On June 12, 2023 AstraZeneca reported that its New Drug Application (NDA) for capivasertib in combination with FASLODEX (fulvestrant) has been accepted and granted Priority Review in the US 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 following recurrence or progression on or after an endocrine-based regimen (Press release, AstraZeneca, JUN 12, 2023, View Source [SID1234632689]).
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The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.1 The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the fourth quarter of 2023.
The NDA is also being reviewed under Project Orbis, an initiative of the FDA which provides a framework for concurrent submission and review of oncology medicines among participating international partners to expedite approval for patients around the world.
Breast cancer is the most common cancer worldwide, with an estimated 2.3 million patients diagnosed each year.2 In the US, more than 290,000 patients are expected to be diagnosed in 2023, with more than 43,000 deaths.3 More than 65% of breast cancer tumors are considered HR-positive and HER2-low or negative.4 Endocrine therapies are widely used for the treatment of HR-positive breast cancer, but many patients with advanced disease develop resistance to 1st-line CDK4/6 inhibitors and endocrine therapies, underscoring the need for additional options.5,6
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "This Priority Review decision underscores the potential of capivasertib to extend the effectiveness of endocrine-based treatment approaches for patients with HR-positive breast cancer who experience tumor progression on, or resistance to these widely used therapies. We look forward to working with the FDA to bring this potential first-in-class AKT inhibitor to patients as quickly as possible."
The NDA is based on data from the CAPItello-291 Phase III trial presented at the 2022 San Antonio Breast Cancer Symposium and recently published online in The New England Journal of Medicine.7
In the trial, 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 hazard ratio [HR] of 0.60, 95% confidence interval [CI] 0.51-0.71; p=<0.001; median progression-free survival (PFS) 7.2 versus 3.6 months).7 Although the overall survival (OS) data were immature at the time of the analysis, early data are encouraging. The trial continues 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.7
In January 2023, capivasertib was granted Fast Track Designation by the FDA in this setting for this patient population.
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.2 More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.2
HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with more than 65% of breast cancer tumors considered HR-positive and HER2-low or negative.4
The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER), 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.5,6,8 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.6 Once this occurs, treatment options are limited – with chemotherapy being the current standard of care – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.4,6,9
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 (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridization (ISH)-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, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), capivasertib is being evaluated 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 400mg 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).
FASLODEX
FASLODEX (fulvestrant) is an endocrine therapy indicated for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy.
In the US, EU and Japan, FASLODEX is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. FASLODEX represents a hormonal treatment approach that helps to slow tumor growth by blocking and degrading the estrogen receptor – a key driver of disease progression.
FASLODEX is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6 and PI3K inhibitors for the treatment of patients with HR-positive advanced breast cancer, and is being evaluated in combination with medicines from other drug classes.