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LYNPARZA® (olaparib) Receives Approval in Japan for the Treatment of Advanced Ovarian Cancer

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LYNPARZA is the First PARP Inhibitor Approved in Japan

LYNPARZA Tablets Approved as Maintenance Treatment for Women with
Platinum-Sensitive Relapsed Ovarian Cancer Regardless of BRCA Mutation
Status

AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States
and Canada, today announced that the Japanese Ministry of Health, Labour
and Welfare has approved LYNPARZA® (olaparib) tablets
(300mg twice daily) for use as a maintenance therapy for patients with
platinum-sensitive relapsed ovarian cancer, regardless of their BRCA
mutation status, who responded to their last platinum-based
chemotherapy. LYNPARZA is the first poly ADP-ribose polymerase (PARP)
inhibitor to be approved in Japan.

Dave Fredrickson, executive vice president, head of the oncology
business unit at AstraZeneca, said, "We are proud to bring this
important first-in-class treatment to women with platinum-sensitive
relapsed ovarian cancer in Japan who currently have very few treatment
options. The trials show that with LYNPARZA maintenance therapy, women
with ovarian cancer can live longer without their disease worsening and
LYNPARZA is well tolerated."

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
"Today's decision is significant for LYNPARZA and, more importantly, for
Japanese patients living with advanced ovarian cancer. Our global
collaboration with AstraZeneca further reinforces how our joint efforts
can advance science for patients and we look forward to working together
to explore the potential of LYNPARZA across multiple tumor types."

The approval was granted on the basis of two randomized trials of
LYNPARZA (olaparib) maintenance therapy for platinum-sensitive relapsed
ovarian cancer, SOLO-2 and Study 19.

Table 1. Summary of key efficacy results from randomized trials:

Analysis      

Reduction in the risk of
disease progression or death
(PFS)

     

Reduction in the risk of
death (OS)

SOLO-2

[gBRCAm]

n=295

      LYNPARZA      

70% (HR 0.30 [95% CI, 0.22-
0.41], P<0.0001; median 19.1
vs
5.5 months by investigator-
assessed analysis)

      Data not yet mature
      Placebo            
Study 19

[PSR OC*]

n=265

LYNPARZA

65% (HR 0.35 [95% CI, 0.25-
0.49], P<0.0001; median 8.4
vs
4.8 months)

27% (HR 0.73 [95% CI,
0.55-0.95]; median 29.8 vs
27.8
months)

      Placebo            

*PSR = Platinum-sensitive recurrent ovarian cancer

 

In SOLO-2, the most common adverse drug reactions (≥20%) of any grade
reported in patients in the LYNPARZA arm were nausea (66.7%), anemia
(39.0%), fatigue (29.7%), vomiting (25.6%), asthenia (24.1%) and
dysgeusia (23.1%).

In Study 19, the most common adverse drug reactions (≥20%) of any grade
reported in patients in the LYNPARZA arm were nausea (64.0%), fatigue
(43.4%) and vomiting (21.3%).

LYNPARZA is also currently under review for use in unresectable or
recurrent BRCA-mutated HER2-negative breast cancer in Japan, with
a decision expected in the second half of 2018 based upon a priority
review.

About Ovarian Cancer in Japan

Worldwide, ovarian cancer is the seventh most-commonly diagnosed cancer
and the eighth most-common cause of cancer deaths in women. In Japan,
more than 9,000 women are diagnosed with ovarian cancer every year and
the five-year survival rate is 58 percent, the lowest among all
gynecological cancers. In 2012, 4,758 women with ovarian cancer died,
which represents one out of every two patients. 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 improving or
maintaining a patient's quality of life.

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. 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 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 (olaparib) 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
(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.

NOTES TO EDITORS

About SOLO-2

SOLO-2 was a phase 3, randomized, double-blinded, multicenter trial
designed to determine the efficacy of LYNPARZA tablets as a maintenance
monotherapy compared with placebo, in patients with platinum-sensitive,
relapsed or recurrent gBRCA-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 (olaparib)
tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a phase II, 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 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
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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