Disease Susceptibility

DUBLIN, Jan. 24, 2024 /PRNewswire/ -- Endo International plc (OTC: ENDPQ) announced today that the peer-reviewed Journal of Hand Surgery Global Open published Collagenase Clostridium Histolyticum for the Treatment of Dupuytren Disease: A Delphi-Based Consensus Study.1 Consensus-based study findings among expert hand surgeons indicate that XIAFLEX® (collagenase clostridium histolyticum) has a wide-ranging application for the appropriate treatment of Dupuytren's contracture in patients with varying degrees of disease severity and functional impairment. Results from the published research indicate a high level of consensus for using XIAFLEX for the treatment of one- or two-finger metacarpophalangeal (MP) joint contractures, most one- or two-finger proximal interphalangeal (PIP) joint contractures, and most combined MP and PIP joint contractures. "Healthcare providers and patients can choose among multiple surgical and nonsurgical treatment options for Dupuytren's disease, and without established guidelines, the process for sorting through those choices can be overwhelming," said Dr. Gary M. Pess, a hand and upper extremity surgeon and lead author of the study. "This study provides insight from experienced hand surgeons about using XIAFLEX to treat varying degrees of Dupuytren's contracture." Dupuytren's disease is a heterogenous fibroproliferative condition of the palmar fascia characterized by the development of fascial nodules and cords that may result in digital contracture affecting hand function.2,3 XIAFLEX is a nonsurgical treatment option for Dupuytren's contracture when a "cord" can be felt composed of two purified collagenases that work to break down collagen when injected into fibrous tissue.4 About the Report Researchers used a modified Delphi method employing three successive, blinded online survey rounds to capture the clinical expertise of panelists and determine if consensus could be reached regarding the use of XIAFLEX for the treatment of Dupuytren's contracture.1 In Round 1, 22 real-world case scenarios were used to determine the panelists' recommendations for using XIAFLEX to treat metacarpophalangeal (MP) and/or proximal interphalangeal (PIP) joint contractures involving a single finger or 2 fingers, with varying degrees of contracture and clinical severity. Each scenario presented a distinct contracture(s) with a series of statements to evaluate the impact of patient- or disease-related features (e.g., age, recurrence, risk of anesthesia, Dupuytren diathesis, poor-quality skin, and post-fasciectomy scarring) on the clinical decision to use XIAFLEX. Researchers captured responses using either yes/no responses or a 5-point Likert scale ("strongly agree," "agree," "deficient information," "disagree," and "strongly disagree"). Level of agreement for each statement was determined, with a consensus threshold of ≥66.7% for agreement ("strongly agree" and "agree") or disagreement ("strongly disagree" and "disagree"). Round 2 included statements that did not meet the ≥66.7% threshold for consensus in round 1 and scenarios that explored the "impact of patient decision" (e.g., patient declines open surgical procedure). Statements were rated as described for round 1. Round 3 reassessed the statements that did not reach consensus in round 2 and explored the clinical decision-making process using an open-ended response methodology. Of the 33 hand surgeons who were invited based on their expertise and experience with treatment for Dupuytren's contracture, 22 agreed to participate in the survey; 20 completed round 1 of the survey, and 19 completed rounds 2 and 3. Overall, 80% had practiced medicine for at least 15 years, and all had completed a fellowship in hand surgery. Ninety percent were board-certified hand surgeons. Consensus-based study findings among expert hand surgeons point to wide-ranging application of XIAFLEX for the treatment of Dupuytren's contracture for patients with varying degrees of disease severity and functional impairment. WHAT IS XIAFLEX®? XIAFLEX is a prescription medicine used to treat adults with Dupuytren's contracture when a "cord" can be felt. It is not known if XIAFLEX is safe and effective in children under the age of 18. IMPORTANT SAFETY INFORMATION FOR XIAFLEX Do not receive XIAFLEX if you have had an allergic reaction to collagenase clostridium histolyticum or any of the ingredients in XIAFLEX, or to any other collagenase product. See the end of the Medication Guide for a complete list of ingredients in XIAFLEX. XIAFLEX can cause serious side effects, including: Tendon rupture or ligament damage. Receiving an injection of XIAFLEX may cause damage to a tendon or ligament in your hand and cause it to break or weaken. This could require surgery to fix the damaged tendon or ligament. Call your healthcare provider right away if you have trouble bending your injected finger (towards the wrist) after the swelling goes down or you have problems using your treated hand after your follow-up visit Nerve injury or other serious injury of the hand. After finger procedures, some people developed tears in the skin (lacerations), and local skin and soft-tissue necrosis (death of skin cells). Some lacerations and necrosis required skin grafting, or other surgery including amputation. Call your healthcare provider right away if you get numbness, tingling, increased pain, or tears in the skin (laceration) in your treated finger or hand after your injection or after your follow-up visit Hypersensitivity reactions, including anaphylaxis. Severe allergic reactions can happen in people who receive XIAFLEX because it contains foreign proteins. Call your healthcare provider right away if you have any of these symptoms of an allergic reaction after an injection of XIAFLEX: hives swollen face breathing trouble chest pain low blood pressure dizziness or fainting Fainting. Fainting (passing out) or near fainting can happen in people who receive XIAFLEX, especially following finger procedures If you have dizziness or feel faint after receiving XIAFLEX, lie down until the symptoms go away. Increased chance of bleeding. Bleeding or bruising at the injection site can happen in people who receive XIAFLEX. Talk to your healthcare provider if you have a problem with your blood clotting. XIAFLEX may not be right for you. Before receiving XIAFLEX, tell your healthcare provider if you have had an allergic reaction to a previous XIAFLEX injection, or have a bleeding problem or any other medical conditions. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using XIAFLEX with certain other medicines can cause serious side effects. Especially tell your healthcare provider if you take medicines to thin your blood (anticoagulants). If you are told to stop taking a blood thinner before your XIAFLEX injection, your healthcare provider should tell you when to restart the blood thinner. Ask your healthcare provider or pharmacist for a list of these medicines if you are unsure. The most common side effects with XIAFLEX for the treatment of Dupuytren's contracture include: swelling of the injection site or the hand bruising or bleeding at the injection site pain or tenderness of the injection site or the hand swelling of the lymph nodes (glands) in the elbow or armpit itching breaks in the skin redness or warmth of the skin pain in the armpit Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects with XIAFLEX. For more information, ask your healthcare provider or pharmacist. Click for full Prescribing Information, including Medication Guide. About Endo Endo (OTC: ENDPQ) is a specialty pharmaceutical company committed to helping everyone we serve live their best life through the delivery of quality, life-enhancing therapies. Our decades of proven success come from passionate team members around the globe collaborating to bring treatments forward. Together, we boldly transform insights into treatments benefiting those who need them, when they need them. Learn more at or connect with us on LinkedIn. Cautionary Note Regarding Forward-Looking Statements Certain information in this press release may be considered "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and any applicable Canadian securities legislation including, but not limited to, the statements by Dr. Pess, any statements relating to product efficacy, potential treatments or indications, therapeutic outcomes or treatment responses, and any statements that refer to expected, estimated or anticipated future results or that do not relate solely to historical facts. Statements including words or phrases such as "believe," "expect," "anticipate," "intend," "estimate," "plan," "will," "may," "look forward," "intend," "guidance," "future," "potential" or similar expressions are forward-looking statements. All forward-looking statements in this communication reflect the Company's current views as of the date of this communication about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to it and on assumptions it has made. Actual results may differ materially and adversely from current expectations based on a number of factors, including, among other things, the outcome of the Company's contingency planning and restructuring activities; the timing, impact or results of any pending or future litigation, investigations, proceedings or claims, including opioid, tax and antitrust related matters; any actual or contingent liabilities; settlement discussions or negotiations; the Company's liquidity, financial performance, cash position and operations; the risks and uncertainties associated with chapter 11 proceedings; the time, terms and ability to complete a chapter 11 plan of reorganization or to pursue an alternative emergence transaction; the risk that the Company's chapter 11 cases may be converted to cases under chapter 7 of the Bankruptcy Code; the adequacy of the capital resources of the Company's businesses and the difficulty in forecasting the liquidity requirements of the operations of the Company's businesses; the unpredictability of the Company's financial results; the Company's ability to discharge claims in chapter 11 proceedings; negotiations with the holders of the Company's indebtedness and its trade creditors and other significant creditors; the risks and uncertainties with performing under the terms of the restructuring support agreement and any other arrangement with lenders or creditors while in chapter 11 proceedings; the performance, including the approval, introduction, and consumer and physician acceptance of new products and the continuing acceptance of currently marketed products; and the Company's ability to obtain and successfully manufacture, maintain and distribute a sufficient supply of products to meet market demand in a timely manner. The Company expressly disclaims any intent or obligation to update these forward-looking statements, except as required to do so by law. Additional information concerning risk factors, including those referenced above, can be found in press releases issued by the Company, as well as the Company's public periodic filings with the U.S. Securities and Exchange Commission and with securities regulators in Canada, including the discussion under the heading "Risk Factors" in the Company's most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q or other filings with the U.S. Securities and Exchange Commission. References Pess G, et al. J Hand Surg Online. 2023; 1-8. Warwick D, et al. Int. J Clin Rheumatol. 2012;7(3):309-323. Warwick D. J Hand Surg Eur Vol. 2017;42(7):665-672. XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use [package insert]. Malvern, PA: Endo Pharmaceuticals Inc. SOURCE Endo International plc

Decision based on CAPItello-291 Phase III trial results which showed the combination reduced the risk of disease progression or death by 40% vs. FASLODEX alone Potential first-in-class AKT inhibitor being reviewed under Project Orbis WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca’s 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. 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 pro 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. 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 patients 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. For more information, please visit and follow us on Twitter @AstraZenecaUS. References FDA. Priority Review. Available at: . Accessed June 2023. 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. American Cancer Society. Key Statistics for Breast Cancer. Available at: . Accessed June 2023. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: . Accessed June 2023. 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. 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. Turner N, et al. Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. NEJM. 2023; 388:2058–70. 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. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Available at: . Accessed June 2023. US-76393 Last Updated 06/23

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-291 1 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 limited 9 – with chemotherapy being the current standard of care 10 – 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. 5. 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. 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.