Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumor mutation in SERENA-6 Phase III trial

Rhea-AI Summary

AstraZeneca (AZN) announced positive interim results from the SERENA-6 Phase III trial for camizestrant, their next-generation oral SERD treatment for HR-positive breast cancer. The trial demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival when combining camizestrant with CDK4/6 inhibitors.

The study evaluated switching to camizestrant combination versus continuing standard aromatase inhibitor treatment in 1st-line treatment of HR-positive, HER2-negative advanced breast cancer patients with emergent ESR1 mutations. The trial enrolled 315 patients and used a novel ctDNA-guided approach to detect endocrine resistance early.

While secondary endpoints including overall survival were immature at interim analysis, the treatment showed promising trends in time to second disease progression. The safety profile was consistent with known data, with low discontinuation rates across both arms.

Positive

• Highly statistically significant improvement in progression-free survival
• Positive trend in time to second disease progression
• Compatible with all three widely approved CDK4/6 inhibitors
• Very low treatment discontinuation rates
• Novel ctDNA monitoring approach enables early intervention

Negative

• Secondary endpoints including overall survival still immature
• Results to patients with emergent ESR1 mutations only

Insights

Oncology Specialist

AstraZeneca's SERENA-6 Phase III trial results represent a potential paradigm shift in HR-positive breast cancer treatment. The trial demonstrated that switching patients to camizestrant (a next-generation oral SERD) from an aromatase inhibitor when ESR1 mutations emerge—while continuing the same CDK4/6 inhibitor—significantly improved progression-free survival.

The study's groundbreaking design used circulating tumor DNA monitoring to detect emerging resistance mechanisms before clinical progression occurs. This approach could fundamentally change how we manage endocrine resistance, potentially establishing a new standard for biomarker-guided treatment adaptation in real-time.

With approximately 30% of patients developing ESR1 mutations during first-line therapy without disease progression, camizestrant addresses a critical unmet need. The positive trend in time to second progression (PFS2) suggests the benefits may extend beyond initial response, though overall survival data remain immature.

Commercially, this positions AstraZeneca advantageously in the competitive landscape of next-generation endocrine therapies. Camizestrant's demonstrated efficacy with all three widely approved CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) provides flexibility in treatment combinations that physicians already trust.

The favorable safety profile with low discontinuation rates comparable to standard therapy suggests camizestrant could be readily incorporated into treatment protocols without adding significant toxicity burden. For AstraZeneca's oncology portfolio, camizestrant could become a cornerstone therapy in HR-positive breast cancer, complementing their existing treatments and potentially establishing a new endocrine therapy backbone in this disease.

Pharmaceutical Analyst

AstraZeneca's positive SERENA-6 results position camizestrant as a potential cornerstone therapy in HR-positive breast cancer, addressing the critical challenge of ESR1 mutation-driven resistance. The market opportunity is substantial, with approximately 30% of the 200,000 first-line HR-positive breast cancer patients developing ESR1 mutations before disease progression.

Competitively, camizestrant demonstrates several advantages over other SERDs in development. Unlike Menarini/Radius's elacestrant (approved only in later lines of therapy) or Sanofi's discontinued amcenestrant program, camizestrant is the first next-generation SERD to show first-line efficacy in combination with all three major CDK4/6 inhibitors. This versatility significantly enhances its commercial potential and clinical utility.

The trial's innovative ctDNA-guided approach represents a potential new standard in precision oncology, moving beyond static treatment paradigms to dynamic, biomarker-guided therapy adjustments. However, implementation will require healthcare systems to adopt regular molecular monitoring capabilities, potentially creating both opportunities for companion diagnostics and challenges for global access.

For AstraZeneca's portfolio strategy, camizestrant complements their existing breast cancer assets, including Enhertu (HER2-directed), capivasertib (AKT inhibitor), and datopotamab deruxtecan (TROP2-directed ADC). This comprehensive approach across breast cancer subtypes strengthens AstraZeneca's competitive position against Pfizer, Novartis, and Eli Lilly in the lucrative breast cancer market.

With data being presented at upcoming medical meetings and shared with regulators, camizestrant could potentially receive approval within 12-18 months, depending on regulatory review timelines and whether additional data on secondary endpoints will be required.

First and only next-generation oral SERD and complete ER antagonist to demonstrate 1st-line benefit in combination with widely approved CDK4/6 inhibitors

WILMINGTON, Del.--(BUSINESS WIRE)-- 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 tumors 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 tumor 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 tumor 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 Hematology 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 tumors 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 realizing 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.^1-3 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.³

Mutations in the ESR1 gene are a key driver of endocrine resistance and are widely tested for in clinical practice.^4,5 These mutations develop during treatment of the disease, becoming more prevalent as the disease progresses and are associated with poor outcomes.^4,5 Approximately 30% of patients with endocrine-sensitive HR-positive disease develop ESR1 mutations during 1st-line treatment without disease progression.¹

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

Notes

HR-positive breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.⁶ More than two million patients were diagnosed with breast cancer in 2022, with more than 665,000 deaths globally.⁶ While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.⁷

HR-positive breast cancer, characterized by the expression of estrogen or progesterone receptors, or both, is the most common subtype of breast cancer with 70% of tumors considered HR-positive and HER2-negative.⁷ ERs often drive the growth of HR-positive breast cancer cells.⁸

Once resistance to the treatment of HR-positive breast cancer with CDK4/6 inhibitors and current endocrine therapies occurs, treatment options are limited and survival rates are low with 35% of patients anticipated to live beyond five years after diagnosis.^3,7,9 The optimization of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research.

SERENA-6
SERENA-6 is a Phase III, double-blind, randomized 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 tumors 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.

Camizestrant
Camizestrant is an investigational, potent, next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist that is currently in Phase III trials for the treatment of HR-positive breast cancer.

AstraZeneca’s broad, robust and innovative clinical development program, including the SERENA-6, SERENA-4, CAMBRIA-1 and CAMBRIA-2 trials, is evaluating the safety and efficacy of camizestrant when used as a monotherapy or in combination with other agents to address a number of areas of unmet need in this specific type of breast cancer.

Camizestrant has demonstrated anti-cancer activity across a range of preclinical models, including those with ER-activating mutations. In the SERENA-2 Phase II trial, camizestrant demonstrated PFS benefit versus fulvestrant irrespective of ESR1 mutation status or prior treatment with CDK4/6 inhibitors in patients with ER-positive locally advanced or metastatic breast cancer, previously treated with endocrine therapy. The SERENA-1 Phase I trial demonstrated that camizestrant is well tolerated and has a promising anti-tumor profile when administered alone or in combination with palbociclib, ribociclib and abemaciclib; three widely used CDK4/6 inhibitors. Combinations with other agents are ongoing in SERENA-1.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is challenging, and redefining, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment.

With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive, HER2-low and HER2-ultralow metastatic breast cancer, and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines fulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, the TROP-2-directed ADC, datopotamab deruxtecan-dlnk and next-generation oral SERD and potential new medicine camizestrant.

PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. AstraZeneca is also exploring the efficacy and safety of saruparib, a potent and selective inhibitor of PARP1, in combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced breast cancer.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to evaluate the potential of datopotamab deruxtecan-dlnk alone and in combination with immunotherapy durvalumab.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca-us.com and follow the Company on social media @AstraZeneca.

References

1. Cerner CancerMPact database. Accessed February 2025.
2. Lin M, et al. Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer. 2020; 10.7150/jca.48944.
3. Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor–positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022; 28(5):821-30.
4. Brett O, et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor‑positive breast cancer. Breast Cancer Res. 2021; 23:85.
5. Zundelevich, A, et al. ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. Breast Cancer Res. 2020; 22:16.
6. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi: 10.3322/caac.21834.
7. National Cancer Institute. Cancer Stat facts: Female breast cancer subtypes. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed February 2025.
8. Scabia V, et al. Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor. Nat Commun. 2022; 10.1038/s41467-022-30898-0.
9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 2025.

US-98587 | Last Updated 2/25

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FAQ

What were the main results of AZN's SERENA-6 Phase III trial for camizestrant?

The trial showed statistically significant improvement in progression-free survival when combining camizestrant with CDK4/6 inhibitors compared to standard treatment in 1st-line HR-positive breast cancer patients with ESR1 mutations.

How many patients were enrolled in AZN's SERENA-6 Phase III trial?

The global trial enrolled 315 adult patients with HR-positive, HER2-negative advanced breast cancer.

What is unique about the SERENA-6 trial's monitoring approach?

It's the first global Phase III trial using ctDNA monitoring to detect endocrine resistance and ESR1 mutations early, allowing therapy switch before disease progression.

What percentage of HR-positive breast cancer patients develop ESR1 mutations during first-line treatment?

Approximately 30% of patients with endocrine-sensitive HR-positive disease develop ESR1 mutations during 1st-line treatment without disease progression.

How did the safety profile of AZN's camizestrant combination therapy compare to existing treatments?

The safety profile was consistent with known data for each medicine, with no new safety concerns and very low discontinuation rates in both trial arms.