U.S. FDA Accepts Regulatory Submission for LYNPARZA® (olaparib) in Metastatic Breast Cancer and Grants Priority Review


October 18, 2017 5:55 am ET

LYNPARZA Has the Potential to Offer a New Treatment Option for Patients with Germline BRCA-Mutated, HER2-Negative Metastatic Breast Cancer

Regulatory Submission Acceptance Is the First for a PARP Inhibitor Beyond Ovarian Cancer

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 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 (gBRCA),
HER2-negative metastatic breast cancer (MBC) who have been previously
treated with chemotherapy either 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 U.S. The sNDA is based on the positive results
from the phase 3 OlympiAD trial published in the New England Journal
of Medicine

LYNPARZA was first approved under the FDA’s Accelerated Approval
program in December 2014, as a capsule formulation, making it the first
PARP inhibitor ever approved. Since then, more than 3,000 advanced
ovarian cancer patients have been treated with LYNPARZA. LYNPARZA
tablets are currently being tested in a range of tumor types, including
breast, prostate and pancreatic cancers.

LYNPARZA tablets are currently approved in the U.S. 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.
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.



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.


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 (olaparib) 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


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,
be aware of a potential for decreased efficacy of LYNPARZA.


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 


, including Patient Information (Medication Guide)

About OlympiAD

OlympiAD is a randomized, open-label, multicenter phase 3 trial
assessing the efficacy and safety of LYNPARZA (olaparib) 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 from across Europe,
Asia, North America and South America.




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. 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

LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio
of compounds targeting DDR mechanisms in cancer cells.

About Metastatic Breast Cancer

Approximately one in eight women are diagnosed with breast cancer in the
U.S. Of these patients, approximately one-third are either
diagnosed with or progress to the metastatic stage of the disease.
Despite treatment options increasing during the past three decades,
there is currently no cure for patients diagnosed with metastatic breast
cancer. 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.

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.

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 (olaparib), 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 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.

Merck’s 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 world’s 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, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect
with us on TwitterFacebookInstagramYouTube
and LinkedIn.

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 company’s 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 company’s 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 company’s 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 company’s 2016 Annual Report on Form 10-K
and the company’s other filings with the Securities and Exchange
Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Pamela Eisele, 267-305-3558
Courtney Ronaldo, 908-740-6132
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898

Unsubscribe from email alerts