First Medicine Targeting BRCA Mutations to
Show Clinical Benefit in Invasive Disease-Free Survival in Adjuvant
Setting Following Chemotherapy Either Before or After
Surgery
AstraZeneca and Merck (NYSE: MRK), known as MSD outside the
United States and Canada, today announced that a supplemental New
Drug Application (sNDA) for LYNPARZA has been accepted and granted
priority review by the U.S. Food and Drug Administration (FDA) for
the adjuvant treatment of patients with BRCA-mutated (BRCAm), human
epidermal growth factor receptor 2 (HER2)-negative high-risk early
breast cancer who have already been treated with chemotherapy
either before or after surgery. The FDA has set a Prescription Drug
User Fee Act (PDUFA), or target action, date during the first
quarter of 2022.
Breast cancer is now the most diagnosed cancer worldwide, with
an estimated 2.3 million patients diagnosed in 2020. Nearly 91% of
all breast cancer patients are diagnosed at an early stage of
disease, and germline BRCA mutations are found in approximately 5%
of patients.
The sNDA was based on results from the Phase 3 OlympiA trial
presented during the 2021 American Society of Clinical Oncology
(ASCO) Annual Meeting and simultaneously published in The New
England Journal of Medicine.
These results showed LYNPARZA demonstrated a statistically
significant and clinically meaningful improvement in invasive
disease-free survival (iDFS), reducing the risk of invasive breast
cancer recurrence, second cancers or death by 42% versus placebo
(HR=0.58 [99.5% CI, 0.41-0.82]; p<0.0001).
The safety and tolerability profile of LYNPARZA in the OlympiA
trial did not differ from that observed in prior clinical trials.
The most common adverse events (AEs) (≥20%) were nausea (57%),
fatigue (40%), anemia (23%) and vomiting (23%). Grade ≥3 AEs were
anemia (9%), neutropenia (5%), leukopenia (3%), fatigue (2%) and
nausea (1%). Approximately 10% of patients treated with LYNPARZA
discontinued treatment due to AEs.
LYNPARZA is approved in the U.S., EU, Japan and several other
countries for the treatment of patients with germline BRCAm,
HER2-negative metastatic breast cancer previously treated with
chemotherapy and, if hormone receptor-positive, endocrine therapy
if appropriate based on results from the Phase 3 OlympiAD trial. In
the EU, this indication also includes patients with locally
advanced breast cancer.
About OlympiA OlympiA is a Phase 3, double-blind,
parallel-group, placebo-controlled, multicenter trial evaluating
the efficacy and safety of LYNPARZA versus placebo as adjuvant
treatment in patients with germline BRCAm, HER2-negative high-risk
early breast cancer who have completed definitive local treatment
and neoadjuvant or adjuvant chemotherapy. The primary endpoint is
iDFS, defined as time from randomization to date of first
loco-regional or distant recurrence or new cancer or death from any
cause.
The OlympiA trial is led by the Breast International Group (BIG)
in partnership with the Frontier Science & Technology Research
Foundation (FSTRF), NRG Oncology, AstraZeneca and Merck.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS There are no contraindications for
LYNPARZA.
WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute
Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of
patients exposed to LYNPARZA monotherapy, and the majority of
events had a fatal outcome. The median duration of therapy in
patients who developed MDS/AML was 2 years (range: <6 months to
>10 years). All of these patients had previous chemotherapy with
platinum agents and/or other DNA-damaging agents, including
radiotherapy.
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 0.8% of patients exposed to
LYNPARZA monotherapy, 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.
Venous Thromboembolic Events: Including pulmonary
embolism, occurred in 7% of patients with metastatic
castration-resistant prostate cancer who received LYNPARZA plus
androgen deprivation therapy (ADT) compared to 3.1% of patients
receiving enzalutamide or abiraterone plus ADT in the PROfound
study. Patients receiving LYNPARZA and ADT had a 6% incidence of
pulmonary embolism compared to 0.8% of patients treated with ADT
plus either enzalutamide or abiraterone. Monitor patients for signs
and symptoms of venous thrombosis and pulmonary embolism, and treat
as medically appropriate, which may include long-term
anticoagulation as clinically indicated.
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%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration
Resistant Prostate Cancer Most common adverse reactions (Grades
1-4) in ≥10% of patients in clinical trials of LYNPARZA for
PROfound were: anemia (46%), fatigue (including asthenia)
(41%), nausea (41%), decreased appetite (30%), diarrhea (21%),
vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea
(10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA for PROfound were:
decrease in hemoglobin (98%), decrease in lymphocytes (62%),
decrease in leukocytes (53%), and decrease in absolute neutrophil
count (34%).
DRUG INTERACTIONS Anticancer Agents: Clinical studies of
LYNPARZA with other myelosuppressive anticancer agents, including
DNA-damaging agents, indicate a potentiation and prolongation of
myelosuppressive toxicity.
CYP3A Inhibitors: Avoid coadministration of strong or
moderate CYP3A inhibitors when using LYNPARZA. If a strong or
moderate CYP3A inhibitor must be coadministered, reduce the dose of
LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice,
Seville oranges, and Seville orange juice during LYNPARZA
treatment.
CYP3A Inducers: Avoid coadministration of strong or
moderate CYP3A inducers when using 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 for LYNPARZA in the United States 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.
HRR Gene-mutated Metastatic Castration Resistant Prostate
Cancer For the treatment of adult patients with deleterious or
suspected deleterious germline or somatic homologous recombination
repair (HRR) gene-mutated metastatic castration-resistant prostate
cancer (mCRPC) who have progressed following prior treatment with
enzalutamide or abiraterone. 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 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 Breast Cancer Early breast cancer is defined as
disease confined to the breast with or without regional lymph node
involvement and the absence of distant metastatic disease. For
women in the U.S., the five-year survival rate is 99% for localized
breast cancer (cancer that is found in only the breast area) and
86% for regional breast cancer (cancer that has spread outside the
breast to nearby structures or lymph nodes). Breast cancer is one
of the most biologically diverse tumor types with various factors
fueling its development and progression. The discovery of
biomarkers in the development of breast cancer has greatly impacted
scientific understanding of the disease.
About BRCA Mutations BRCA1 and BRCA2 (breast cancer
susceptibility genes 1/2) are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
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, 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 over 130 years, Merck, known as MSD
outside 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.
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Inc., Kenilworth, N.J., USA (the “company”) includes
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