WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US and Canada) today announced that the US Food and Drug Administration (FDA) has accepted and granted priority review for a supplemental New Drug Application (sNDA) for the use of LYNPARZA® (olaparib) tablets in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic settings. A Prescription Drug User Fee Act (PDUFA) date is set for the first quarter of 2018.
This is the first submission for a poly ADP-ribose polymerase (PARP) inhibitor outside ovarian cancer and the third indication submission for LYNPARZA in the US. The sNDA is based on the positive results from the Phase III OlympiAD trial published in the New England Journal of Medicine.1
LYNPARZA was first approved in December 2014 as a capsule formulation, making it the first ever PARP inhibitor to be approved.2Since then, LYNPARZA has been used to treat more than 3,000 advanced ovarian cancer patients.3 LYNPARZA tablets are currently being tested in a range of tumor types, including breast, prostate, and pancreatic cancers.4,5,6
LYNPARZA tablets are currently approved in the US as a maintenance treatment for adult patients with recurrent, epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.7,8 The medicine is also indicated for use in adult patients with deleterious or suspected deleterious gBRCA-mutated advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy; patients for this indication are selected for therapy based on an FDA-approved companion diagnostic.7
IMPORTANT SAFETY INFORMATION
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.
WARNINGS AND PRECAUTIONS
There are no contraindications for LYNPARZA.
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 of these patients also had a history of previous cancer or bone marrow dysplasia.
Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts 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 treatment with LYNPARZA 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 after receiving the final dose.
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 after 3 or more lines of chemotherapy (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%).
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, be aware of a potential for decreased efficacy of LYNPARZA.
USE IN SPECIFIC POPULATIONS
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.
Lactation: No data are available regarding the presence of olaparib in human milk, the effects on the breastfed infant, or the effects 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.
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).
Please see complete Prescribing Information, including Patient Information (Medication Guide)
NOTES TO EDITORS
OlympiAD is a randomized, open-label, multicenter Phase III trial assessing the efficacy and safety of LYNPARZA tablets (300mg twice daily) compared 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 trial was conducted in 19 countries across Europe, Asia, North America and South America.1,9
About LYNPARZA® (olaparib)
LYNPARZA was the first FDA-approved oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumor DNA damage response (DDR) pathway deficiencies to potentially kill cancer cells.2,10,11 Specifically, in vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.7
LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.2,10,11
About Metastatic Breast Cancer
Approximately one in eight women are diagnosed with breast cancer in the US.12 Of these patients, approximately one-third are either diagnosed with or progress to the metastatic stage of the disease.13 Despite treatment options increasing during the past three decades, there is currently no cure for patients diagnosed with metastatic breast cancer.14,15 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.13
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.16
About the AstraZeneca and Merck Strategic Oncology Collaboration
On July 27, 2017, AstraZeneca and Merck & Co., Inc., announced a global strategic oncology collaboration to co-develop and co-commercialize AstraZeneca’s LYNPARZA, the world’s first and leading 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 and is aimed at maximizing the potential of LYNPARZA to become the preferred backbone of combination therapies. 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.
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.
|1.||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|
|2.||US Food and Drug Administration. FDA approves Lynparza to treat advanced ovarian cancer. Accessed October 2017.|
|3.||Data on File, US-11033, AstraZeneca Pharmaceuticals LP.|
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 October 2017.
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 October 2017.
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 October 2017.
|7.||LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.|
|8.||Ledermann J, Harter P, Gourley M, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-1392.|
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 October 2017.
|10.||O’Connor M. Targeting the DNA damage response in cancer. Mol Cell. 2015;60:547-560. Accessed October 2017.|
|11.||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.|
National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer. Available Online. Accessed October 2017.
|13.||O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(3):20–29.|
American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Available Online. Accessed October 2017.
American Cancer Society. Managing Cancer as a Chronic Illness. Available Online. Accessed October 2017.
National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed October 2017.