AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US
(Merck: known as MSD outside the US and Canada) today presented
data from the Phase III OlympiAD trial, showing the final overall
survival (OS) results for LYNPARZA® (olaparib) in metastatic breast
cancer at the American Association for Cancer Research (AACR)
Annual Meeting in Chicago, April 14-18, 2018.
The trial compared LYNPARZA with chemotherapy (physician’s
choice of capecitabine, eribulin or vinorelbine) for patients with
germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast
cancer (MBC) and met its primary endpoint of progression-free
survival (PFS).
Results at AACR include updated findings from the secondary
endpoint of overall survival (OS). While the trial was not powered
to demonstrate a statistically-significant difference, the median
OS was 19.3 months in patients treated with LYNPARZA and 17.1
months for patients treated with chemotherapy (HR 0.90; 95% CI
0.66-1.23; p=0.513). At the final OS data cut-off (64% maturity),
nearly 13% of patients remained on LYNPARZA and no patients
remained on chemotherapy.
Sean Bohen, Executive Vice President, Global Medicines
Development and Chief Medical Officer at AstraZeneca, said:
“OlympiAD is the first Phase III trial to demonstrate disease
control with a PARP inhibitor in BRCA-mutated HER2-negative
metastatic breast cancer. While the trial was not powered to show
overall survival compared to chemotherapy, the results are another
encouraging marker in the use of LYNPARZA for this patient
population.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “For patients and physicians, these results are meaningful in
that they support the progression-free survival endpoint – which
showed that patients treated with LYNPARZA gained seven months
chemotherapy-free time – and reinforce the importance of
identifying BRCA status to optimize metastatic breast cancer
management.”
LYNPARZA is indicated in patients with gBRCAm HER2-negative MBC
previously treated with chemotherapy. Hormone receptor
(HR)-positive breast cancer should have been treated with prior
endocrine therapy or be considered inappropriate for endocrine
treatment. An FDA-approved companion diagnostic is required for
this indication.
When analyzing the predefined subgroups, the results were
consistent with the overall analysis, which did not show a
statistically-significant difference between arms. The greatest
difference was seen in patients who had not received chemotherapy
in the metastatic setting with a median difference in OS of 7.9
months with LYNPARZA (HR 0.51; 95% CI 0.29-0.90; nominal p=0.02;
median 22.6 vs 14.7 months).
Table 1: Predefined subgroups for OS
analysis
Subgroup Median OS
(months)
HR 95% CI
Nominal p Value LYNPARZA
Physician’schoice
ofchemotherapy
Prior
chemotherapy for metastatic breast cancer
No
(1st line) 22.6 14.7 0.51
0.29-0.90 0.02 Yes (2nd line / 3rd line) 18.8
17.2 1.13 0.79-1.64 0.52
Prior platinum-based chemotherapy for breast cancer
No 20.3 19.6 0.91
0.64-1.33 0.63 Yes 17.2 13.3
0.83 0.49-1.45 0.49
Receptor
status
Estrogen receptor positive (ER+) and/or
hormone-receptor positive (HR+) 21.8 21.3 0.86
0.55-1.36 0.51 Triple-negative breast
cancer (TNBC) 17.4 14.9 0.93
0.62-1.43 0.75
The safety profile of LYNPARZA remained consistent with the
primary analysis. Serious adverse events (AEs) (Grade ≥3) were
reported in 38% of patients who received LYNPARZA vs 49.5% of
patients in the chemotherapy arm. AEs leading to drug
discontinuation were 4.9% for LYNPARZA vs 7.7% for chemotherapy.
AEs leading to dose reductions were 25.4% for LYNPARZA vs 30.8% for
chemotherapy. AEs leading to dose interruptions were 36.1% for
LYNPARZA vs 28.6% for chemotherapy. Please see Important Safety
Information below.
These results build on previously reported findings, which
demonstrated LYNPARZA significantly improved PFS (HR 0.58; 95% CI
0.43-0.80; p=0.0009 median 7.0 vs 4.2 months) and showed data
beyond initial disease progression, prolonging time to second
progression or death (PFS2) by 3.9 months (HR 0.57; 95% CI
0.40-0.83; p=0.003 median 13.2 months vs 9.3 months). Previously
reported findings also showed LYNPARZA doubled objective response
rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]). The data from the
OlympiAD trial can be found in the August 10, 2017 issue of the New
England Journal of Medicine.
In January 2018, LYNPARZA was approved by the US FDA in the
treatment of gBRCAm metastatic breast cancer based on the OlympiAD
data.
A Phase III trial (n=1800), OlympiA, is evaluating LYNPARZA as
an adjuvant treatment in patients with gBRCA HER2-negative breast
cancer, with results expected in 2020. The trial is powered to
assess potential benefit in OS.
LYNPARZA is approved in the US for advanced ovarian cancer and
has treated more than 4,000 patients. 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.
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.
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 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).
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.
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 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).
NOTES TO EDITORS
About OlympiAD
OlympiAD is a global, randomized, open-label, multi-center Phase
III trial of 302 patients, assessing the efficacy and safety of
LYNPARZA tablets (300 mg twice daily) compared to chemotherapy
(physician’s choice of capecitabine, eribulin or vinorelbine). A
total of 205 patients were randomized to receive LYNPARZA and 97
patients were randomized to receive chemotherapy.
Patients in the OlympiAD trial had germline BRCA-mutated,
HER2-negative (hormone receptor-positive or triple negative) breast
cancer and received LYNPARZA for treatment in the metastatic
setting. Prior to enrollment, 71% of patients had received no more
than two previous chemotherapy treatments for metastasized breast
cancer and 28% of patients had received prior platinum-based
chemotherapy. Also enrolled were patients with HR+ breast cancer
who had received at least one endocrine therapy (adjuvant therapy
or therapy for metastatic disease) and had disease progression
during therapy, unless they had disease for which the endocrine
therapy was considered inappropriate.
The primary endpoint was PFS. Secondary endpoints included OS,
time to second progression or death, objective response rate,
health-related quality of life and safety and tolerability.
About Metastatic Breast Cancer (MBC)
PRs, ERs and HER2 receptors may be expressed on breast cancer
cells. A patient’s breast cancer will test either negative or
positive for these three receptors. If a tumor tests positive for
PR and/or ER, it is considered hormone-receptor positive. If a
tumor tests negative for all three receptors, it is considered
triple negative. These receptors indicate which hormones or other
proteins may be promoting growth of the cancer.
Metastatic Breast Cancer (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 and nearby lymph nodes.
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 for five years after diagnosis.
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.
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.
About 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 and cells become unstable. As a result, cells are
more likely to develop additional genetic alterations that can lead
to cancer.
About LYNPARZA® (olaparib)
LYNPARZA was 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 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.
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 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 PD-L1/PD-1
inhibitors for a range of tumor types. Working together, the
companies will 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 Oncology as one of AstraZeneca’s Four
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, DDR 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 therapy areas - Oncology, Cardiovascular, Renal &
Metabolism 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.
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