Capivasertib Plus FASLODEX® (fulvestrant) Reduced the Risk of Disease Progression or Death by 40% Versus FASLODEX in Advanced HR-Positive Breast Cancer

CAPItello-291 Phase III trial results presented at SABCS 2022 show potential of capivasertib as first-in-class AKT inhibitor

WILMINGTON, Del.--(BUSINESS WIRE)--Detailed results from the CAPItello-291 Phase III trial showed AstraZeneca’s capivasertib in combination with FASLODEX^® (fulvestrant) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo plus FASLODEX in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low or negative, locally advanced or metastatic breast cancer, following recurrence or progression on, or after, endocrine therapy (with or without a CDK4/6 inhibitor).¹ Results will be presented today in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Results showed capivasertib in combination with FASLODEX demonstrated a 40% reduction in the risk of disease progression or death versus placebo plus FASLODEX in the overall trial population (based on a hazard ratio [HR] of 0.60, 95% confidence interval [CI] 0.51-0.71; p=<0.001; median 7.2 versus 3.6 months).¹ In the AKT pathway biomarker-altered population, capivasertib plus FASLODEX reduced the risk of disease progression or death by 50% versus placebo plus FASLODEX (HR of 0.50, 95% CI 0.38-0.65; p=<0.001; median 7.3 versus 3.1 months).¹ Alterations within the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast cancer, affecting up to 50% of patients with advanced HR-positive breast cancer.^2-4

Nicholas Turner, MD, PhD, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, and principal investigator in the CAPItello-291 Phase III trial, said: “These data demonstrate the practice-changing potential of capivasertib as a new treatment option for patients with advanced HR-positive breast cancer. Critically, this potentially first-in-class treatment has shown it delays disease progression for those who have progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Capivasertib brings important progress to an area with persistent treatment gaps as the first therapy of its kind shown to be effective in a Phase III trial in patients with advanced HR-positive, HER2-low or negative breast cancer. We believe these results which showed benefit in all-comers and biomarker positive populations can reshape HR-positive breast cancer treatment, and that capivasertib can become an important new option for patients.”

Summary of results: CAPItello-291¹

	Capivasertib plus FASLODEX n=355	Placebo plus FASLODEX n=353
Median PFS in overall population (months)	7.2	3.6
HR (95% CI)	0.60 (0.51-0.71)
p-value	p=<0.001
Median PFS in the biomarker-altered population (months)	7.3	3.1
HR (95% CI)	0.50 (0.38-0.65)
p-value	p=<0.001
ORR in overall population	22.9%	12.2%
ORR in biomarker-altered population	28.8%	9.7%

HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate

Confirmed objective response rate (ORR) was 22.9% for the capivasertib plus FASLODEX arm versus 12.2% for the placebo plus FASLODEX arm in the overall trial population, and 28.8% versus 9.7%, respectively, in the biomarker-altered population.¹ Although the overall survival (OS) data were immature at the time of the analysis, early data are encouraging.¹ The trial will continue to assess OS as a key secondary endpoint.

The safety profile of capivasertib plus FASLODEX was similar to that observed in previous trials evaluating this combination.¹ In the overall trial population, the most frequent any grade adverse events (AEs) with capivasertib plus FASLODEX occurring in 20% or more of patients were diarrhea (72.4%), nausea (34.6%), rash (group term including rash, rash macular, maculo-papular rash, rash papular and rash pruritic; 38%) fatigue (20.8%) and vomiting (20.6%).¹ The most frequent Grade 3 or higher AEs occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%).¹

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

HR-positive breast cancer

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.⁵ More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.⁵

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.⁶

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER),⁷ 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.^8,9 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.⁹ Once this occurs, treatment options are limited⁹ – with chemotherapy being the current standard of care¹⁰ – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.⁶

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.

CAPItello-291

CAPItello-291 is a Phase III, double-blind, randomized trial that is part of a larger clinical program focused on capivasertib, an investigational AKT (serine/threonine kinase) inhibitor. CAPItello-291 is evaluating the efficacy of capivasertib in combination with FASLODEX versus placebo plus FASLODEX for the treatment of locally advanced (inoperable) or metastatic HR-positive, HER2-low or negative breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumors have qualifying alterations in the AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumors had these alterations.

Capivasertib

Capivasertib is an investigational oral treatment currently in Phase III trials for the treatment of multiple subtypes of breast cancer, prostate cancer and a Phase II trial for hematologic malignancies. A potent, selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), capivasertib is being evaluated as a monotherapy and in combination with existing therapies in tumors harboring alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumors reliant on signaling via this pathway for survival. Capivasertib 400 mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

The capivasertib clinical research program is investigating the safety and efficacy of capivasertib when used alone and in combination with established treatment regimens.

Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

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 next-generation SERD 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.	Turner, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Presented at: San Antonio Breast Cancer Symposium, 6-10 December 2022, San Antonio, Texas, USA.
2.	Howell S J, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION). J Clin Oncol. 2022; 23:851-64.
3.	Hortobagyi G N, et al. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol. 2016; 34:419-26.
4.	Millis S Z, et al. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565-73.
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6.	National Cancer Institute. Surveillance, Epidemiology and End Results Program. https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed December 2022.
7.	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.
8.	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.
9.	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.
10.	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.