Patients treated with LYNPARZA and
bevacizumab lived without disease progression for 37.2 months vs.
17.7 months median for bevacizumab alone
One in two women with advanced ovarian
cancer has an HRD-positive tumor
AstraZeneca and Merck &
Co., Inc., Kenilworth, NJ, US (Merck: known as MSD outside the US
and Canada) today announced LYNPARZA® (olaparib) in combination
with bevacizumab has been approved in the US 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. Patients
will be selected for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.
The approval by the US Food
and Drug Administration (FDA) was based on a biomarker subgroup
analysis from the Phase III PAOLA-1 trial which showed
LYNPARZA in combination
with bevacizumab reduced the risk of disease progression or death
by 67% (equal to a hazard ratio of 0.33). The addition of LYNPARZA
also improved progression-free survival (PFS) to a median of 37.2
months versus 17.7 months with bevacizumab alone in patients with
HRD-positive advanced ovarian cancer.
Approximately one in two women
with advanced ovarian cancer has an HRD-positive tumor. For
patients with advanced ovarian cancer, the primary aim of 1st-line
treatment is to delay disease progression for as long as possible
with the intent to achieve long-term remission.
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. The combination of LYNPARZA and bevacizumab now
provides women with HRD-positive advanced ovarian cancer with a new
standard of care and I look forward to seeing this translate into
clinical practice.”
Dave Fredrickson, Executive
Vice President, Oncology Business Unit, 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 more 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 for the diagnosis and tailoring
of treatment for women with advanced ovarian cancer.”
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 1st-line maintenance treatment.”
Fatal adverse reactions occurred in 1 patient due to concurrent
pneumonia and aplastic anemia. Serious adverse reactions occurred
in 31% of patients who received LYNPARZA/bevacizumab. Serious
adverse reactions in >5% of patients included hypertension (19%)
and anemia (17%).
The most common adverse reactions (Grades 1-4) occurring in ≥10%
of patients treated with LYNPARZA/bevacizumab and at ≥5% frequency
compared to placebo/bevacizumab 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%).
The full results from the Phase III PAOLA-1 trial can be found
in The New England Journal of Medicine.
Financial considerations Following this approval for
LYNPARZA in the US, AstraZeneca will receive from Merck $100m in
Collaboration Revenue, anticipated to be booked by the Company
during the second quarter of 2020.
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).
NOTES TO EDITORS
About Ovarian Cancer Approximately 22,000 women in the
United States are diagnosed with ovarian cancer (including ovarian,
fallopian tube and primary peritoneal cancers) each year. Ovarian
cancer ranks fifth in cancer deaths among women, accounting for
more deaths than any other cancer of the female reproductive
system. The risk of developing ovarian cancer is increased in women
with specific inherited genetic abnormalities, including BRCA1/2
mutations.
Most women are diagnosed with advanced (Stage III or IV) ovarian
cancer and have a five-year survival rate of approximately 30%.
Approximately 50% of ovarian cancers are HRD-positive, including
BRCA1/2 mutation. Some 22% of ovarian cancers have a BRCA1/2
mutation.
About PAOLA-1 PAOLA-1 is a double-blind, Phase III trial
testing the efficacy and safety of LYNPARZA (300 mg twice daily) in
combination with bevacizumab vs. bevacizumab alone, as a 1st-line
maintenance treatment for newly diagnosed advanced FIGO Stage
III-IV high-grade serous or endometrioid ovarian, fallopian tube,
or peritoneal cancer patients who had a complete or partial
response to 1st-line treatment with platinum-based chemotherapy and
bevacizumab. AstraZeneca and Merck announced in August 2019 that
the trial met its primary endpoint of PFS.
Simultaneously, the Myriad Genetics myChoice® CDx test has been
approved in the US as a companion diagnostic for LYNPARZA in this
new indication.
About Homologous Recombination Deficiency HRD, which
defines a sub-group of ovarian cancer, encompasses a wide range of
genetic abnormalities, including BRCA mutations. As with BRCA gene
mutations, HRD interferes with normal cell DNA repair mechanisms
and confers sensitivity to PARP inhibitors including LYNPARZA.
About LYNPARZA LYNPARZA® (olaparib) 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 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. LYNPARZA is being tested
in a range of DDR-deficient tumor types and is the foundation of
AstraZeneca’s industry-leading portfolio of compounds targeting DDR
mechanisms in cancer cells.
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.
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 key 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 main therapy areas
- Oncology, Cardiovascular, Renal & Metabolism and Respiratory.
The Company also is selectively active in the areas of
autoimmunity, neuroscience and infection. 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 us on Twitter @AstraZenecaUS.
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