LYNPARZA® (olaparib) Approved by FDA for First-Line Maintenance Therapy in BRCA-Mutated Advanced Ovarian Cancer

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December 19, 2018 3:16 pm ET

AstraZeneca and Merck’s LYNPARZA Reduced the Risk of Disease Progression or Death by 70 Percent Compared to Placebo Following Response to Platinum-Based Chemotherapy

First PARP Inhibitor Approved in First-Line Maintenance for BRCAm Advanced Ovarian Cancer

KENILWORTH, N.J.–(BUSINESS WIRE)–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 approved LYNPARZA for use as maintenance treatment of adult
patients with deleterious or suspected deleterious germline or somatic BRCA-mutated
(gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian
tube or primary peritoneal cancer who are in complete or partial
response to first-line platinum-based chemotherapy. Patients with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal cancer
are selected for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.

This is the first regulatory approval for a PARP inhibitor in the
first-line maintenance setting for BRCAm advanced ovarian cancer.
The approval was based on positive results from the pivotal Phase 3
SOLO-1 trial in which LYNPARZA reduced the risk of disease progression
or death by 70 percent in patients with BRCAm advanced ovarian
cancer who were in complete or partial response to platinum-based
chemotherapy (HR=0.30 [95% CI, 0.23-0.41]; p<0.0001) compared to placebo.

Dave Fredrickson, executive vice president, head of the oncology
business unit, AstraZeneca, said, “Women with ovarian cancer are often
first diagnosed with advanced disease, which is associated with poor
outcomes. In SOLO-1, LYNPARZA in the first-line maintenance setting
reduced the risk of disease progression or death by 70 percent for
patients with BRCAm advanced ovarian cancer. Today’s approval is
a critical advancement and brings us closer to our goal of helping these
patients achieve long-term remission.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“The expanded approval of LYNPARZA based upon the SOLO-1 trial has the
potential to change medical practice and reinforces the importance of
knowing a woman’s BRCA status at diagnosis. We continue to work
in collaboration with AstraZeneca on our overall goal of improving
outcomes for patients.”

In the SOLO-1 trial, with median 41 months of follow-up, the median
progression-free survival (PFS) for patients treated with LYNPARZA
(n=260) was not reached compared to 13.8 months for patients treated
with placebo (n=131). In the trial, 60 percent of patients receiving
LYNPARZA remained progression-free at three years, compared to 27
percent of patients receiving placebo. The data from the SOLO-1 trial
can be found in the October 21, 2018, online issue of the New England
Journal of Medicine
.

The most common adverse reactions (ARs) in ≥10 percent of patients
taking LYNPARZA in the SOLO-1 trial were nausea (77%), fatigue (67%),
abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%),
constipation (28%), upper respiratory tract
infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%),
dizziness (20%), decreased appetite (20%), neutropenia (17%), dyspepsia
(17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia
(11%), and stomatitis (11%). The most common Grade ≥3 ARs were anemia
(21%) and neutropenia (6%). Dose interruptions due to an AR of any grade
occurred in 52 percent of patients receiving LYNPARZA and 17 percent of
those receiving placebo. Seventy-two percent (n=186) of patients on
LYNPARZA remained on the recommended starting dose of 300 mg (two 150 mg
tablets twice daily) versus 97 percent (n=126) on placebo. Adverse
reactions that most frequently led to discontinuation in patients
treated with LYNPARZA were fatigue (3.1%), anemia (2.3%), and nausea
(2.3%). Eighty-eight percent (n=230) of patients on LYNPARZA continued
treatment without an AR-related discontinuation versus 98 percent
(n=127) on placebo.

Kathleen Moore, co-principal investigator of the SOLO-1 trial and
associate director for clinical research, Stephenson Cancer Center at
The University of Oklahoma, Oklahoma City, Oklahoma, said, “SOLO-1 is
truly a landmark trial in gynecologic cancer. This approval will likely
change the way we treat women with BRCA-mutated advanced ovarian
cancer. The ability to offer this important first-line maintenance
treatment option to eligible patients may slow down or even stop the
natural course of disease progression.”

AstraZeneca and Merck are exploring additional trials in advanced
ovarian cancer, including the ongoing GINECO/ENGOTov25 Phase 3 trial,
PAOLA-1. This trial is testing the effect of LYNPARZA in combination
with bevacizumab as a maintenance treatment for patients with
newly-diagnosed, advanced ovarian cancer, regardless of their BRCA
status. Results are expected during the second half of 2019.

IMPORTANT SAFETY INFORMATION

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
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—First-Line Maintenance BRCAm Advanced
Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in
clinical trials of LYNPARZA in the first-line maintenance setting
for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain
(45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%),
upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis
(28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%),
neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI
(13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in
clinical trials of LYNPARZA in the first-line maintenance setting for
SOLO-1
were: decrease in hemoglobin (87%), increase in mean
corpuscular volume (87%), decrease in leukocytes (70%), decrease in
lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease
in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA in the maintenance setting for SOLO-2
were: 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%), decreased appetite
(21%), and dyspepsia (20%).

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/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%), mean corpuscular
volume elevation (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 metastatic 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. 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 or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients with
severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No adjustment to the starting dose is necessary
in patients with mild renal impairment (CLcr=51-80 mL/min) but patients
should be monitored closely for toxicity. 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).

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or
suspected deleterious germline or somatic BRCA-mutated (gBRCAm
or sBRCAm) advanced epithelial ovarian, fallopian tube or
primary peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal cancer
for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

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.

Advanced gBRCAm ovarian cancer

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.

gBRCAm, HER2-negative metastatic breast cancer

In patients with deleterious or suspected deleterious gBRCAm, human
epidermal growth factor receptor 2 (HER2)-negative metastatic breast
cancer who have 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 therapy.
Select patients for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.

Please

click
here for complete Prescribing Information, including Patient Information
(Medication Guide)


.

Financial Considerations

Under the oncology collaboration with AstraZeneca and following this new
approval for LYNPARZA, AstraZeneca will receive $70 million as ongoing
externalization revenue.

About SOLO-1

SOLO-1 is a Phase 3, randomized, double-blinded, placebo-controlled,
multi-center trial to evaluate the efficacy and safety of LYNPARZA
tablets (300 mg twice daily) as maintenance monotherapy compared with
placebo in patients with BRCAm advanced ovarian cancer following
first-line platinum-based chemotherapy. The trial randomized 391
patients with a deleterious or suspected deleterious germline or somatic BRCA1
or BRCA2 mutation who were in clinical complete or partial
response following platinum-based chemotherapy. Patients were randomized
(2:1) to receive LYNPARZA or placebo for up to two years or until
disease progression. Patients who had a partial response at two years
were permitted to stay on therapy at the investigator’s discretion. The
primary endpoint was PFS and key secondary endpoints included time to
second disease progression or death, time to first subsequent treatment
and overall survival.

About LYNPARZA

®

(olaparib)

LYNPARZA is a first-in-class PARP inhibitor and the first targeted
treatment to potentially exploit DNA damage response (DDR) pathway
deficiencies, such as BRCA mutations, to preferentially kill
cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of
PARP bound to DNA single-strand breaks, stalling of replication forks,
their collapse and the generation of DNA double-strand breaks and cancer
cell death. LYNPARZA is being tested in a range of tumor types with
defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by
AstraZeneca and Merck, has a broad and advanced clinical trial
development program, and AstraZeneca and Merck are working together to
understand how it may affect multiple PARP-dependent tumors as a
monotherapy and in combination across multiple cancer types.

About Ovarian Cancer

Approximately 22,000 women in the U.S. are diagnosed with ovarian cancer
(including ovarian, fallopian tube, and primary peritoneal cancers) each
year. Among women in the U.S., it is the ninth most common cancer and
the fifth leading cause of cancer death.

The risk of developing ovarian cancer is increased in women with
specific inherited genetic abnormalities, including BRCA
mutations.

About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role in
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,
and cells become unstable. 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

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, the world’s first PARP
inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for
multiple cancer types. Working together, the companies will develop
LYNPARZA and selumetinib in combination with other potential new
medicines and as monotherapies. 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, the potential
to bring new hope to people with cancer drives our purpose and
supporting accessibility to our cancer medicines is our commitment.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the largest development
programs in the industry across more than 30 tumor types. We also
continue to strengthen our portfolio through strategic acquisitions and
are prioritizing the development of several promising oncology
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 TwitterFacebookInstagram,
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and LinkedIn.

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