U.S. FDA Approves LYNPARZA (olaparib) in Germline BRCA-Mutated Metastatic Breast Cancer

Business Wire 12-Jan-2018 12:45 PM

LYNPARZA is the Only PARP Inhibitor Approved for Use Beyond Ovarian Cancer

LYNPARZA Reduced Risk of Disease Progression or Death by 42 Percent Compared to Standard of Care Chemotherapy

KENILWORTH, N.J.--(BUSINESS WIRE)-- AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. 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.

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 outside of 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.

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, This additional approval for LYNPARZA, based on the compelling data from the OlympiAD trial, represents an important advance for women with germline BRCA-mutated HER2-negative metastatic breast cancer, 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 3 OlympiAD trial, which investigated LYNPARZA (olaparib) versus physicians 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 percent (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 percent (95% CI 44-60), double the response rate for those in the chemotherapy arm (n=66), which was 23 percent (95% CI 13-35). Additionally, patients experienced a confirmed complete response rate of 7.8 percent for LYNPARZA compared to 1.5 percent 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.

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, said Dr. Susan M. Domchek, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, and national leader on the OlympiAD trials. While there is currently no cure for metastatic breast cancer, todays 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 U.S. living with metastatic breast cancer who have an inherited BRCA mutation, todays 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 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 percent compared to the chemotherapy arm, which was 8 percent. Please see Important Safety Information below.

This is the third indication approved for LYNPARZA (olaparib) in the U.S., where it has been used to treat nearly4,000 advanced ovarian cancer patients. 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.

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. 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.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 (olaparib)and to not donate sperm during this time.

Adverse ReactionsMaintenance 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 ReactionsAdvanced 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 ReactionsgBRCAm, 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 (olaparib) 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 (olaparib)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.

NOTES TO EDITORS

About OlympiAD

OlympiAD is a randomized, open-label, multicenter phase 3 trial assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to physicians choice of chemotherapy in 302 patients with HER2-negative metastatic breast cancer with gBRCA1 or gBRCA2 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.

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated breast cancer, which was HR+ or triple negative, and received LYNPARZA (olaparib) 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.

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

About Metastatic Breast Cancer

Three main receptors drive tumor growth in breast cancer: Progesterone Receptors (PR), estrogen receptors (ER) and HER2 receptors. A patients breast cancer will test either negative or positive for these three receptors. If a tumor tests positive for PR and/or ER, it is considered HR+. If a tumor tests negative for all three receptors, it is considered triple negative.

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.

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 percent of patients survive five years after diagnosis. Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving, or at least maintaining, a patients quality of life.

It is estimated that in 2018, there will be approximately 155,000 women in the U.S. living with MBC, and this number is projected to increase to approximately 160,000 by the year 2020.

About Germline BRCA Mutations

BRCA1 and BRCA2are 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.

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. 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.

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 worlds 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 PD-L1/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.

Mercks Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey from lab to clinic to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the worlds most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimers disease and infectious diseases including HIV and Ebola. For more information, visitwww.merck.comandconnect with us on Twitter,Facebook,Instagram,YouTube andLinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the company) includes forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the companys management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the companys ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the companys patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the companys 2016 Annual Report on Form 10-K and the companys other filings with the Securities and Exchange Commission (SEC) available at the SECs Internet site (www.sec.gov).

Please see complete Prescribing Information for LYNPARZA (olaparib), including Patient Information (Medication Guide)

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View source version on businesswire.com: http://www.businesswire.com/news/home/20180112005486/en/

Merck Media:Pamela Eisele, 267-305-3558Courtney Ronaldo, 908-442-5695orInvestors:Teri Loxam, 908-740-1986Michael DeCarbo, 908-740-1807

Source: Merck

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