated when the tumor begins to develop this resistance mechanism, looking for it through a simple blood sample called liquid biopsy".

"The Serena-6 study - underlines Alberto Zambelli, associate professor of Oncology at the University of Milan-Bicocca and Director of Oncology at the Asst Papa Giovanni XXIII in Bergamo - demonstrates that switching from an aromatase inhibitor to camizestrant in combination with any of the three Cdk4/6 inhibitors, after the appearance of an Esr1 mutation, more than halved the risk of disease progression or death and significantly delayed the worsening of quality of life. In this way, it is possible to significantly prolong the clinical benefit of the first line, treating the developing resistance, before it causes disease progression and worsening of quality of life. The study can lead to a paradigm shift and redefine the approach to drug resistance in this type of tumor. For the first time, the therapeutic strategy is not changed at the time of clinical and radiological progression, but at the time of 'molecular progression', with the aim of interfere early with a known resistance mechanism, the Esr1 mutation. In this way, we move from a reactive approach, represented by the use of the oral Serd in second line, to a proactive one, that is, the early introduction of the oral Serd, camizestrant, at the appearance of the Esr1 mutation, before the progression of the disease".

“As the first pivotal study to demonstrate the clinical value of monitoring circulating tumor DNA to identify emerging resistance and adjust therapy early, Serena-6 is redefining the clinical paradigm in breast cancer,” said Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca. “Camizestrant is the first and only next-generation oral selective estrogen receptor degrader (SERD) and full estrogen receptor antagonist to demonstrate benefit in the first-line setting in combination with approved CDK4/6 inhibitors, and these results support its potential as a new standard endocrine therapy in the treatment of HR-positive breast cancer.”