LYNPARZA is the first and only PARP
inhibitor approved for use beyond ovarian cancer
LYNPARZA reduced the risk of disease
progression or death by 42% compared to standard of care
chemotherapy
AstraZeneca and Merck (Merck: known as MSD outside the US and
Canada) today announced that the US Food and Drug Administration
(FDA) has approved LYNPARZA® (olaparib), for use in patients
with deleterious or suspected deleterious germline BRCA-mutated
(gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative
metastatic breast cancer who have been previously treated with
chemotherapy in the neoadjuvant, adjuvant or metastatic setting.
Patients with hormone receptor positive (HR+) breast cancer should
have been treated with a prior endocrine therapy or be considered
inappropriate for endocrine therapy. Patients are selected for
therapy based on an FDA-approved companion diagnostic from Myriad
Genetics.1
Dave Fredrickson, Executive Vice President, Head of the Oncology
Business Unit, AstraZeneca, said: “This new approval for LYNPARZA
makes it the first and only PARP inhibitor approved in metastatic
breast cancer, and the only PARP inhibitor approved beyond ovarian
cancer. This is significant for breast cancer patients, as the
identification of BRCA status, in addition to hormone receptor and
HER2 status, becomes a potentially critical step in the management
of their disease.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “This additional approval for LYNPARZA represents an
important advance for women with HER2-negative metastatic breast
cancer with a germline BRCA mutation, which is a difficult-to-treat
cancer. Moreover, this approval adds further impetus to our
important collaboration with AstraZeneca in developing cancer
therapies.”
The approval was based on data from the randomized, open-label,
Phase III OlympiAD trial, which investigated LYNPARZA versus
physician’s choice of chemotherapy (capecitabine, eribulin or
vinorelbine). In the trial, LYNPARZA significantly prolonged
progression-free survival (PFS) compared with chemotherapy, and
reduced the risk of disease progression or death by 42% (HR 0.58;
95% CI 0.43-0.80; P=0.0009 median 7.0 vs 4.2 months). Patients with
measurable disease taking LYNPARZA (n=167) experienced an objective
response rate of 52% (95% CI 44-60), double the response rate for
those in the chemotherapy arm (n=66) which was 23% (95% CI 13-35).
Additionally, patients experienced a confirmed complete response
rate of 7.8% for LYNPARZA compared to 1.5% for the chemotherapy
arm. The data from the OlympiAD trial can be found in the June 2017
issue of the New England Journal of Medicine.1,2
Dr. Susan M. Domchek, Executive Director of the Basser Center
for BRCA at the Abramson Cancer Center of the University of
Pennsylvania, and a national leader on the OlympiAD trials said:
“Patients diagnosed with BRCA-related metastatic breast cancer are
often younger than other breast cancer patients, and their disease
is often much more aggressive and difficult to treat. While there
is currently no cure for metastatic breast cancer, today’s approval
offers a new, targeted option that may help to delay disease
progression for these patients.”
Sue Friedman, Executive Director and founder of the nonprofit
organization, Facing Our Risk of Cancer Empowered (FORCE), said:
“We know there are limited treatment options for patients with
metastatic breast cancer. For the portion of the 155,000 women
in the US living with metastatic breast cancer who have an
inherited BRCA mutation, today’s news is encouraging. By undergoing
genetic testing for BRCA mutations, we can gain critical
information that will inform personalized treatment options
specifically for women with this mutation.”
The most common adverse reactions (≥20%) in the OlympiAD trial
of patients who received LYNPARZA were nausea (58%), anemia (40%),
fatigue (including asthenia) (37%), vomiting (30%), neutropenia
(27%), respiratory tract infection (27%), leukopenia (25%),
diarrhea (21%) and headache (20%). The percentage of patients who
discontinued treatment in the LYNPARZA arm was 5% compared to the
chemotherapy arm which was 8%. Please see Important Safety
Information below.
This is the third indication approved for LYNPARZA in the US,
where it has been used to treat nearly 4,000 advanced ovarian
cancer patients.1,3 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
settings, including breast, ovarian, prostate and pancreatic
cancers.4-7
Sustainable and Ongoing Externalization Revenue
Under the oncology collaboration with Merck, announced in July
2017, AstraZeneca is potentially eligible for more than $6 billion
of future Sustainable and Ongoing Externalization Revenue in the
form of sales-related and approval-related payments in addition to
option payments until 2019. Following this new approval for
LYNPARZA, AstraZeneca will receive $70 million in Sustainable and
Ongoing Externalization Revenue.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONSThere are no contraindications for
LYNPARZA.
WARNINGS AND PRECAUTIONSMyelodysplastic 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.
FemalesAdvise 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.
MalesAdvise 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 SettingMost 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 cancerMost
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 cancerMost
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 INTERACTIONSAnticancer 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 POPULATIONSLactation: 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).
DOSING AND ADMINISTRATIONTo 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.
INDICATIONSLYNPARZA 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 previously 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 treatment. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
Please see complete Prescribing Information,
including Patient Information (Medication Guide).
– ENDS –
NOTES TO EDITORS
About OlympiADOlympiAD is a randomized, open-label,
multicenter Phase III trial assessing the efficacy and safety of
LYNPARZA tablets (300 mg twice daily) compared to physician’s
choice of chemotherapy in 302 patients with HER2-negative
metastatic breast cancer with germline BRCA1 or BRCA2 mutations,
which are confirmed or suspected to be deleterious. The
international trial was conducted in 19 countries across Europe,
Asia, North America and South America.2,8
Patients in the OlympiAD trial had HER2-negative gBRCA1- or
gBRCA2-mutated breast cancer, which was HR+ or triple negative, and
received LYNPARZA for metastatic disease. Approximately half of the
patients in the LYNPARZA and chemotherapy arm of the trial were HR+
(n=152), and approximately half were triple negative (n=150). Among
the 205 patients treated with LYNPARZA, the median age was 44 years
(range: 22 to 76). Before enrollment, patients had prior treatment
with an anthracycline (unless contraindicated) and a taxane
chemotherapy either in the neoadjuvant, adjuvant or metastatic
setting and no more than two prior lines of chemotherapy for
metastatic disease. HR+ patients had received at least one
endocrine medicine or were not eligible for endocrine medicines.
Prior treatments with endocrine medicines were not counted as prior
lines of chemotherapy.2,8
The primary endpoint of the trial was PFS as measured by a
Blinded Independent Central Review.2,8 Secondary endpoints included
overall survival, time to second progression or death, objective
response rate, and effect on health-related quality of life.2,8
About Metastatic Breast Cancer (MBC)Three main receptors
drive tumor growth in breast cancer: Progesterone receptors (PR),
estrogen receptors (ER) and HER2 receptors.9,10 A patient’s breast
cancer will test either negative or positive for these three
receptors.9,10 If a tumor tests positive for PR and/or ER, it is
considered HR+.9 If a tumor tests negative for all three receptors,
it is considered triple negative.9
MBC is the most advanced stage of breast cancer (Stage IV), and
occurs when cancer cells have spread beyond the initial tumor site
to other parts of the body outside of the breast.11,12
Despite the increase in treatment options during the past three
decades, there is currently no cure for patients diagnosed with MBC
and only 26.9% of patients survive five years after diagnosis.13-15
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.16
It is estimated that in 2018, there will be approximately
155,000 women in the US living with MBC, and this number is
projected to increase to approximately 160,000 by the year
2020.17
About Germline BRCA MutationsBRCA1 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, and cells
become unstable. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.18
About LYNPARZA® (olaparib)LYNPARZA is the
first FDA-approved oral poly ADP-ribose polymerase (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.19-21 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.1
LYNPARZA is being investigated 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.19-21
About the AstraZeneca and Merck Strategic Oncology
CollaborationIn July 2017, AstraZeneca and Merck (known as MSD
outside the United States and Canada) announced a global strategic
oncology collaboration to co-develop and co-commercialize LYNPARZA,
the world’s first 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. 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 OncologyAstraZeneca 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 AstraZenecaAstraZeneca 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 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.
Media Inquiries
Michele Meixell +1 302 885 2677Stephanie Wiswall +1 302 885
2677
References
- LYNPARZA (olaparib) Tablets Prescribing
Information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
- 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
- Data on File, US-16345, AstraZeneca
Pharmaceuticals LP.
- 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 January 2018.
- National Institutes of Health. Olaparib
Maintenance Monotherapy in Patients with BRCA Mutated Ovarian
Cancer Following First Line Platinum Based Chemotherapy. (SOLO-1)
Available Online. Accessed January 2018.
- 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 January 2018.
- 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 January 2018.
- 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 January 2018.
- American Cancer Society. Breast Cancer
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2018.
- American Cancer Society. Breast Cancer
HER2 Status. Available Online. Accessed January 2018.
- Cleveland Clinic. Diseases and
Conditions: Breast Cancer. Available Online. Last Updated
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- American Cancer Society. Managing
Cancer as a Chronic Illness. Available Online. Accessed January
2018
- National Cancer Institute. SEER Cancer
Fact Sheet: Female Breast Cancer. Available Online. Accessed
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- O’Shaughnessy J. Extending survival
with chemotherapy in metastatic breast cancer. The Oncologist.
2005;10(3):20–29.
- CancerMPact.Khapps.com: ONC-Prevalence
of Metastatic Breast Cancer in Women 2014-2020. Accessed January
2018.
- National Cancer Institute. BRCA1 and
BRCA2: Cancer Risk and Genetic Testing. Available Online. Accessed
January 2018.
- US Food and Drug Administration. FDA
approves Lynparza to treat advanced ovarian cancer. Accessed
January 2018.
- O’Connor M. Targeting the DNA damage
response in cancer. Mol Cell. 2015; 60:547-560. Accessed January
2018.
- 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.
US-14448 Last Updated 1/18
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