LYNPARZA has the potential to offer a new
treatment option for patients with germline BRCA-mutated,
HER2-negative metastatic breast cancer
Regulatory submission acceptance is first
for a PARP inhibitor beyond 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 accepted and granted priority review
for a supplemental New Drug Application (sNDA) for the use of
LYNPARZA® (olaparib) tablets in patients with germline BRCA-mutated
(gBRCAm), HER2-negative metastatic breast cancer who have been
previously treated with chemotherapy in the neoadjuvant, adjuvant,
or metastatic settings. A Prescription Drug User Fee Act (PDUFA)
date is set for the first quarter of 2018.
This is the first submission for a poly ADP-ribose polymerase
(PARP) inhibitor outside ovarian cancer and the third indication
submission for LYNPARZA in the US. The sNDA is based on the
positive results from the Phase III OlympiAD trial published in the
New England Journal of Medicine.1
LYNPARZA was first approved in December 2014 as a capsule
formulation, making it the first ever PARP inhibitor to be
approved.2 Since then, LYNPARZA has been used to treat more than
3,000 advanced ovarian cancer patients.3 LYNPARZA tablets are
currently being tested in a range of tumor types, including breast,
prostate, and pancreatic cancers.4,5,6
LYNPARZA tablets are currently approved in the US as a
maintenance treatment for adult patients with recurrent, epithelial
ovarian, fallopian tube or primary peritoneal cancer who are in a
complete or partial response to platinum-based chemotherapy,
regardless of BRCA status.7,8 The medicine is also indicated for
use in adult patients with deleterious or suspected deleterious
gBRCA-mutated advanced ovarian cancer, who have been treated with
three or more prior lines of chemotherapy; patients for this
indication are selected for therapy based on an FDA-approved
companion diagnostic.7
IMPORTANT SAFETY INFORMATION
DOSING AND ADMINISTRATION
To avoid substitution errors and overdose, do not substitute
LYNPARZA tablets with LYNPARZA capsules on a
milligram-to-milligram basis due to differences in the dosing and
bioavailability of each formulation. Recommended tablet dose is 300
mg, taken orally twice daily, with or without food. Continue
treatment until disease progression or unacceptable toxicity. For
adverse reactions, consider dose interruption or dose
reduction.
WARNINGS AND PRECAUTIONS
There are no contraindications for LYNPARZA.
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
of these patients also had a history of previous cancer or bone
marrow dysplasia.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood counts 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 treatment
with LYNPARZA 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. Advise females of reproductive
potential of the potential risk to a fetus and to use effective
contraception during treatment and for 6 months after receiving the
final dose.
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 after 3 or more lines of chemotherapy (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%).
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, be aware of a potential for decreased efficacy
of LYNPARZA.
USE IN SPECIFIC POPULATIONS
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Lactation: No data are available regarding the
presence of olaparib in human milk, the effects on the breastfed
infant, or the effects 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.
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).
Please see complete Prescribing
Information, including Patient Information (Medication
Guide)
NOTES TO EDITORS
About OlympiAD
OlympiAD is a randomized, open-label, multicenter Phase III
trial assessing the efficacy and safety of LYNPARZA tablets (300mg
twice daily) compared to ‘physician’s choice’ chemotherapy
(capecitabine, vinorelbine, eribulin) in 302 patients with
HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2
mutations, which are predicted or suspected to be deleterious. The
international trial was conducted in 19 countries across Europe,
Asia, North America and South America.1,9
About LYNPARZA® (olaparib)
LYNPARZA was the first FDA-approved oral poly ADP-ribose
polymerase (PARP) inhibitor that may exploit tumor DNA damage
response (DDR) pathway deficiencies to potentially kill cancer
cells.2,10,11 Specifically, in vitro studies have shown that
olaparib-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complexes,
resulting in DNA damage and cancer cell death.7
LYNPARZA is the foundation of AstraZeneca’s industry-leading
portfolio of compounds targeting DDR mechanisms in cancer
cells.2,10,11
About Metastatic Breast Cancer
Approximately one in eight women are diagnosed with breast
cancer in the US.12 Of these patients, approximately one-third are
either diagnosed with or progress to the metastatic stage of the
disease.13 Despite treatment options increasing during the past
three decades, there is currently no cure for patients diagnosed
with metastatic breast cancer.14,15 Thus, the primary aim of
treatment is to slow progression of the disease for as long as
possible, improving or at least maintaining, a patient’s quality of
life.13
About Germline BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
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. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.16
About the AstraZeneca and Merck Strategic Oncology
Collaboration
On July 27, 2017, AstraZeneca and Merck & Co., Inc.,
announced a global strategic oncology collaboration to co-develop
and co-commercialize AstraZeneca’s LYNPARZA, the world’s first and
leading PARP inhibitor, and potential new medicine selumetinib, a
MEK inhibitor, for multiple cancer types. The collaboration is
based on increasing evidence that PARP and MEK inhibitors can be
combined with PDL-1/PD-1 inhibitors for a range of tumor types and
is aimed at maximizing the potential of LYNPARZA to become the
preferred backbone of combination therapies. Working together, the
companies will jointly develop LYNPARZA and selumetinib in
combination with other potential new medicines and as a
monotherapy. 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 New Oncology as one of AstraZeneca’s five
Growth Platforms 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 & Metabolic
Diseases 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.
References
1. Robson M, Im SA, Senkus E, et al. Olaparib
for metastatic breast cancer in patients with a germline BRCA
mutation. N Engl J Med. 2017; DOI: 10.1056/NEJMoa1706450 2. US Food
and Drug Administration. FDA approves Lynparza to treat advanced
ovarian cancer. Accessed October 2017. 3. Data on File, US-11033,
AstraZeneca Pharmaceuticals LP. 4.
US National Institutes of Health. Olaparib
as Adjuvant Treatment in Patients With Germline BRCA Mutated High
Risk HER2 Negative Primary Breast Cancer (OlympiA). Available
Online. Accessed October 2017.
5.
US National Institutes of Health. Study of
Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in
Men With Metastatic Castration-Resistant Prostate Cancer (PROfound
Study). Available Online. Accessed October 2017.
6.
US National Institutes of Health. Olaparib
in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed
on First Line Platinum-Based Chemotherapy (POLO). Available Online.
Accessed October 2017.
7. LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca
Pharmaceuticals LP, Wilmington, DE. 8. Ledermann J, Harter P,
Gourley M, et al. Olaparib maintenance therapy in
platinum-sensitive relapsed ovarian cancer. N Engl J Med.
2012;366:1382-1392. 9.
US National Institutes of Health.
Assessment of the Efficacy and Safety of Olaparib Monotherapy
Versus Physicians Choice Chemotherapy in the Treatment of
Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations
(OlympiAD). Available Online. Accessed October 2017.
10. O’Connor M. Targeting the DNA damage response in cancer. Mol
Cell. 2015;60:547-560. Accessed October 2017. 11. Tutt ANJ, Lord
CJ, McCabe N. Exploiting the DNA repair defect in BRCA mutant cells
in the design of new therapeutic strategies for cancer. Cold Spring
Harb Symp Quant Biol. 2005;70:139-148. 12.
National Cancer Institute. SEER Cancer
Stat Facts: Female Breast Cancer. Available Online. Accessed
October 2017.
13. O’Shaughnessy J. Extending survival with chemotherapy in
metastatic breast cancer. The Oncologist. 2005;10(3):20–29. 14.
American Cancer Society. Breast Cancer
Facts & Figures 2015-2016. Available Online. Accessed October
2017.
15.
American Cancer Society. Managing Cancer
as a Chronic Illness. Available Online. Accessed October 2017.
16.
National Cancer Institute. BRCA1 and
BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed
October 2017.
US-14682 Last Updated 10/17
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