AstraZeneca and Merck’s LYNPARZA reduced the
risk of disease progression or death by 70% compared to placebo
following response to platinum-based chemotherapy
First PARP inhibitor approved in 1st-line
maintenance for BRCAm advanced ovarian cancer
AstraZeneca and Merck & Co., Inc., (Merck: known as MSD
outside the US and Canada) today announced that the US 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
1st-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 1st-line maintenance setting for BRCAm advanced ovarian cancer.
The approval was based on positive results from the pivotal Phase
III SOLO-1 trial in which LYNPARZA reduced the risk of disease
progression or death by 70% 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.”
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% of
patients receiving LYNPARZA remained progression-free at 3 years
compared to 27% 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% 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% of patients receiving
LYNPARZA and 17% 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%
(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% (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 ovarian cancer, including the
ongoing GINECO/ENGOTov25 Phase III 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 Merck
and following this new approval for LYNPARZA, AstraZeneca will
receive $70 million as Ongoing Externalization Revenue.
About SOLO-1
SOLO-1 is a Phase III 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 2 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
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.
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 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. Among women in the United States, 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.
AstraZeneca is committed to the continued development of our
R&D portfolio for ovarian cancer, with a focus on improved care
for all patients.
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 & 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 olaparib, the world’s first PARP inhibitor,
and potential new medicine selumetinib, a MEK inhibitor, for
multiple cancer types. Working together, the companies will develop
olaparib and selumetinib in combination with other potential new
medicines and as monotherapies. Independently, the companies will
develop olaparib 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 main 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 us on Twitter @AstraZenecaUS.
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