LYNPARZA® (olaparib) Approved by US FDA in Germline BRCA-Mutated Metastatic Breast Cancer

LYNPARZA is the first and only PARP inhibitor approved for use beyond ovarian cancer

LYNPARZA reduced the risk of disease progression or death by 42% compared to standard of care chemotherapy

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca and Merck (Merck: known as MSD outside the US and Canada) today announced that the US Food and Drug Administration (FDA) has approved LYNPARZA^® (olaparib), for use in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor positive (HR+) breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Patients are selected for therapy based on an FDA-approved companion diagnostic from Myriad Genetics.¹

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit, AstraZeneca, said: “This new approval for LYNPARZA makes it the first and only PARP inhibitor approved in metastatic breast cancer, and the only PARP inhibitor approved beyond ovarian cancer. This is significant for breast cancer patients, as the identification of BRCA status, in addition to hormone receptor and HER2 status, becomes a potentially critical step in the management of their disease.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “This additional approval for LYNPARZA represents an important advance for women with HER2-negative metastatic breast cancer with a germline BRCA mutation, which is a difficult-to-treat cancer. Moreover, this approval adds further impetus to our important collaboration with AstraZeneca in developing cancer therapies.”

The approval was based on data from the randomized, open-label, Phase III OlympiAD trial, which investigated LYNPARZA versus physician’s choice of chemotherapy (capecitabine, eribulin or vinorelbine). In the trial, LYNPARZA significantly prolonged progression-free survival (PFS) compared with chemotherapy, and reduced the risk of disease progression or death by 42% (HR 0.58; 95% CI 0.43-0.80; P=0.0009 median 7.0 vs 4.2 months). Patients with measurable disease taking LYNPARZA (n=167) experienced an objective response rate of 52% (95% CI 44-60), double the response rate for those in the chemotherapy arm (n=66) which was 23% (95% CI 13-35). Additionally, patients experienced a confirmed complete response rate of 7.8% for LYNPARZA compared to 1.5% for the chemotherapy arm. The data from the OlympiAD trial can be found in the June 2017 issue of the New England Journal of Medicine.^1,2

Dr. Susan M. Domchek, Executive Director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, and a national leader on the OlympiAD trials said: “Patients diagnosed with BRCA-related metastatic breast cancer are often younger than other breast cancer patients, and their disease is often much more aggressive and difficult to treat. While there is currently no cure for metastatic breast cancer, today’s approval offers a new, targeted option that may help to delay disease progression for these patients.”

Sue Friedman, Executive Director and founder of the nonprofit organization, Facing Our Risk of Cancer Empowered (FORCE), said: “We know there are limited treatment options for patients with metastatic breast cancer. For the portion of the 155,000 women in the US living with metastatic breast cancer who have an inherited BRCA mutation, today’s news is encouraging. By undergoing genetic testing for BRCA mutations, we can gain critical information that will inform personalized treatment options specifically for women with this mutation.”

The most common adverse reactions (≥20%) in the OlympiAD trial of patients who received LYNPARZA were nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%) and headache (20%). The percentage of patients who discontinued treatment in the LYNPARZA arm was 5% compared to the chemotherapy arm which was 8%. Please see Important Safety Information below.

This is the third indication approved for LYNPARZA in the US, where it has been used to treat nearly 4,000 advanced ovarian cancer patients.^1,3 LYNPARZA has a broad clinical development program, and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple settings, including breast, ovarian, prostate and pancreatic cancers.^4-7

Sustainable and Ongoing Externalization Revenue

Under the oncology collaboration with Merck, announced in July 2017, AstraZeneca is potentially eligible for more than $6 billion of future Sustainable and Ongoing Externalization Revenue in the form of sales-related and approval-related payments in addition to option payments until 2019. Following this new approval for LYNPARZA, AstraZeneca will receive $70 million in Sustainable and Ongoing Externalization Revenue.

IMPORTANT SAFETY INFORMATION

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.

ADVERSE REACTIONS—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: 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%), and decreased appetite (21%).

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 gBRCAm ovarian cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including 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 gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-negative 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%).

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 hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.
Renal Impairment: No adjustment to the starting dose is necessary in 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 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

DOSING AND ADMINISTRATION
To avoid substitution errors and overdose, do not substitute LYNPARZA tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.

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

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.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) 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.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously 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 treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information, including Patient Information (Medication Guide).

– ENDS –

NOTES TO EDITORS

About OlympiAD
OlympiAD is a randomized, open-label, multicenter Phase III trial assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to physician’s choice of chemotherapy in 302 patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations, which are confirmed or suspected to be deleterious. The international trial was conducted in 19 countries across Europe, Asia, North America and South America.^2,8

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated breast cancer, which was HR+ or triple negative, and received LYNPARZA for metastatic disease. Approximately half of the patients in the LYNPARZA and chemotherapy arm of the trial were HR+ (n=152), and approximately half were triple negative (n=150). Among the 205 patients treated with LYNPARZA, the median age was 44 years (range: 22 to 76). Before enrollment, patients had prior treatment with an anthracycline (unless contraindicated) and a taxane chemotherapy either in the neoadjuvant, adjuvant or metastatic setting and no more than two prior lines of chemotherapy for metastatic disease. HR+ patients had received at least one endocrine medicine or were not eligible for endocrine medicines. Prior treatments with endocrine medicines were not counted as prior lines of chemotherapy.^2,8

The primary endpoint of the trial was PFS as measured by a Blinded Independent Central Review.^2,8 Secondary endpoints included overall survival, time to second progression or death, objective response rate, and effect on health-related quality of life.^2,8

About Metastatic Breast Cancer (MBC)
Three main receptors drive tumor growth in breast cancer: Progesterone receptors (PR), estrogen receptors (ER) and HER2 receptors.^9,10 A patient’s breast cancer will test either negative or positive for these three receptors.^9,10 If a tumor tests positive for PR and/or ER, it is considered HR+.⁹ If a tumor tests negative for all three receptors, it is considered triple negative.⁹

MBC is the most advanced stage of breast cancer (Stage IV), and occurs when cancer cells have spread beyond the initial tumor site to other parts of the body outside of the breast.^11,12

Despite the increase in treatment options during the past three decades, there is currently no cure for patients diagnosed with MBC and only 26.9% of patients survive five years after diagnosis.^13-15 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.¹⁶

It is estimated that in 2018, there will be approximately 155,000 women in the US living with MBC, and this number is projected to increase to approximately 160,000 by the year 2020.¹⁷

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, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.¹⁸

About LYNPARZA^® (olaparib)
LYNPARZA is the first FDA-approved oral poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells.^19-21 Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.¹

LYNPARZA is being investigated in a range of DDR-deficient tumor types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.^19-21

About the AstraZeneca and Merck Strategic Oncology Collaboration
In July 2017, AstraZeneca and Merck (known as MSD outside the United States and Canada) announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PDL-1/PD-1 inhibitors for a range of tumor types. Working together, the companies will jointly develop LYNPARZA and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About 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 at least six new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five 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, 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.

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 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.

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References

1. LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
2. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017; DOI: 10.1056/NEJMoa1706450
3. Data on File, US-16345, AstraZeneca Pharmaceuticals LP.
4. US 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 January 2018.
5. National Institutes of Health. Olaparib Maintenance Monotherapy in Patients with BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy. (SOLO-1) Available Online. Accessed January 2018.
6. US 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 January 2018.
7. US National Institutes of Health. Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study). Available Online. Accessed January 2018.
8. US 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 January 2018.
9. American Cancer Society. Breast Cancer Hormone Receptor Status. Available Online. Accessed January 2018.
10. American Cancer Society. Breast Cancer HER2 Status. Available Online. Accessed January 2018.
11. Cleveland Clinic. Diseases and Conditions: Breast Cancer. Available Online. Last Updated September 5, 2013. Accessed January 2018.
12. Mayo Clinic. Breast Cancer Diagnosis. Available Online. Last Updated August 16, 2016. Accessed January 2018.
13. American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Available Online. Accessed January 2018.
14. American Cancer Society. Managing Cancer as a Chronic Illness. Available Online. Accessed January 2018
15. National Cancer Institute. SEER Cancer Fact Sheet: Female Breast Cancer. Available Online. Accessed January 2018.
16. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(3):20–29.
17. CancerMPact.Khapps.com: ONC-Prevalence of Metastatic Breast Cancer in Women 2014-2020. Accessed January 2018.
18. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed January 2018.
19. US Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Accessed January 2018.
20. O’Connor M. Targeting the DNA damage response in cancer. Mol Cell. 2015; 60:547-560. Accessed January 2018.
21. Tutt ANJ, Lord CJ, 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 Biol. 2005; 70:139-148.

US-14448 Last Updated 1/18