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Biopharmaceuticals Oncology

 News Release - February 17, 2017

LYNPARZA(TM) (olaparib) Meets Primary Endpoint in Phase III Trial in BRCA-Mutated Metastatic Breast Cancer

WILMINGTON, Del.--(Healthcare Sales & Marketing Network)--AstraZeneca today announced positive results from its Phase III OlympiAD trial comparing LYNPARZA™ (olaparib) tablets (300mg twice daily) to physician’s choice of a standard of care chemotherapy in the treatment of patients with HER2-negative metastatic breast cancer harboring germline BRCA1 or BRCA2 mutations.1 Patients treated with LYNPARZA showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) compared with those who received chemotherapy (capecitabine, vinorelbine or eribulin).

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “These results are positive news for patients with BRCA-mutated metastatic breast cancer, a disease with a high unmet need, and are the first positive Phase III data for a PARP inhibitor beyond ovarian cancer. This is highly encouraging for the development of our broad portfolio which aims to treat multiple cancers by targeting DNA damage response pathways.”

Initial findings from the OlympiAD study indicate that the safety profile of LYNPARZA was consistent with previous studies.

A full evaluation of the OlympiAD data is ongoing and the results will be submitted for presentation at a forthcoming medical meeting. AstraZeneca will be working with regulatory authorities to make LYNPARZA available to patients with this type of breast cancer.

LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.1,2 LYNPARZA capsules (400mg twice daily) are currently approved in the US as a monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2

Important Safety Information About LYNPARZA™ (olaparib)

WARNINGS AND PRECAUTIONS

There are no contraindications for LYNPARZA.

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1% of patients treated with LYNPARZA, and the majority of those reports were fatal. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. In a randomized placebo-controlled trial, MDS/AML occurred in 2% of patients treated with LYNPARZA. All of these patients had previous chemotherapy with platinum agents and/or other DNA damaging agents, including radiotherapy, and some of these patients also had a history of previous cancer or of bone marrow dysplasia.

Monitor patients for hematological toxicity at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE 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 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, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation. Discontinue if pneumonitis is confirmed.

Embryo-Fetal Toxicity: LYNPARZA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy by using effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

ADVERSE REACTIONS

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia (34%), nausea (75%), fatigue (including asthenia) (68%), vomiting (43%), diarrhea (31%), dysgeusia (21%), dyspepsia (25%), headache (25%), decreased appetite (25%), nasopharyngitis/pharyngitis/URI (43%), cough (21%), arthralgia/musculoskeletal pain (32%), myalgia (25%), back pain (25%), dermatitis/rash (25%), and abdominal pain/discomfort (47%).

Common lab abnormalities (Grades 1-4) included anemia (90%), neutropenia (32%), thrombocytopenia (30%), lymphopenia (56%), mean corpuscular volume elevation (85%), and increase in creatinine (30%).

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 and moderate CYP3A inhibitors. If the strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit and Seville oranges during LYNPARZA treatment.

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

USE IN SPECIFIC POPULATIONS

Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from LYNPARZA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Renal Impairment: No dosage adjustment is necessary for patients with mild renal impairment (CLcr 51-80 mL/min). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose to 300 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Hepatic Impairment: There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 times upper limit of normal).

About Metastatic Breast Cancer

Approximately one in eight women are diagnosed with breast cancer in the United States.3 Of these patients, approximately one-third are either diagnosed with or progress to the metastatic stage of the disease.4 Despite treatment options increasing during the past three decades, there is currently no cure for patients diagnosed with metastatic breast cancer.5,6 Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving or at least maintaining, a patient’s quality of life.4

About OlympiAD

OlympiAD is a randomized, multi-center Phase III trial assessing the efficacy and safety of LYNPARZA (300mg twice daily) to ‘physician’s choice’ chemotherapy (capecitabine, vinorelbine, eribulin) in 302 patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations, which are predicted or suspected to be deleterious. The international study was conducted in 19 countries from across Europe, Asia, North America and South America.1

The primary endpoint of the trial was progression-free survival (PFS) as measured by a Blinded Independent Central Review (BICR). Secondary endpoints include overall survival (OS), time to second progression or death (PFS2), objective response rate (ORR), and effect on health-related quality of life (HRQoL).1

About Germline BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.7

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall. Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts.7

About LYNPARZATM (olaparib)

LYNPARZATM (olaparib) was the first FDA-approved oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumor DNA damage response (DDR) pathway deficiencies to preferentially kill cancer cells.8-10 Specifically, in vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.2 LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DNA damage response (DDR) mechanisms in cancer cells.8-10

LYNPARZATM is currently being investigated in another separate non-metastatic breast cancer Phase III study called OlympiA.11

LYNPARZA tablets are currently being investigated in monotherapy and in combinations in a range of tumor types including ovarian, prostate, and pancreatic cancer.12-15 LYNPARZA tablets are an investigational formulation and are not FDA-approved for any use.1,10

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that have the potential to transform patients’ lives and the Company’s future. With at least 6 new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advancing Oncology as one of AstraZeneca’s six Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms -- immuno-oncology, the genetic drivers of cancer 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.

About 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 main therapy areas - Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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. National Institutes of Health. Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations (OlympiAD). Available Online. Accessed February 2017.
  2. LYNPARZA (olaparib) Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
  3. National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer. Available Online. Accessed February 2017.
  4. O’Shaughnessy J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. The Oncologist 2005;10(3):20–29.
  5. American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Available Online. Accessed February 2017.
  6. American Cancer Society. Managing Cancer as a Chronic Illness. Available Online. Accessed February 2017.
  7. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed February 2017.
  8. Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Available Online. Accessed February 2017.
  9. O’Connor M. ‘Targeting The DNA Damage Response In Cancer’ (2015) Mol Cell.60.547-560. Accessed February 2017.
  10. Tutt A N J, Lord C J, McCabe N. Exploiting the DNA Repair Defect in BRCA Mutant Cells in the Design of New Therapeutic Strategies for Cancer. Cold Spring Harb Symp Quant Niol. 2005;70:139-48.
  11. National Institutes of Health. Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA). Available Online. Accessed February 2017.
  12. National Institutes of Health. Olaparib Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy (SOLO-1). Available Online. Accessed February 2017.
  13. National Institutes of Health. Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. Available Online. Accessed February 2017.
  14. National Institutes of Health. Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy (POLO). Available Online. Accessed February 2017.
  15. National Institutes of Health. Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer. Available Online. Accessed February 2017.


Source: AstraZeneca

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