US FDA Accepts Regulatory Submission For LYNPARZA (olaparib) Maintenance Therapy in Newly-Diagnosed, BRCA-mutated Advanced Ovarian Cancer and Grants Priority Review
Business Wire 12-Nov-2018 6:55 AM
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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