Approval would expand use of AstraZeneca and
MSD’s LYNPARZA to patients in the 1st-line setting following
platinum-based chemotherapy
First regulatory submission acceptance for a
PARP inhibitor as a 1st-line maintenance treatment for advanced
ovarian cancer
AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US
(Merck: known as MSD outside the US and Canada) today announced
that the US Food and Drug Administration (FDA) has accepted a
supplemental New Drug Application (sNDA) and granted priority
review for the approval of LYNPARZA (olaparib) (two 150 mg tablets
twice daily) as a maintenance treatment in patients with
newly-diagnosed, BRCA-mutated (BRCAm) advanced ovarian cancer who
were in complete or partial response following 1st-line standard
platinum-based chemotherapy. A Prescription Drug User Fee Act
(PDUFA) date is set for the first quarter of 2019.
This is the first regulatory submission acceptance for a poly
ADP-ribose polymerase (PARP) inhibitor in the advanced ovarian
cancer 1st-line maintenance setting, and if approved will be the
fourth indication for LYNPARZA in the US.
This submission was based on positive results from the pivotal
Phase III SOLO-1 trial. The trial
showed a statistically-significant and clinically-meaningful
improvement in progression-free survival (PFS) for LYNPARZA
compared to placebo, reducing the risk of disease progression or
death by 70% in patients with newly-diagnosed, 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<0.001). With median 41 months of follow-up, the median PFS for
patients treated with LYNPARZA (n=260) was not reached compared to
13.8 months for patients treated with placebo (n=131). Of those in
the trial receiving LYNPARZA, 60% remained progression-free at 36
months compared to 27% of women in the placebo arm. These data were
recently presented for the first time at the European Society for
Medical Oncology (ESMO) 2018 Congress and published online in the
New England Journal of Medicine.
LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP)
inhibitor approved in the US since 2014. LYNPARZA has a broad
clinical-development program and AstraZeneca and Merck are working
together to deliver LYNPARZA as quickly as possible to more
patients across multiple cancer types, including prostate and
pancreatic cancers.
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—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA in the maintenance setting
for SOLO-2: 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%), and decreased appetite
(21%).
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 (including 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%), increase in mean corpuscular volume (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 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 hepatic impairment (Child-Pugh
classification A). There are no data in patients with moderate or
severe hepatic impairment.
Renal Impairment: No adjustment to the starting dose is
necessary in patients with mild renal impairment (CLcr=51-80
mL/min). 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:
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.
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.
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 see complete Prescribing Information,
including Patient Information (Medication Guide).
– ENDS –
About the SOLO-1 Phase III Trial
SOLO-1 is a Phase III randomized, double-blind,
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 newly diagnosed patients with
BRCAm advanced ovarian cancer following platinum-based
chemotherapy. The trial randomized 391 patients with a deleterious
or suspected deleterious 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 (at the
investigator’s discretion). The primary endpoint was
investigator-assessed progression free survival and key secondary
endpoints included time to second disease progression or death,
time to first subsequent treatment and overall survival.
About Ovarian Cancer
Approximately 20,000 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 LYNPARZA® (olaparib)
LYNPARZA is the 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. Specifically, in
vitro studies have shown that LYNPARZA-induced cytotoxicity
may involve inhibition of PARP enzymatic activity and increased
formation of PARP-DNA complexes, resulting in DNA damage and cancer
cell death.
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 in
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 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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