AstraZeneca Demonstrates Growing Leadership in Breast Cancer at SABCS with Data From Its Innovative Medicines and Robust Pipeline

New data from the DESTINY-Breast01 trial reinforce the efficacy of ENHERTU ® in HER2-positive metastatic breast cancer

New data from the SERENA-1 Phase I trial show strong efficacy and safety profile for next-generation oral SERD AZD9833 in HR-positive advanced breast cancer

AstraZeneca will unveil new developments across a range of stages and subtypes of breast cancer at the 2020 San Antonio Breast Cancer Symposium (SABCS), which will be held virtually from 8 to 11 December.

Key abstracts include:

• New data from the DESTINY-Breast01 Phase II trial, which reinforce the durable efficacy seen with ENHERTU ® (fam-trastuzumab deruxtecan-nxki) in HER2-positive metastatic breast cancer following two or more prior anti-HER2 based regimens

• New results from the SERENA-1 Phase I trial, which demonstrate strong efficacy and safety for a next-generation oral selective oestrogen receptor degrader (SERD), AZD9833 as a monotherapy and in combination with CDK4/6 inhibitor, palbociclib, in HR-positive, HER2-negative advanced breast cancer

José Baselga, Executive Vice President, Oncology R&D, said: “We are committed to transforming outcomes for women diagnosed or living with breast cancer by advancing a new generation of promising potential new medicines. The updates from the comprehensive DESTINY breast program reflect the potential of ENHERTU to help a wide range of breast cancer patients, while the encouraging data from the SERENA-1 Phase I trial paves the way for a clinical development program to help patients with hormone receptor-positive disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Significant progress has been made to improve outcomes for those living with breast cancer but there is still much work to be done. At SABCS 2020, our dedication to transforming the lives of those living with breast cancer will be front and center. With new updates from six different approved and potential new medicines, we are directly addressing patients’ greatest unmet needs and are potentially redefining treatment. Additionally, we are making an impact through collaborations with the scientific community to accelerate innovation.”

New, longer-term data from DESTINY-Breast01 to be presented at SABCS will highlight the updated efficacy and safety profiles of ENHERTU in patients with previously-treated HER2-positive metastatic breast cancer with an additional 9.4 months of follow up.

Furthermore, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) will showcase several TiP abstracts that highlight how the companies are building on the impressive results of ENHERTU in patients with HER2-positive metastatic breast cancer. These include trials to explore the potential of ENHERTU in earlier lines of treatment and stages of disease and in new breast cancer settings, including patients with low levels of HER2 expression. They also include combinations with other anti-cancer medicines such as paclitaxel, FASLODEX (fulvestrant), IMFINZI (durvalumab) and the potential new medicine capivasertib, an AKT-inhibitor.

AstraZeneca will present new efficacy and safety results from the dose escalation and expansion cohort of SERENA-1, a Phase I clinical trial of next-generation oral SERD AZD9833 as a monotherapy and in combination with the CDK4/6 inhibitor palbociclib in women with HR-positive breast cancer.

Building on the updated SERENA-1 findings, the Company will present two Phase II trial-in-progress (TiP) abstracts for the potential new medicine AZD9833, evaluating its efficacy and safety in previously treated post-menopausal women with advanced breast cancer and its biological effects in women with treatment-naïve early-stage breast cancer.

AstraZeneca is also presenting real-world evidence to understand outcomes for patients with germline BRCA mutations, and treatment patterns among patients with HER2-positive metastatic breast cancer. The Company will also showcase data on the potential role of artificial intelligence and digital pathology in measuring levels of HER2 expression in patients with breast cancer.

Additionally, AstraZeneca recognizes the important role of externally sponsored scientific research (ESR) in expanding the medical and scientific understanding of the Company’s medicines, and in identifying associated areas of unmet need in breast cancer. More than half of the AstraZeneca abstracts at this year’s SABCS are ESR studies with AstraZeneca medicines across the various subtypes of breast cancer.

Abstracts to be presented at 2020 SABCS featuring AstraZeneca medicines and pipeline molecules include:*

Abstract Title		Lead Author		Abstract Details
ENHERTU (fam-trastuzumab deruxtecan-nxki) 1
Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer		Modi S		PD3-06 Spotlight Poster-Discussion 3 – Advances in HER2 Positive Disease Date: Wednesday, December 9, 2020 Time: 6:30-7:45pm CT
Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: a 2-part, phase 1b, multicenter, open-label study		Hamilton E		PD3-07 Spotlight Poster-Discussion 3 - Advances in HER2 Positive Disease Date: Wednesday, December 9, 2020 Time: 6:30-7:45pm CT
Novel approach to HER2 quantification: digital pathology coupled with AI-based image and data analysis delivers objective and quantitative HER2 expression analysis for enrichment of responders to trastuzumab deruxtecan (T-DXd; DS-8201), specifically in HER2-low patients		Gustavson M		PD6-01 Spotlight Poster-Discussion 6 - Novel Approaches to Pathology and Imaging Date: Thursday, December 10, 2020 Time: 3:30-4:45pm CT
A real-world evidence study of treatment patterns among patients with HER2-positive metastatic breast cancer		Collins J		PS7-82 Poster Session 7 - Epidemiology Date: Wednesday, December 9, 2020 Time: 8:00am CT
Solti-1804 HER2-PREDICT: A biomarker research study of DS8201-A-U301 -U302 and -U303 Trials [TiP]*		Prat A		OT-03-07 Ongoing Trials Posters - Antibody-drug Conjugates Date: Wednesday, December 9, 2020 Time: 8:00am CT
Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual, invasive early breast cancer after neoadjuvant therapy: a randomized, phase 3 trial (DESTINY-Breast05) [TiP]		Geyer CE Jr		OT-03-01 Ongoing Trials Posters – Antibody-drug Conjugates Date: Wednesday, December 9, 2020 Time: 8:00am CT
Trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator’s choice of chemotherapy in patients with hormone receptor–positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic setting: a randomized, global phase 3 trial (DESTINYBreast06) [TiP]		Bardia A		OT-03-09 Ongoing Trials Posters - Antibody-drug Conjugates Date: Wednesday, December 9, 2020 Time: 8:00am CT
Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: a phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [TiP]		Andre F		OT-03-04 Ongoing Trials Posters - Antibody-drug Conjugates Date: Wednesday, December 9, 2020 Time: 8:00am CT
Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: a phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [TiP]		Jhaveri K		OT-03-05 Ongoing Trials Posters - Antibody-drug Conjugates Date: Wednesday, December 9, 2020 Time: 8:00am CT
LYNPARZA (olaparib) 2
Real-world clinical outcomes of patients with BRCA-mutated (BRCAm) HER2-negative metastatic breast cancer: a CancerLinQ ® study		Miller R		PS7-66 Poster Session 7 - Epidemiology Date: Wednesday, December 9, 2020 Time: 8:00am CT
DOLAF- An international multicenter phase II trial of durvalumab (MEDI4736) plus OLAparib plus Fulvestrant in metastatic or locally advanced ER-positive, HER2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib*		Guiu S		OT-13-05 Ongoing Trials Posters – Immunotherapy Date: Wednesday, December 9, 2020 Time: 8:00am CT
Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer: results of Phase I expansion cohorts		Krebs MG		PS11-18 Poster Session 11 – Systemic Therapies II – New Date: Wednesday, December 9, 2020 Time: 8:00am CT
FASLODEX (fulvestrant)
Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III Estrogen Receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): an ALTERNATE trial analysis. (Alliance A011106)*		Ellis MJ		PD2-10 Spotlight Poster Discussion 2 – Refining Targeted Therapy in HR+ Disease Date: Wednesday, December 9, 2020 Time: 5:15-6:30pm CT
Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive and HER2 negative breast cancer resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106)*		Ma CX		GS4-05 General Session 4 Date: Friday, December 11, 2020 Time: 9:45-10:00am ET
Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL)*		Perez-Garcia JM		PS10-17 Poster Session 10 – Systemic Therapies I – Targeted Date: Wednesday, December 9, 2020 Time: 8:00am CT
Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial*		Malorni L		PS5-05 Poster Session 5 – Response Prediction Biomarkers II Date: Wednesday, December 9, 2020 Time: 8:00am CT
GEICAM/2014-03 (Registem): a prospective registry of unresectable locally advanced or metastatic breast cancer: Characteristics of a subset of patients with triple negative subtype*		Jara C		PS7-25 Poster Session 7 Epidemiology Wednesday, December 9, 2020: 8:00 AM CT
Evaluating serum thymidine kinase in hormone receptor positive metastatic breast cancer patients receiving first line endocrine therapy in the SWOG S0226 trial*		Paoletti I		PS2-04 Poster Session 2 – Markers, Pathology Date: Wednesday, December 9, 2020 Time: 8:00am CT
Characteristics of HR+/HER2- patients with recurrent disease by HER2 expression from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM)*		Alvarez I		PS7-24 Poster Session 7 - Epidemiology Date: Wednesday, December 9, 2020 Time: 8:00am CT
GEICAM/2014-03 (Registem): A prospective registry of advanced breast cancer: a subset of triple negative breast cancer patients with HER2 low expression*		Jara C		PS7-35 Poster Session 7 - Epidemiology Date: Wednesday, December 9, 2020 Time: 8:00am CT
Characteristics of HR+/HER2- patients with recurrent disease from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM)*		Alvarez I		PS7-08 Poster Session 7 – Epidemiology Date: Wednesday, December 9, 2020 Time: 8:00am CT
Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial*		Pascual J		PS5-02 Poster Session 5 – Response Prediction Biomarkers II Date: Wednesday, December 9, 2020 Time: 8:00am CT
Plk1 expression and efficacy of palbociclib in advanced hormonal receptor-positive breast cancer patients from PEARL study (GEICAM/2012-03)*		Guerro-Zotano A		PS2-01 Poster Session 2 – Markers, Pathology Date: Wednesday, December 9, 2020 Time: 8:00am
Mutational profile from circulating tumor DNA in triple negative breast cancer: results from the prospective registry of unresectable locally advanced or metastatic breast cancer GEICAM/2014-03 (RegistEM)*		Guerro-Zotano A		PS5-22 Poster Session 5 – Response Prediction Biomarkers II Date: Wednesday, December 9, 2020 Time: 8:00am CT
Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: Validation using a novel gene signature of HER2 activation		Alsaleem M		PS6-11 Poster Session 6 – Prognostic Factors Date: Wednesday, December 9, 2020 Time: 8:00am CT
AZD9833
Updated data from SERENA-1: A phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer		Baird R		PS11-05 Poster Session 11 – Systemic Therapies II – New Date: Wednesday, December 9, 2020 Time: 8:00am CT
SERENA-2: A randomised, open-label, parallel-group, multicentre phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer		Oliveria M		OT-09-02 Ongoing Trials Posters – Endocrine Therapy Date: Wednesday, December 9, 2020 Time: 8:00am CT
A randomised, open-label, parallel-group, multicentre phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) [TiP]		Oliveria M		OT-09-02 Ongoing Trials Posters – Endocrine Therapy Date: Wednesday, December 9, 2020 Time: 8:00am CT
A randomised, pre-surgical study to investigate the biological effects of AZD9833 in women with ER-positive HER2-negative primary breast cancer (SERENA-3) [TiP]		Robertson J F R		OT-09-05 Ongoing Trials Posters – Endocrine Therapy Date: Wednesday, December 9, 2020 Time: 8:00am CT

*Denotes ESR

FDA-Approved Indication for ENHERTU

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

IMPORTANT SAFETY INFORMATION

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Adverse Reactions

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

• Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
• Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
• Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
• Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
• Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%).
• Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide .

IMPORTANT SAFETY INFORMATION for LYNPARZA® (olaparib) tablets

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

ADVERSE REACTIONS—First-Line Maintenance BRCA m Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%) and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced g BRCA m Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced g BRCA m ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced g BRCA m ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—g BRCA m, HER2-Negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance g BRCA m Metastatic Pancreatic Adenocarcinoma

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCA m Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA -mutated (g BRCA m or s BRCA m) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance HRD Positive Advanced Ovarian Cancer in Combination with Bevacizumab

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

• a deleterious or suspected deleterious BRCA mutation, and/or
• genomic instability

Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced g BRCA m Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA m) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

g BRCA m, HER2-Negative Metastatic Breast Cancer

For the treatment of adult patients with deleterious or suspected deleterious g BRCA m, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance g BRCA m Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious g BRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

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

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.

SELECT SAFETY INFORMATION for IMFINZI ® (durvalumab) injection for intravenous use

• Serious, potentially fatal risks were seen with IMFINZI in the CASPIAN trial. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%).
• Immune-mediated adverse reactions including immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies (including thyroid disorders, adrenal insufficiency, type 1 diabetes, and hypophysitis), nephritis, dermatologic reactions, other immune-mediated adverse reactions, infection, and infusion-related reactions were reported in patients receiving IMFINZI in the CASPIAN trial.
• The most common adverse reactions (≥20%) were nausea, fatigue/asthenia and alopecia.
• Advise women not to become pregnant or breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.
• The safety and effectiveness of IMFINZI have not been established in pediatric patients.

U.S. FDA-APPROVED INDICATIONS

IMFINZI is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:

• Have disease progression during or following platinum-containing chemotherapy.
• Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Please see complete Prescribing Information , including Patient Information.

Notes

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. AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines fulvestrant and goserelin and the next-generation SERD and potential new medicine AZD9833. PARP inhibitor, LYNPARZA (olaparib) , was the first targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research LYNPARZA in metastatic breast cancer patients with an inherited BRCA mutation, and are exploring new opportunities to treat these patients earlier in their disease state. Building on the first approval of ENHERTU , a HER2-directed antibody drug conjugate , in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings. To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy durvalumab in combination with other oncology medicines, including LYNPARZA and ENHERTU, investigating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan (DS-1062).

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS .

References

1. Enhertu is developed and commercialised in collaboration with Daiichi Sankyo worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights.
2. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. in the US and Canada).

US-48294 | 12/20

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