LYNPARZA reduced the risk of disease
progression or death by 47% in patients whose disease had not
progressed on at least 16 weeks of a first-line platinum-based
chemotherapy regimen Only PARP inhibitor approved
in germline BRCA-mutated metastatic pancreatic
cancer
AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US
(Merck: known as MSD outside the US and Canada) today announced
that LYNPARZA® (olaparib) has been approved in the US for
the maintenance treatment of adult patients with deleterious or
suspected deleterious germline BRCA-mutated (gBRCAm) metastatic
pancreatic adenocarcinoma whose disease has not progressed on at
least 16 weeks of a first-line platinum-based chemotherapy regimen.
Patients will be selected for therapy based on an FDA-approved
companion diagnostic for LYNPARZA.
The approval follows the
recommendation by the US FDA Oncologic Drugs Advisory Committee
(ODAC) on December 17 for LYNPARZA in this indication and was based
on results from the pivotal Phase III POLO trial published
in The New England Journal of
Medicine and presented at the 2019 American Society of Clinical
Oncology Annual Meeting.
Results showed a statistically
significant and clinically meaningful improvement in
progression-free survival, where LYNPARZA nearly doubled the time
patients with gBRCAm metastatic pancreatic cancer lived without
disease progression or death to a median of 7.4 months vs. 3.8
months on placebo (HR 0.53 [95% CI 0.35-0.81], p=0.0035).
The safety and tolerability
profile of LYNPARZA in the POLO trial was in line with that
observed in prior clinical trials.
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: “Patients with advanced pancreatic cancer historically
have faced poor outcomes due to the aggressive nature of the
disease and limited treatment advances over the last few decades.
LYNPARZA is now the only approved targeted medicine in
biomarker-selected patients with advanced pancreatic cancer.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “LYNPARZA embodies Merck’s and AstraZeneca’s commitment to
advance the treatment of challenging types of cancer, including
metastatic pancreatic cancer. The expanded approval of LYNPARZA
represents a significant milestone for patients and supports the
value of germline BRCA testing in patients with this disease.”
Hedy L. Kindler, Co-Principal Investigator of the POLO trial and
Professor of Medicine, University of Chicago Medicine, said:
“Today’s approval of olaparib based on the POLO results gives
clinicians an important 1st-line maintenance treatment option which
nearly doubled the progression-free survival benefit in patients
with germline BRCA-mutated metastatic pancreatic cancer.”
Julie Fleshman, President and CEO, Pancreatic Cancer Action
Network, said: “Metastatic pancreatic cancer patients have been
waiting a long time for new therapy options for their devastating
disease. Today’s approval of LYNPARZA provides an exciting new
treatment option for patients with germline BRCA-mutated metastatic
pancreatic cancer.”
The Pancreatic Cancer Action Network (PanCAN) is a US-based
organization that supports and advocates on behalf of the patients,
caregivers and communities affected by pancreatic cancer.
The most common adverse reactions (ARs) ≥10% 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%), nasopharyngitis (12%), neutropenia (12%), dysgeusia
(11%) and stomatitis (10%). Grade 3 or above ARs were anemia (11%),
fatigue (5%), neutropenia (4%), decreased appetite (3%),
thrombocytopenia (3%), abdominal pain (2%), vomiting (1%) and
arthralgia (1%). ARs led to dose reduction in 17% of patients on
LYNPARZA while 6% of patients discontinued treatment.
LYNPARZA is currently approved for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer regardless of BRCA
status. It is approved as first-line maintenance treatment in BRCAm
advanced ovarian cancer following response to platinum-based
chemotherapy. It is also approved for germline BRCAm HER2-negative
metastatic breast cancer previously treated with chemotherapy. For
first-line maintenance in advanced ovarian cancer and the
metastatic breast cancer setting, physicians should select patients
for therapy based on an FDA-approved companion diagnostic for
LYNPARZA.
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%).
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.
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.
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 see complete Prescribing Information, including
Patient Information (Medication Guide).
NOTES TO EDITORS
About POLO
POLO is a Phase III randomized, double-blinded,
placebo-controlled, multi-center study of LYNPARZA tablets (300 mg
twice daily) as maintenance monotherapy vs. placebo. The trial
randomized 154 patients with gBRCAm metastatic pancreatic cancer
whose disease had not progressed on 1st-line platinum-based
chemotherapy. Patients were randomized (3:2) to receive LYNPARZA or
placebo until disease progression. The primary endpoint was PFS and
key secondary endpoints include overall survival, time to second
disease progression, overall response rate, disease control rate
and health-related quality of life. Phase III POLO results were
published in The New England Journal of Medicine and presented at
the 2019 American Society of Clinical Oncology Annual Meeting.
The results showed a statistically significant and clinically
meaningful improvement in progression-free survival, where LYNPARZA
nearly doubled the time patients with gBRCAm metastatic pancreatic
cancer lived without disease progression or death to a median of
7.4 months vs. 3.8 months on placebo and reduced the risk of
disease progression or death by 47% (HR 0.53 [95% CI, 0.35-0.81],
p=0.0035).
The safety and tolerability profile of LYNPARZA in the POLO
trial was in line with that observed in prior clinical trials.
Based on the results of POLO,
the National Comprehensive Cancer Network (NCCN) guidelines have
been updated in July 2019 to recommend LYNPARZA as maintenance
treatment for gBRCAm pancreatic cancer.
About Pancreatic Cancer
In the U.S. this year, it is expected that more than 55,000
people will be diagnosed with pancreatic cancer and over 45,750
people will die of this disease. Early diagnosis of pancreatic
cancer is difficult, as often there are no symptoms.
There are two types of pancreatic cancer. Exocrine tumors, of
which the most common type is pancreatic ductal adenocarcinoma
(PDAC), start in the exocrine cells, where enzymes help to digest
food. Neuroendocrine tumors start in neuroendocrine cells, which
produce hormones, such as insulin, that control different functions
of the body.
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 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 LYNPARZA® (olaparib)
LYNPARZA is a first-in-class PARP inhibitor and the first
targeted treatment to potentially exploit DNA damage response (DDR)
in cells/tumors harboring a deficiency in homologous recombination
repair (HRR), such as mutations in BRCA1 or BRCA2. 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 PARP-dependent tumor
types with defects and dependencies in the DDR pathway.
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 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 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.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly-growing portfolio of new medicines that has the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines to be launched between 2014 and 2020, and a
broad pipeline of small molecules and biologics in development, we
are committed to advance Oncology as a growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to our core capabilities, we actively pursue innovative
partnerships and investments that accelerate the delivery of our
strategy, as illustrated by our investment in Acerta Pharma in
hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal &
Metabolism and Respiratory. AstraZeneca operates in over 100
countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit
www.astrazeneca-us.com and follow the Company on Twitter
@AstraZenecaUS.
US-30599 Last Updated 12/19
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