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 ofdisease
progression or death(PFS)
Reduction in the risk ofdeath (OS)
SOLO-2
[gBRCAm]
n=295
LYNPARZA
70% (HR 0.30 [95% CI, 0.22-0.41],
P<0.0001; median 19.1vs 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 8.4vs 4.8 months)
27% (HR 0.73 [95% CI,0.55-0.95]; median
29.8 vs27.8 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
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Please see complete Prescribing Information
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(Medication Guide)
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