LYNPARZA® (olaparib) Receives Positive EU CHMP Opinion in Platinum-Sensitive Relapsed Ovarian Cancer

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February 23, 2018 7:30 am ET

AstraZeneca and Merck’s New LYNPARZA Tablet Formulation Recommended for Maintenance Therapy Regardless of BRCA Status

AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United
States and Canada, today announced that the Committee for Medicinal
Products for Human Use (CHMP) of the European Medicines Agency has
adopted a positive opinion, recommending a marketing authorization of
LYNPARZA® (olaparib) tablets (300 mg twice daily) for use as
a maintenance therapy for patients with platinum-sensitive relapsed high
grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer
who are in complete response or partial response to platinum-based
chemotherapy. LYNPARZA is recommended for treatment in this
setting regardless of patients’ BRCA mutation status.

Sean Bohen, executive vice president, global medicines development and
chief medical officer at AstraZeneca, said, “The data show that LYNPARZA
provides long-term disease control, delaying the need for further
chemotherapy for this broader group of women with platinum-sensitive
relapsed ovarian cancer, irrespective of their BRCA status. It
also offers a well-characterized safety and tolerability profile, which
is critical to help enable patients to stay on treatment.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“We welcome this positive opinion based upon data which indicate the
potential impact for LYNPARZA as maintenance therapy for women with
platinum-sensitive relapsed ovarian cancer. We look forward to our
continued work with AstraZeneca to bring LYNPARZA to patients in the EU.”

The CHMP recommendation is based on two randomized trials, SOLO-2 and
Study 19, which showed LYNPARZA (olaparib) reduced the risk of disease
progression or death for platinum-sensitive relapsed patients compared
to placebo.

Summary of key efficacy results from randomized trials:

Analysis   SOLO-2

[germline BRCA-mutated]

n=295

  Study 19

[platinum-sensitive relapsed]

n=265

LYNPARZA Placebo LYNPARZA Placebo
Reduction in the risk of disease progression or death (PFS) 70%

(HR 0.30 [95% CI, 0.22-0.41], P<0.0001; median 19.1 vs 5.5 months)*

65%

(HR 0.35 [95% CI, 0.25-0.49], P<0.0001; median 8.4 vs 4.8 months)*

Reduction in the risk of death (OS) Data not yet mature 27% (HR 0.73 [95% CI, 0.55-0.95], P=0.02138**;

median 29.8 vs 27.8 months)***

PFS = progression-free survival; OS = overall survival

* By investigator-assessed analysis

** P-value considered nominal as criterion for statistical significance
(P<0.0095) not met

*** Not adjusted for treatment crossover

The most frequently observed adverse reactions across clinical trials in
patients receiving LYNPARZA monotherapy (≥10%) were nausea, vomiting,
diarrhea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite,
dizziness and anemia.

LYNPARZA, the first poly ADP-ribose polymerase (PARP) inhibitor
approved, was initially licensed as a capsule formulation. The new
tablet formulation will reduce dosing from eight capsules twice daily to
two tablets twice daily.

LYNPARZA is available in nearly 60 countries and has treated more than
20,000 patients globally. It has the broadest clinical development
program of any PARP inhibitor, and AstraZeneca and Merck are working
together to bring LYNPARZA to more patients across multiple cancers. In
January 2018, LYNPARZA was approved by the U.S. Food and Drug
Administration for use in metastatic breast cancer, becoming the first
PARP inhibitor licensed beyond ovarian cancer.

Indications for LYNPARZA (olaparib) in the U.S.

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.

Important Safety Information for LYNPARZA

®


(olaparib)

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
(olaparib) 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 (olaparib) 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 (olaparib). 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.

NOTES TO EDITORS

About Ovarian Cancer in Europe

Among women in Europe, ovarian cancer is the fifth most common cancer
and the sixth leading cause of cancer death. The five-year survival rate
for ovarian cancer in Europe is 38 percent. In 2012, there were nearly
65,000 new cases diagnosed and around 42,700 deaths. As there is no cure
for relapsed ovarian cancer, the primary aim of treatment is to slow
progression of the disease for as long as possible and improve or
maintain the patient’s quality of life.

About SOLO-2

SOLO-2 was a phase 3, randomized, double-blinded, multicenter trial
designed to determine the efficacy of LYNPARZA (olaparib) tablets
compared to placebo as maintenance monotherapy in patients with
platinum-sensitive relapsed or recurrent germline BRCA-mutated
ovarian, fallopian tube and primary peritoneal cancer. The trial,
conducted in collaboration with the European Network for Gynaecological
Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National
pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomized 295
patients with documented germline BRCA1 or BRCA2 mutations
who had received at least two prior lines of platinum-based chemotherapy
and were in complete or partial response. Eligible patients were
randomized to receive 300mg LYNPARZA tablets twice daily or placebo
tablets twice daily.

About Study 19

Study 19 was a phase 2, randomized, double-blinded, placebo-controlled,
multicenter trial, which evaluated the efficacy and safety of LYNPARZA
compared with placebo in relapsed, high-grade serous ovarian cancer
patients. The trial randomized 265 patients regardless of BRCA
mutation status and who had completed at least two courses of
platinum-based chemotherapy and their most recent treatment regimen.
Eligible patients were randomized to receive LYNPARZA maintenance
monotherapy at a dose of 400mg per day or matching placebo.

About LYNPARZA

®

(olaparib)

LYNPARZA is a first in-class poly ADP-ribose polymerase (PARP) inhibitor
and the first targeted treatment to potentially exploit tumor DNA damage
response (DDR)-pathway deficiencies 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.

LYNPARZA is being investigated in a range of DDR-deficient tumor types.

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 (olaparib), 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
PD-L1/PD-1 inhibitors for a range of tumor types. Working together, the
companies will 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.

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Please see complete 

Prescribing
Information


for LYNPARZA (olaparib), including Patient
Information (Medication Guide)



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