SERENA-2 Phase II trial results presented at SABCS 2022 show potential of camizestrant as next-generation SERD in endocrine therapy

Detailed results from the SERENA-2 Phase II trial showed AstraZeneca’s next-generation oral selective estrogen receptor degrader (ngSERD) camizestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) at both 75mg and 150mg dose levels versus FASLODEX^® (fulvestrant) 500mg in post-menopausal patients with estrogen receptor (ER)-positive locally advanced or metastatic breast cancer, previously treated with endocrine therapy. Results will be presented today in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS).

In the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% at a 75mg dose (based on a hazard ratio [HR] of 0.58, 90% confidence interval [CI] 0.41-0.81; p=0.0124; median PFS of 7.2 versus 3.7 months) and 33% at a 150mg dose (HR 0.67, 90% CI 0.48-0.92; p=0.0161; median PFS of 7.7 versus 3.7 months) compared to FASLODEX, the current SERD standard of care.

Among the prespecified subgroup of patients with ESR1 mutations – comprising 36.7% of the trial population – camizestrant showed a 67% reduction in the risk of disease progression or death at a 75mg dose (HR 0.33, 90% CI 0.18-0.58; median PFS of 6.3 versus 2.2 months) and a 45% reduction at a 150mg dose (HR 0.55, 90% CI 0.33-0.89; median PFS of 9.2 versus 2.2 months) compared to FASLODEX. Efficacy was also seen in patients without a detectable ESR1 mutation, with a 22% and 24% reduction in the risk of disease progression or death (HR 0.78, 90% CI 0.50-1.22 and HR 0.76, 90% CI 0.48-1.20) respectively for the 75mg and 150mg dose levels.

A clinically meaningful PFS benefit was also observed across other prespecified subgroups, including in patients with previously treated with prior cyclin-dependent kinase (CDK) 4/6 inhibitors, those with lung and/or liver metastases and those with ER-driven disease.

Mafalda Oliveira, MD, PhD, Vall d’Hebron Hospital and Vall d‘Hebron Institute of Oncology in Barcelona, Spain, and lead investigator for the SERENA-2 Phase II trial, said: “These data reflect an important step toward a potential new treatment option for patients with advanced ER-positive disease. Based on the SERENA-2 results, camizestrant was well tolerated at both doses and significantly improved patient outcomes, nearly doubling median progression-free survival in this setting compared with the current SERD standard of care.”

Cristian Massacesi, Chief Medical Officer & Oncology Chief Development Officer, Oncology R&D, AstraZeneca, said: “SERENA-2 showed a meaningful improvement over fulvestrant, demonstrating the potential of camizestrant, our next-generation SERD, to optimize outcomes for patients with advanced ER-driven breast cancer, irrespective of ESR1 mutation status and prior treatment with CDK4/6 inhibitors. Our focus on bringing new medicines to patients across the breast cancer spectrum is unwavering and we look forward to additional findings from our ongoing Phase III development program for camizestrant including SERENA-4 and SERENA-6.”

Summary of results: SERENA-2

Camizestrant was generally well tolerated, and its safety profile was consistent with that observed in previous trials with no new safety signals identified. The most frequent treatment-emergent adverse events (TEAEs) were photopsia (12.2%, 24.7%, 35.0% and 0%) and bradycardia (5.4%, 26.0%, 40.0% and 0%), for 75mg, 150mg or 300mg camizestrant or fulvestrant, respectively, all of which were Grade 1 or 2. TEAEs at Grade 3 or higher occurred in 1.4%, 2.7%, 5.0% and 1.4% of patients in the 75mg, 150mg and 300mg camizestrant or fulvestrant arms, respectively, with only two patients in the 75mg camizestrant arm and no patients in the 150mg, 300mg camizestrant or fulvestrant arms discontinuing therapy due to TEAEs.

AstraZeneca has a broad clinical development program for camizestrant in advanced breast cancer. The SERENA-6 Phase III trial is assessing camizestrant in combination with CDK4/6 inhibitors for the 1st-line treatment of patients with HR-positive metastatic breast cancer who have developed detectable ESR1 mutations during treatment with aromatase inhibitors, and the SERENA-4 Phase III trial is evaluating camizestrant plus palbociclib (CDK4/6 inhibitor) for the 1st-line treatment of patients with HR-positive, locally advanced or metastatic breast cancer. The indication sought for SERENA-6 has been granted Fast Track Designation by the US Food and Drug Administration.

Important Safety Information About FASLODEX^® (fulvestrant) injection

Contraindications

• FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX

Warnings and Precautions

Risk of Bleeding

• Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use

Hepatic Impairment

• FASLODEX is metabolized primarily in the liver. A 250 mg dose is recommended in patients with moderate hepatic impairment (Child-Pugh class B). FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

Injection Site Reaction

• Use caution while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. Injection site-related events, including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported with FASLODEX injection

Embryo-Fetal Toxicity and Lactation

• Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating FASLODEX
• Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during FASLODEX treatment and for 1 year after the last dose. Advise lactating women not to breastfeed during treatment with FASLODEX and for 1 year after the final dose because of the potential risk to the infant

Immunoassay Measurement of Serum Estradiol

• Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels

Adverse Reactions

Monotherapy

• The most common adverse reactions occurring in ≥5% of patients receiving FASLODEX 500 mg were injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, myalgia, vomiting, anorexia, diarrhea, asthenia, musculoskeletal pain, cough, dyspnea, and constipation
• Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-dependent

Combination Therapy – FASLODEX plus ribociclib

• The most frequently reported (≥5%) Grade 3 or 4 adverse reactions in patients receiving FASLODEX plus ribociclib in descending frequency were neutropenia, leukopenia, infections, and abnormal liver function tests
• The most common adverse reactions (≥20%) of any grade reported in patients receiving FASLODEX 500 mg plus ribociclib 600 mg/day were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash
• Additional adverse reactions in patients receiving FASLODEX plus ribociclib included asthenia, dyspepsia, thrombocytopenia, dry skin, dysgeusia, electrocardiogram QT prolonged, dry mouth, vertigo, dry eye, lacrimation increased, erythema, hypocalcemia, blood bilirubin increased, and syncope

Combination Therapy—FASLODEX plus palbociclib

• The most frequently reported Grade ≥3 adverse reactions in patients receiving FASLODEX plus palbociclib in descending frequency were neutropenia and leukopenia
• Adverse reactions (≥10%) of any grade reported in patients receiving FASLODEX 500 mg plus palbociclib 125 mg/day by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia
• Additional adverse reactions occurring at an overall incidence of <10% of patients receiving FASLODEX plus palbociclib included asthenia, aspartate aminotransferase increased, dysgeusia, epistaxis, lacrimation increased, dry skin, alanine aminotransferase increased, vision blurred, dry eye, and febrile neutropenia

Combination Therapy—FASLODEX plus abemaciclib

• The most frequently reported (≥5%) Grade 3 or 4 adverse reactions in patients receiving FASLODEX plus abemaciclib were neutropenia, diarrhea, leukopenia, anemia, and infections
• The most common adverse reactions (≥20%) of any grade reported in patients receiving FASLODEX 500 mg plus abemaciclib 150 mg twice daily were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache

Indications for FASLODEX

Monotherapy

FASLODEX is an estrogen receptor antagonist indicated for the treatment of:

• Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy
• HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy

Combination Therapy

FASLODEX is indicated for the treatment of:

• HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib as initial endocrine-based therapy or following disease progression on endocrine therapy
• HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy

Please see full Prescribing Information for FASLODEX with Patient Information

Notes

Hormone Receptor (HR)-positive breast cancer

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.¹ More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.¹

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both) is the most common subtype of breast cancer with approximately 70% of breast cancer tumors considered HR-positive and HER2-low or negative.²

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER),³ and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.^4,5 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.⁵ Once this occurs, the treatment options are limited⁵ – with chemotherapy being the current standard of care⁶ – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.²

Optimizing endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research.

SERENA-2

SERENA-2 is a randomized, open-label, parallel group, multicenter Phase II trial evaluating camizestrant at several dose levels compared to FASLODEX in advanced ER-positive, HER2-negative breast cancer. The primary endpoints are PFS defined by response evaluation criteria in solid tumors (RECIST) version 1.1 for 75mg camizestrant versus FASLODEX and for 150mg camizestrant versus FASLODEX. 240 patients were randomized to receive camizestrant or FASLODEX until disease progression. Secondary endpoints include safety, objective response rate and clinical benefit rate at 24 weeks.

Camizestrant

Camizestrant is a potent, next-generation oral SERD and pure ERα antagonist, that has demonstrated anti-cancer activity across a range of preclinical models, including those with ER-activating mutations.

AstraZeneca has a broad clinical development program 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 HR-positive breast cancer.

In addition to SERENA-2 and the ongoing SERENA-4 and SERENA-6 trials, 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, a CDK4/6 inhibitor. Combinations with other agents are ongoing in SERENA-1.

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, 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 and HER2-low 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 FASLODEX and goserelin and aims to reshape the HR-positive space with ngSERD and potential new medicine camizestrant as well as a potential first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc., known as MSD outside the US and Canada continue to research olaparib in these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy durvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib and fam-trastuzumab deruxtecan-nxki.

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 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 operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

References

1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
2. National Cancer Institute. Surveillance, Epidemiology and End Results Cancer Stat Facts: Female Breast Cancer Subtypes. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed December 2022.
3. 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.
4. 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.
5. 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.
6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Available at: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419. Accessed December 2022.

US-71678 Last Updated 12/22

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