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Study to evaluate effectiveness of switching treatment to elacestrant in early breast cancer based on the detection of molecular relapse with Signatera™ Approximately 1,900 early-stage breast cancer patients to be screened at 120+ sites in Europe AUSTIN, Texas--(BUSINESS WIRE)-- Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, today announced its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, will be used in a new breast cancer study called TREAT ctDNA (EORTC 2129-BCG). This international, multi-center, randomized, phase III clinical trial is being conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group in collaboration with Natera and Menarini Group (Menarini), a leading international pharmaceutical and diagnostics company. The primary objective of the study is to evaluate whether elacestrant (ORSERDU®), a new oral endocrine monotherapy, can delay and/or prevent occurrence of distant metastasis or death compared to standard endocrine therapy in ER+/HER2- early-stage breast cancer patients with molecular relapse, which is defined as the presence of circulating tumor DNA (ctDNA) without clinical or radiographic evidence of recurrence. Over 200 patients who are ctDNA-positive by Signatera will be randomized to continue standard endocrine treatment or switch to elacestrant. Patients in both the control and experimental arms are expected to potentially benefit from timely detection of recurrence. “We are excited to offer to our high-risk, ctDNA positive, ER+/HER2- early-stage breast cancer patients the possibility to participate in the TREAT ctDNA trial. We aim to study the value of the new selective estrogen receptor degrader (SERD), elacestrant, in reducing the rate of late distant relapses for these patients,” said Prof. Michail Ignatiadis, chair of the EORTC Breast Cancer Group and director of the Breast Medical Oncology Clinic and Program at the Jules Bordet Institut. “We are grateful to partner with EORTC in our efforts to establish the utility of treatment on molecular recurrence, prompted by using Signatera to identify MRD-positive patients before clinically apparent relapse,” said Minetta Liu, M.D., chief medical officer of oncology at Natera. “Collaborations with leading clinical trial organizations like EORTC are needed as we seek to demonstrate the power of treatment on molecular recurrence across cancer indications. We believe this represents a paradigm shift in a patient’s cancer journey, wherein ctDNA testing may serve as a critical tool to catch relapse earlier, enable treatment while disease burden is still low, and ultimately improve patient outcomes.” The study will screen approximately 1,900 patients across more than 120 sites in 12 countries throughout Europe and is expected to launch before the end of the year. About Elacestrant (ORSERDU®) European Union Indication: ORSERDU (elacestrant) was approved by the European Commission in September 2023 as a monotherapy for the treatment of postmenopausal women, and men, with estrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer (mBC) with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK4/6 inhibitor. More information, including prescribing information and important safety information, is available here. About Signatera Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer (stage IIb and higher) and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 50 peer-reviewed papers. About Natera Natera™ is a global leader in cell-free DNA testing, dedicated to oncology, women’s health, and organ health. We aim to make personalized genetic testing and diagnostics part of the standard of care to protect health, and inform earlier, more targeted interventions that help lead to longer, healthier lives. Natera’s tests are validated by more than 150 peer-reviewed publications that demonstrate high accuracy. Natera operates ISO 13485-certified and CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in Austin, Texas and San Carlos, California. For more information, visit . Forward-Looking Statements All statements other than statements of historical facts contained in this press release are forward-looking statements and are not a representation that Natera’s plans, estimates, or expectations will be achieved. These forward-looking statements represent Natera’s expectations as of the date of this press release, and Natera disclaims any obligation to update the forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including with respect to whether the results of clinical or other studies will support the use of our product offerings, the impact of results of such studies, our expectations of the reliability, accuracy and performance of our tests, or of the benefits of our tests and product offerings to patients, providers and payers. Additional risks and uncertainties are discussed in greater detail in “Risk Factors” in Natera’s recent filings on Forms 10-K and 10-Q and in other filings Natera makes with the SEC from time to time. These documents are available at and .

Trial expected to screen more than 1900 early-stage breast cancer patients at 120+ sites in 12 countries across Europe, commencing in Q4 2023 Study will evaluate whether elacestrant can delay occurrence of metastasis or death compared to standard adjuvant endocrine therapy in early-stage ER+/HER2-breast cancer patients with late ctDNA-relapse BRUSSELS and FLORENCE, Italy, Oct. 19, 2023 /PRNewswire/ -- The European Organisation for Research and Treatment of Cancer (EORTC) and the Menarini Group (Menarini), a leading international pharmaceutical and diagnostics company, today announced they have launched a new study for breast cancer patients: EORTC 2129-BCG TREAT ctDNA, a clinical trial supported by the EORTC Breast Cancer Group. Menarini and its subsidiary, Stemline, will provide elacestrant. A molecular residual disease (MRD) test for the detection of circulating tumour DNA (ctDNA) will also be used. The study was submitted under the new Clinical Trial Regulation, and it is expected to start the activation process in the fourth quarter of 2023. ORSERDU® (elacestrant) was approved by the European Commission in September 2023 as a monotherapy for the treatment of postmenopausal women, and men, with estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer (mBC) with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK4/6 inhibitor. "We are excited to offer to our high-risk, ctDNA positive, ER+/HER2- early-stage breast cancer patients the possibility to participate in the Treat ctDNA trial. ctDNA positive patients will be identified using a personalised assay. We aim to study the value of the new selective estrogen receptor degrader (SERD), elacestrant, in reducing the rate of late distant relapses for these patients," said Prof. Michail Ignatiadis, chair of the EORTC Breast Cancer Group and Director of the Breast Medical Oncology Clinic and Program at the Jules Bordet Institut. This intergroup trial, managed by the EORTC Breast Cancer Group, will be jointly conducted with several national and international cancer clinical research groups, including the German SUCCESS group under the umbrella of BIG (Breast International Group). Twelve countries have been selected to participate in the trial (Italy, France, Belgium, Spain, Ireland, Cyprus, Germany, Greece, the Netherlands, Portugal, Sweden and Switzerland) with more than 120 sites expected to screen approximately 1960 patients. The randomised, open label, superiority phase III trial will evaluate whether elacestrant can delay the occurrence of metastasis or death compared to standard adjuvant endocrine therapy in patients with early-stage ER+/HER2- breast cancer and molecular relapse. "The Menarini Group is glad to partner with EORTC on this important study, to expand our understanding of how elacestrant may potentially benefit ER+/HER2- patients with early-stage breast cancer," said Elcin Barker Ergun, CEO of the Menarini Group. "Evaluating new treatments with a manageable safety profile, such as elacestrant, is important as we seek new options for this population." After verification that patients meet the eligibility criteria, they will enter the ctDNA screening phase of the study, in which plasma samples will be collected and tested the to detect the presence of ctDNA. The test will be performed every six months from study entry until the end of accrual. Patients with a positive ctDNA test, who do not have metastasis and who fulfill the eligibility criteria, will be randomised to either the standard endocrine treatment arm (the same treatment they were receiving before detection of ctDNA) or to the elacestrant arm. Patients will be randomised to one of the two treatment arms within four weeks of receiving their test results, with the goal of randomising 110 patients in each arm. Patients in both the control and experimental arms will benefit from timely detection of macroscopic disease relapse. About elacestrant (ORSERDU®) European Union Indication: ORSERDU (elacestrant) monotherapy is indicated for the treatment of postmenopausal women, and men, with estrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK4/6 inhibitor. Important Safety Information from the ORSERDU SmPC Hepatic Impairment: Administration of ORSERDU should be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepatic impairment (Child-Pugh B). In the absence of clinical data, ORSERDU is not recommended in patients with severe hepatic impairment (Child-Pugh C). Concomitant use with CYP3A4 Inducers and/or inhibitors: Concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU should be avoided. Concomitant use of strong or moderate CYP3A4 inducers with ORSERDU should be avoided. Thromboembolic events: Thromboembolic events are commonly observed in patients with advanced breast cancer and have been observed in clinical studies with ORSERDU. This should be taken into consideration when prescribing ORSERDU to patients at risk. Adverse Reactions: Serious adverse reactions reported in ≥ 1% of patients included nausea, dyspnoea, and thromboembolism (venous). The most common (≥ 10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased. The most common Grade ≥3 (≥2%) adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%), anaemia (2%), back pain (2%), and bone pain (2%). Nausea: Nausea was reported in 35% of patients. Grade 3-4 nausea events were reported in 2.5% of patients. Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence of nausea was generally lower in subsequent cycles (i.e., over time). Elderly: Gastrointestinal disorders were reported more frequently in patients aged ≥ 75 years. Fertility, pregnancy, and lactation: ORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. Based on the mechanism of action of elacestrant and findings from reproductive toxicity studies in animals, ORSERDU can cause foetal harm when administered to pregnant women. Females of reproductive potential should be advised to use effective contraception during treatment with ORSERDU and for one week after the last dose. It is recommended that lactating women should not breast-feed during treatment with ORSERDU and one week after the last dose of ORSERDU. Based on findings from animal studies and its mechanism of action, ORSERDU may impair fertility in females and males of reproductive potential. Effects on ability to drive and use machines: Fatigue, asthenia, and insomnia have been reported in some patients taking ORSERDU. Caution should be observed by patients who experience those adverse reactions when driving or operating machinery. The safety and efficacy of ORSERDU in children from birth to 18 years of age has not been established. To report SUSPECTED ADVERSE REACTIONS: [email protected] To Report a Product Complaint: [email protected] To Request Medical Information : [email protected] Elacestrant is also being investigated in several clinical trials in metastatic breast cancer disease, alone or in combination with other therapies: ELEVATE (NCT05563220); ELECTRA (NCT05386108); and ELCIN (NCT05596409). Elacestrant is also planned to be evaluated in early breast cancer disease. The Menarini Group obtained global licensing rights for elacestrant in July 2020 from Radius Health, Inc. The Menarini Group is now fully responsible for global registration, commercialization, and further development activities for elacestrant. About EORTC Breast Cancer Group The EORTC Breast Cancer Group (BCG) is a group of the most important academic hospitals in Europe aiming to develop new standards of care for breast cancer patients through innovation. Our research focus is the evaluation of innovative treatments and multidisciplinary approaches to increase survival and improve quality of life of all breast cancer patients. About The Menarini Group The Menarini Group is a leading international pharmaceutical and diagnostics company, with a turnover of over $4.4 billion and over 17,000 employees. Menarini is focused on therapeutic areas with high unmet needs with products for cardiology, oncology, pneumology, gastroenterology, infectious diseases, diabetology, inflammation, and analgesia. With 18 production sites and 9 Research and Development centers, Menarini's products are available in 140 countries worldwide. For further information, please visit . About Stemline Stemline, a wholly-owned subsidiary of the Menarini Group, is a commercial-stage biopharmaceutical company focused on the development and commercialization of novel oncology therapeutics. Stemline commercializes ORSERDU® (elacestrant) in the United States and in the E.U., an oral endocrine therapy indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Stemline also commercializes ELZONRIS® (tagraxofusp-erzs), a novel targeted treatment directed to CD123 for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic cancer, in the United States and Europe, which is the only approved treatment for BPDCN in the US and EU to date. Stemline also commercializes NEXPOVIO® in Europe, an XPO1 inhibitor for multiple myeloma. Stemline also has an extensive clinical pipeline of small molecules and biologics in various stages of development for a host of solid and hematologic cancers. Logo - SOURCE Menarini Industrie Farmaceutiche Riunite

The European Organisation for Research and Treatment of Cancer (EORTC) and health and beauty care company, Pierre Fabre, have begun a phase 3 study to assess a combination therapy for patients with stage 2 BRAF-mutant melanoma. Melanoma develops through unrepaired DNA damage to skin cells, which triggers mutations that can multiply and form malignant tumours. It is estimated that around 324,000 new cases of melanoma are diagnosed globally each year, with approximately half being BRAF mutations, a key target in the treatment of metastatic melanoma. Although considerable progress has been made in treating advanced melanoma activating the BRAF mutation, there still remains a high unmet need in earlier stages of the disease. It is estimated that around 18% of stage 2B and 25% of stage 2C patients die from melanoma within ten years of diagnosis. The study – COLUMBUS-AD – will assess whether the combination of BRAF and MEK inhibitors Braftovi (encorafenib) and Mektovi (binimetinib) can prolong recurrence-free survival (RFS) and improve distant metastasis-free survival (DMFS) and overall survival (OS) as compared to placebo in participants with surgically resected stage 2B-C BRAF V600E/K-mutant cutaneous melanoma. The COLUMBUS-AD study will enrol over 800 patients, beginning in April 2022, with 160 sites in up to 25 countries internationally taking part. Patients involved in the study will have had surgery for a stage 2B-C melanoma with a BRAF V600E/K mutation and must have made a full recovery from the surgery. Patients will receive Braftovi and Mektovi or placebo for up to 12 months and will have a monthly follow-up during the treatment period, and then every three months up to year three. Further follow-ups will then happen regular intervals, with patient follow-ups continuing for ten years. “Pierre Fabre’s partnership with EORTC is now accelerating with the opening of COLUMBUS-AD”, said Dr Deborah Szafir, executive vice president, head of medical and patient consumer division at Pierre Fabre. “Building on the clinical benefits that our medicines have demonstrated in advanced disease, we are eager for patients with a BRAF-mutated tumour to explore the adjuvant setting in an earlier stage of the disease as the unmet medical need remains high.” Results for the primary endpoint (Recurrence Free Survival) are expected by 2027 and Overall Survival results should be released by 2035.