ETCAMAH® (camizestrant) in combination with a CDK4/6 inhibitor approved in the US for 1st-line advanced HR-positive breast cancer

Approval based on SERENA-6 Phase III trial results which showed combination reduced the risk of disease progression or death by 56% in patients with an emergent ESR1 tumor mutation

Innovative treatment strategy has potential to reshape 1st-line treatment paradigm for patients in this setting

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca’s ETCAMAH^® (camizestrant) in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor (abemaciclib, palbociclib or ribociclib) has been approved in the US for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor (AI) and CDK4/6 inhibitor therapy, based on a US Food and Drug Administration (FDA)-authorized test.

The accelerated approval was based on results from the pivotal SERENA-6 Phase III trial presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine.¹

Kevin Kalinsky, MD, MS, FASCO, Division Director of Medical Oncology, Winship Cancer Institute of Emory University and investigator for the trial, said: “The combination provides an important new option for the one in three patients with this form of advanced breast cancer whose tumors 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.”

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 tumor DNA and is the first and only medicine of its type in the 1st-line setting.”

In a planned interim analysis of the SERENA-6 trial, ETCAMAH in combination with a CDK4/6 inhibitor reduced the risk of disease progression or death by 56% versus standard-of-care treatment with an AI (anastrozole or letrozole) in combination with a CDK4/6 inhibitor (based on a hazard ratio [HR] of 0.44; 95% confidence interval [CI]:0.31-0.60; p<0.00001; median PFS 16.0 versus 9.2 months). While data for the key secondary endpoints of time to second disease progression (PFS2) and overall survival (OS) were immature at the time of the interim analysis, a subsequent pre-planned analysis demonstrated a statistically significant and clinically meaningful PFS2 benefit of 25.7 months versus 19.1 months in favor of the ETCAMAH combination (HR: 0.63; 95% CI: 0.46-0.86; p=0.00373) and OS continued to mature in favor of the ETCAMAH combination (HR: 0.87; 95% CI: 0.57-1.30). The trial will continue to assess OS as a key secondary endpoint.

The safety profile of ETCAMAH in combination with palbociclib, ribociclib or abemaciclib in the SERENA-6 trial 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.¹

In the US, breast cancer is the most common cancer in women, with more than 300,000 new patients diagnosed annually, and more than 42,000 deaths.² Approximately 37,000 patients with HR-positive metastatic breast cancer in the US 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.^3-5 However, resistance to these therapies frequently develop in many patients.⁵ Once this occurs, treatment options are limited and survival rates are low with just over a third of patients anticipated to live beyond five years after diagnosis.^5,6 Mutations in the ESR1 gene are a key driver of endocrine resistance and are associated with poor outcomes, emerging during treatment of the disease and becoming more prevalent as the disease progresses.^7,8 Approximately 30% of patients with endocrine sensitive HR-positive disease develop ESR1 mutations during 1st-line treatment before disease progression.³

Concurrently with this approval, the FDA also approved a companion diagnostic test to detect emerging ESR1 resistance mutations in the circulating tumor DNA (ctDNA) of patients with HR-positive, HER2-negative advanced or metastatic breast cancer. SERENA-6 is the first global, double-blind, registrational Phase III trial to use a ctDNA-guided approach to detect the emergence of endocrine resistance and inform a switch in therapy before disease progression. The innovative trial design used ctDNA monitoring via a blood test at the time of routine tumor scans every two to three months to identify patients for early signs of endocrine resistance via the emergence of ESR1 mutations. Following detection of an ESR1 mutation without disease progression, the endocrine therapy of patients was switched to ETCAMAH from ongoing treatment with an AI, while continuing combination with the same CDK4/6 inhibitor.

ETCAMAH is also approved in more than 30 countries across the globe, including in the EU, Japan, Canada, the UK and several other countries based on the SERENA-6 Phase III trial.

IMPORTANT SAFETY INFORMATION

WARNING: ARRHYTHMIA RISK WITH CONCOMITANT USE OF QTc INTERVAL PROLONGING DRUGS   ETCAMAH in combination with ribociclib, a QTc interval prolonging drug and a strong CYP3A inhibitor, or in combination with other QTc interval prolonging drugs, can increase the risk of Torsades de Pointes (TdP), other ventricular arrhythmias, and sudden death.   Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of TdP. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently.   Obtain electrocardiogram (ECG) prior to initiation and monitor heart rate (HR) and QTc interval during treatment. Assess and correct electrolyte abnormalities prior to initiation and during treatment. Withhold ETCAMAH until resolution of QTc interval prolongation and resume or permanently discontinue ETCAMAH based on severity.

WARNINGS AND PRECAUTIONS

QTc Interval Prolongation: ETCAMAH in combination with a CDK4/6 inhibitor (CDK4/6i) is associated with QTc interval prolongation. When ETCAMAH is used in combination with ribociclib, a CDK4/6i, there is potential for increased risk of TdP, other ventricular arrhythmias, and sudden death. One Grade 4 case of TdP was observed in a dose-finding trial when ETCAMAH was used with ribociclib. In SERENA-6, QTc interval prolongation occurred in 2.6% of patients treated with ETCAMAH in combination with a CDK4/6i. QTc interval prolongation led to dose interruption in 0.6% of patients. No patients in SERENA-6 discontinued ETCAMAH due to QTc interval prolongation. ETCAMAH also causes bradycardia, which increases the risk of QTc interval prolongation.

Perform an ECG prior to initiating ETCAMAH, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated. Obtain serum electrolytes at baseline and during treatment as clinically indicated, and correct electrolyte abnormalities. Avoid concomitant use of ETCAMAH in combination with a CDK4/6i with products that cause QTc interval prolongation, are strong CYP3A inhibitors, and/or are drugs known to lower HR.

For QTc >500 msec or QTc >480 msec and prolongation from baseline >60 msec, withhold ETCAMAH. If other contributing causes are identified, then treat or correct the contributing causes.  Resume ETCAMAH when QTc returns to <480 msec. Reassess ECGs weekly for the first 2 weeks of treatment, and periodically during treatment as clinically indicated. Permanently discontinue ETCAMAH if QTc interval prolongation is either >500 msec or >60 msec change from baseline AND associated with any: TdP, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia.

Bradycardia: ETCAMAH causes a decrease in HR. Bradycardia increases the risk for life-threatening arrhythmias and sudden death when concomitant QTc interval prolongation is present, such as when ETCAMAH is used in combination with ribociclib, both a QTc interval prolonging product and a strong CYP3A inhibitor. In SERENA-6, bradycardia occurred in 8% of patients. The mean HR decrease from baseline was approximately 13 beats per minute (bpm) with the maximum decrease observed on day 15. Median time to onset was 17 days (range 13 to 283) after starting ETCAMAH. No patients discontinued ETCAMAH due to bradycardia. Dose interruption occurred in 3.9% of patients. The safety of ETCAMAH has not been established in patients with a baseline resting HR <55 bpm as these patients were excluded from SERENA-6. Monitor HR more frequently during the first 30 days of treatment in patients with bradycardia (HR <60 bpm) at baseline and those on concomitant medications known to lower HR (eg, beta-blockers).

For symptomatic (Grade 2 or above) bradycardia, withhold ETCAMAH until symptoms resolve. Obtain ECG to evaluate etiology. If a contributing concomitant medication is identified, modify the dosage or discontinue this medication, as appropriate, until bradycardia symptoms resolve, then resume ETCAMAH. Consider reassessing the HR after restart. Permanently discontinue for persistent symptomatic bradycardia.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions, including laboratory abnormalities, with ETCAMAH in combination with a CDK4/6i were decreased neutrophils (68%), decreased leukocytes (66%), decreased hemoglobin (47%), decreased lymphocytes (39%), decreased platelets (36%), visual disturbances (34%), and fatigue (23%).

Permanent discontinuation due to adverse reactions occurred in 1.3% of patients. Adverse reactions that resulted in permanent discontinuation of ETCAMAH included gastroesophageal reflux disease, cholestasis and hepatic cytolysis (0.6% each). Dosage interruption of ETCAMAH due to adverse reactions occurred in 22% of patients.

Visual disturbances: For visual disturbances limiting instrumental ADLs (activities of daily living) (Grade 2) or above, withhold ETCAMAH until symptoms resolve to Grade 1 or below. Refer to an eye professional for an ophthalmic examination and treatment and reassess at the next visit.

For other Grade 3 or higher adverse reactions: Withhold ETCAMAH until resolution to Grade 2 or below, then resume. Permanently discontinue for recurrence of Grade 3 or higher adverse reactions.

DRUG INTERACTIONS

• Strong CYP3A Inhibitors: Monitor for increased adverse reactions to ETCAMAH and modify the dosage as recommended
• Strong and Moderate CYP3A Inducers: Avoid the use of strong CYP3A inducers. Use caution with the co-administration of a moderate CYP3A inducer.
  • Avoid concomitant use of moderate CYP3A inducers for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib. If concomitant use cannot be avoided, increase the ETCAMAH dosage from 75 mg once daily to 150 mg once daily. After the moderate CYP3A inducer has been discontinued for at least 14 days, resume the ETCAMAH dosage used prior to initiation of the moderate CYP3A inducer
  • For patients who are receiving ETCAMAH in combination with ribociclib concomitantly with a moderate CYP3A inducer, no ETCAMAH dosage modification is recommended
• CYP2C9 and/or CYP2C19 Substrates: Avoid concomitant use of ETCAMAH with CYP2C9 or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 or CYP2C19 substrate
• Certain CYP3A Substrates: Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions
• Drugs that Prolong the QTc Interval: ETCAMAH is indicated in combination with a CDK4/6i and there is increased risk of QTc interval prolongation with ribociclib, a strong CYP3A inhibitor that can prolong the QTc interval. Refer to the ribociclib Prescribing Information for dosage modifications. Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of TdP. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently. ETCAMAH in combination with a CDK4/6i is associated with QTc interval prolongation
• Drugs that Cause Bradycardia: Avoid concomitant use of ETCAMAH with other products known to cause bradycardia. Monitor for signs and symptoms of bradycardia if concomitant use cannot be avoided. ETCAMAH causes decreases in HR that are dose and baseline HR dependent.

Refer to the Prescribing Information for the co-administered CDK4/6i for dosage modification guidelines related to adverse reactions, organ impairment, and drug-drug interactions.

SPECIAL POPULATIONS

Pregnancy: Based on findings in animals and mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Lactation: Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ETCAMAH and for 1 week after the last dose.

Females and Males of Reproductive Potential: ETCAMAH can cause fetal harm when administered to pregnant women. Verify pregnancy status of female patients of reproductive potential prior to initiating ETCAMAH. Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose. Refer to the Prescribing Information of the CDK4/6i palbociclib, if used in combination with ETCAMAH, for contraception information and use for the longest recommended post-treatment duration. ETCAMAH may impair fertility in female and male patients.

Pediatric Use: Safety and effectiveness have not been established in pediatric patients.

Hepatic Impairment: In patients with severe (Child-Pugh C) hepatic impairment, when ETCAMAH is combined with ribociclib, reduce the dosing frequency to every other day.

No dosage modifications are required in other patients with hepatic impairment of any level, or when ETCAMAH is combined with abemaciclib or palbociclib, although patients with moderate or severe hepatic impairment (Child-Pugh B or C) should be monitored for increased adverse reactions and dosage modified as recommended.

INDICATION
ETCAMAH in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) is indicated for the treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, based on an FDA-authorized test.

This indication is approved under accelerated approval based on progression-free survival as measured from detection of ESR1 mutation. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Please see full Prescribing Information, including Boxed WARNING, and Patient Information for ETCAMAH.

Notes

HR-positive breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.⁹ More than two million patients were diagnosed with breast cancer in 2024, with more than 690,000 deaths globally.⁹ 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.⁶

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.⁶ ERs often drive the growth of HR-positive breast cancer cells.¹⁰

Globally, more than 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 ER-driven disease, which are often paired with CDK4/6 inhibitors.^3-5

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 ETCAMAH 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.

ETCAMAH® (camizestrant)
ETCAMAH is a potent, next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist, administered orally, once daily. The recommended dose of ETCAMAH in combination with a CDK4/6 inhibitor is 75 mg.

ETCAMAH in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) is approved in the US, EU, Japan and several other countries for the treatment of adult patients with HR-positive (or ER-positive), HER2-negative locally advanced or metastatic breast cancer upon detection or emergence of ESR1 mutation and without disease progression during 1st-line endocrine therapy based on the results from the SERENA-6 Phase III trial.

The broad, robust and innovative ETCAMAH clinical development program, including the SERENA-4, CAMBRIA-1 and CAMBRIA-2 Phase III trials, is evaluating the safety and efficacy of ETCAMAH when used as a monotherapy or in combination with CDK4/6 inhibitors to address a number of areas of unmet need in HR-positive, HER2-negative breast cancer.

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 antibody drug conjugate (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, ETCAMAH.

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 MSD (Merck & Co., Inc. in the US and Canada) continue to research olaparib in these settings. AstraZeneca is also exploring the potential of saruparib, a potent and selective inhibitor of PARP1, in combination with ETCAMAH 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.

About AstraZeneca
AstraZeneca (LSE/STO/NYSE: AZN) 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

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US-66134 Last Updated 07/26