Improved the Median Time to Disease
Progression (37.2 months) vs. Bevacizumab Alone (17.7 months)
Following Response to Platinum-Based Chemotherapy with
Bevacizumab
Approximately One in Two Women with Advanced
Ovarian Cancer Has an HRD-Positive Tumor
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 in combination with
bevacizumab as a first-line maintenance treatment of adult patients
with advanced epithelial ovarian, fallopian tube or primary
peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy and whose cancer is
associated with homologous recombination deficiency (HRD) positive
status defined by either a deleterious or suspected deleterious
BRCA mutation, and/or genomic instability. Patients will be
selected for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
The approval was based on a biomarker subgroup analysis of 387
patients with HRD-positive tumors from the Phase 3 PAOLA-1 trial,
which showed that LYNPARZA in combination with bevacizumab reduced
the risk of disease progression or death by 67% (HR 0.33 [95% CI,
0.25-0.45]). It improved progression-free survival (PFS) to a
median of 37.2 months vs. 17.7 months with bevacizumab alone in
patients with HRD-positive advanced ovarian cancer.
The most common adverse reactions (ARs) ≥10% in the overall
trial population for PAOLA-1 when treated with LYNPARZA in
combination with bevacizumab (N=535) and at a ≥5% frequency
compared to bevacizumab alone (N=267) were fatigue (53% vs. 32%),
nausea (53% vs. 22%), anemia (41% vs. 10%), lymphopenia (24% vs.
9%), vomiting (22% vs. 11%) and leukopenia (18% vs. 10%). Grade 3
or above ARs were anemia (17% vs. <1%), lymphopenia (7% vs. 1%),
fatigue (5% vs. 2%), nausea (2% vs. 1%), leukopenia (2% vs. 2%) and
vomiting (2% vs. 2%). Additional adverse reactions that occurred in
≥10% of patients receiving LYNPARZA in combination with bevacizumab
irrespective of the frequency compared to bevacizumab alone were
diarrhea (18%), neutropenia (18%), urinary tract infection (15%)
and headache (14%). Fatal adverse reactions occurred in one patient
due to concurrent pneumonia and aplastic anemia. Serious adverse
reactions occurred in 31% of patients who received LYNPARZA in
combination with bevacizumab. Serious adverse reactions in >5%
of patients included hypertension (19%) and anemia (17%).
In addition, venous thromboembolic events occurred more commonly
in patients receiving LYNPARZA in combination with bevacizumab (5%)
than in those receiving bevacizumab alone (1.9%). ARs led to dose
interruption in 54% of patients on LYNPARZA in combination with
bevacizumab, while 41% of patients on LYNPARZA in combination with
bevacizumab had a dose reduction. Discontinuation of treatment due
to ARs occurred in 20% of patients on LYNPARZA in combination with
bevacizumab.
Approximately one in two women with advanced ovarian cancer has
an HRD-positive tumor. For patients with advanced ovarian cancer,
the primary aim of first-line maintenance treatment is to delay
disease progression for as long as possible.
Isabelle Ray-Coquard,
principal investigator of the PAOLA-1 trial and medical oncologist,
Centre Léon Bérard and President of the GINECO group, said,
“Ovarian cancer is a devastating disease. The magnitude of benefit
in HRD-positive patients in the PAOLA-1 trial is impactful. I look
forward to seeing this translate into clinical
practice.”
Dave Frederickson, executive vice president, head of the
oncology business unit, AstraZeneca, said, “This approval
represents another milestone for LYNPARZA in patients with ovarian
cancer. The median progression-free survival of more than three
years offers new hope for women to delay relapse in this
difficult-to-treat disease. These results further establish that
HRD-positive is a distinct subset of ovarian cancer and HRD testing
is now a critical component of diagnosis and tailoring of treatment
for women with advanced ovarian cancer.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “Advances in understanding the role of
biomarkers and PARP inhibition have fundamentally changed how
physicians treat this aggressive type of cancer. Today’s approval
based on the PAOLA-1 trial highlights the importance of HRD testing
at diagnosis to identify those who may benefit from LYNPARZA in
combination with bevacizumab as a first-line maintenance
treatment.”
The full results from the Phase 3 PAOLA-1 trial were published
in The New England Journal of Medicine.
Regulatory reviews are currently underway in the European Union,
Japan and other countries for LYNPARZA in combination with
bevacizumab as a first-line maintenance treatment for patients with
advanced ovarian cancer. As part of a broad development program,
LYNPARZA is being assessed as a monotherapy and in combination
across multiple tumor types.
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—First-Line Maintenance Advanced Ovarian
Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients
treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for
placebo/bevacizumab in the first-line maintenance setting
for PAOLA-1 were: nausea (53%), fatigue (including asthenia)
(53%), anemia (41%), lymphopenia (24%), vomiting (22%) and
leukopenia (18%). In addition, the most common adverse reactions
(≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of
the frequency compared with the placebo/bevacizumab arm were:
diarrhea (18%), neutropenia (18%), urinary tract infection (15%),
and headache (14%).
In addition, venous thromboembolic events occurred more commonly
in patients receiving LYNPARZA/bevacizumab (5%) than in those
receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients for LYNPARZA in combination with bevacizumab in the
first-line maintenance setting for PAOLA-1 were:
decrease in hemoglobin (79%), decrease in lymphocytes (63%),
increase in serum creatinine (61%), decrease in leukocytes (59%),
decrease in absolute neutrophil count (35%), and decrease in
platelets (35%).
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%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients
in clinical trials of LYNPARZA in the first-line maintenance
setting for POLO were: fatigue (60%), nausea (45%),
abdominal pain (34%), diarrhea (29%), anemia (27%), decreased
appetite (25%), constipation (23%), vomiting (20%), back pain
(19%), arthralgia (15%), rash (15%), thrombocytopenia (14%),
dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia
(11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the first-line
maintenance setting for POLO were: increase in serum creatinine
(99%), decrease in hemoglobin (86%), increase in mean corpuscular
volume (71%), decrease in lymphocytes (61%), decrease in platelets
(56%), decrease in leukocytes (50%), and decrease in absolute
neutrophil count (25%).
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 dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA 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 for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD Positive Advanced Ovarian Cancer
in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of
adult patients with advanced epithelial ovarian, fallopian tube or
primary peritoneal cancer who are in complete or partial response
to first-line platinum-based chemotherapy and whose cancer is
associated with homologous recombination deficiency (HRD) positive
status defined by either:
- a deleterious or suspected deleterious BRCA mutation
and/or
- genomic instability
Select patients 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
For the treatment of adult 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.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. 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).
About PAOLA-1
PAOLA-1 is a double-blind Phase 3 trial evaluating the efficacy
and safety of LYNPARZA in combination with standard-of-care
bevacizumab vs. bevacizumab alone, as a first-line maintenance
treatment for advanced FIGO Stage III-IV high grade serous or
endometroid ovarian, fallopian tube, or peritoneal cancer patients
who had a complete or partial response to first-line treatment with
platinum-based chemotherapy and bevacizumab.
PAOLA-1 is an ENGOT (European Network of Gynaecological
Oncological Trial groups) trial, sponsored by ARCAGY Research
(Association de Recherche sur les CAncers dont GYnécologiques) on
behalf of GINECO (Groupe d’Investigateurs National des Etudes des
Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group
specializing in clinical and translational research in patients’
cancers and a member of the GCIG (Gynecologic Cancer
InterGroup).
In the U.S., eligible advanced ovarian cancer patients will be
selected for therapy based on the FDA-approved myChoice HRD Plus,
an HRD test designed to detect when a tumor has lost the ability to
repair double-stranded DNA breaks. Myriad Genetics, Inc. owns and
commercializes myChoice HRD Plus.
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
Ovarian cancer is the fifth most common cause of death from
cancer in women in the United States. This year, it is estimated
that more than 21,000 women will be diagnosed with ovarian cancer
and nearly 14,000 women will die of this disease.
Women with ovarian cancer are often diagnosed with advanced
disease, which has a five-year survival rate of about 48%. For
newly diagnosed advanced ovarian cancer, the primary aim of
treatment is to delay progression of the disease for as long as
possible. BRCA1/2 mutations are found in approximately 22% of all
ovarian cancers and approximately 50% of ovarian cancers are
HRD-positive.
About Homologous Recombination Deficiency
HRD encompass a wide range of genetic abnormalities, including
BRCA mutations, that can be detected using tests. As the BRCA gene
drives DNA repair via homologous recombination, mutation of this
gene leads to homologous recombination deficiency thereby
interfering with normal cell DNA repair mechanisms. BRCA mutations
are just one of many HRDs which confer sensitivity to PARP
inhibitors including LYNPARZA.
About the AstraZeneca and Merck Strategic Oncology
Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth,
NJ, US, known as MSD outside the United States and Canada,
announced a global strategic oncology collaboration to co-develop
and co-commercialize certain oncology products, including LYNPARZA,
the world’s first PARP inhibitor, for multiple cancer types.
Working together, the companies will develop these products in
combination with other potential new medicines and as
monotherapies. Independently, the companies will develop these
oncology products 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 125 years, Merck, 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 in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube 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
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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
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including interest rate and currency exchange rate fluctuations;
the impact of the recent global outbreak of novel coronavirus
disease (COVID-19); the impact of pharmaceutical industry
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including obtaining regulatory approval; the company’s ability to
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