AstraZeneca and Merck’s LYNPARZA Added to
Bevacizumab Reduced the Risk of Disease Progression or Death by 41%
in the Overall Trial Population of Women Who Responded to
Platinum-Based Chemotherapy
AstraZeneca and Merck (NYSE: MRK), known as MSD outside the
United States and Canada, today announced detailed positive results
from the Phase 3 PAOLA-1 trial showing LYNPARZA added to
bevacizumab demonstrated a statistically significant and clinically
meaningful improvement in progression-free survival (PFS) in women
with newly-diagnosed advanced ovarian cancer who had a complete or
partial response to first-line treatment with platinum-based
chemotherapy and bevacizumab.
The trial compared LYNPARZA when added to standard-of-care (SoC)
bevacizumab versus bevacizumab alone in women in the first-line
maintenance setting, irrespective of their genetic biomarker status
or outcome from previous surgery. Investigator-assessed results
showed LYNPARZA added to bevacizumab reduced the risk of disease
progression or death by 41% and improved PFS to a median of 22.1
months versus 16.6 months for those treated with bevacizumab alone
(HR 0.59 [95% CI, 0.49-0.72], p<0.0001).
The sensitivity analysis of blinded independent central review
(BICR) of PFS was consistent, showing a similar improvement with a
median of 26.1 months for LYNPARZA added to bevacizumab versus 18.3
months for bevacizumab alone (HR 0.63 [95% CI, 0.51-0.77],
p<0.0001).
The safety and tolerability profile of LYNPARZA and bevacizumab
were consistent with those known from previous trials for each
medicine.
The results were presented at the Presidential Symposium of the
2019 European Society of Medical Oncology (ESMO) congress in
Barcelona, Spain (Abstract #LBA2_PR).
Dr. José Baselga, executive vice president, Oncology R&D,
AstraZeneca, said, “This trial was designed to reflect everyday
clinical practice and used a global standard-of-care treatment with
LYNPARZA. We are working with regulatory authorities to bring
LYNPARZA to these patients as quickly as possible.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “PAOLA-1 is the second positive Phase 3 trial
involving LYNPARZA in the first-line maintenance setting for
advanced ovarian cancer. Following the positive SOLO-1 trial, we
are encouraged by the PAOLA-1 results which reaffirm AstraZeneca
and Merck’s ongoing commitment to explore potential treatment
options for more women with ovarian cancer.”
Isabelle Ray Coquard, principal investigator of the PAOLA-1
trial and medical oncologist, Department of Medical Oncology at the
Clinical Science Institute of the Léon Bérard Centre and President
of the GINECO (Groupe d’Investigateurs National des Etudes des
Cancers Ovariens et du sein) group, said, “The goal of first-line,
including maintenance treatment for women with newly-diagnosed
advanced ovarian cancer, is to delay relapse. Unfortunately, the
risk of relapse is high, as two out of three women relapse within
three years of initial diagnosis. In PAOLA-1, the results of
LYNPARZA added to bevacizumab were significant and have the
potential to change clinical practice in how women with advanced
ovarian cancer are treated in the first-line maintenance
setting.”
The trial also included exploratory sub-group analyses including
BRCA-mutated (BRCAm) and broader homologous recombination
deficiency (HRD) populations. In the BRCAm-positive sub-group,
LYNPARZA added to SoC bevacizumab vs. bevacizumab alone resulted in
median PFS of 37.2 months versus 21.7 months (HR 0.31 [95% CI,
0.20-0.47]) and 18.9 months versus 16 months in the non-BRCAm
sub-group (HR 0.71 [95% CI, 0.58-0.88]). For the HRD-positive
sub-group, median PFS for LYNPARZA added to bevacizumab was 37.2
months versus 17.7 months with bevacizumab alone (HR 0.33 [95% CI,
0.25-0.45]). In the HRD-positive, non-BRCAm sub-group, there was a
median PFS of 28.1 months with LYNPARZA added to bevacizumab versus
16.6 months on bevacizumab alone (HR 0.43 [95% CI, 0.28-0.66]). The
HRD-negative/unknown sub-group results showed a median PFS of 16.9
months for LYNPARZA added to bevacizumab vs. 16 months for
bevacizumab alone (HR 0.92 [95% CI, 0.72-1.17]).
Summary of PFS in overall population:
Median in months
Hazard Ratio (95% CI)
LYNPARZA + bevacizumab
bevacizumab alone
PFS (investigator assessed)
(n=806)
22.1
16.6
0.59 (0.49-0.72)
p<0.0001
PFS (BICR)
26.1
18.3
0.63 (0.51-0.77)
p<0.0001
Summary of PFS in exploratory subgroup analyses:
Median in months
Hazard Ratio (95% CI)
LYNPARZA + bevacizumab
bevacizumab alone
PFS by BRCAm status
BRCAm (n=237)
37.2i.
21.7
0.31 (0.20-0.47)
Non-BRCAm (n=569)
18.9
16.0
0.71 (0.58-0.88)
PFS by HRD status
HRD-positive (n=387)
37.2i.
17.7
0.33 (0.25-0.45)
HRD-positive, non-BRCAm (n=152)
28.1i.
16.6
0.43 (0.28-0.66)
HRD-negative/unknown (n=419)
16.9
16.0
0.92 (0.72-1.17)
i The median PFS estimate is immature at
this time (below 50% maturity) and will evolve with additional
follow up
The most common adverse events (AEs) ≥20% for LYNPARZA plus
bevacizumab compared to bevacizumab alone were nausea (53% vs.
22%), fatigue (53% vs. 32%), hypertension (46% vs. 60%), anemia
(41% vs. 10%), lymphopenia (24% vs. 10%), vomiting (22% vs. 11%)
and arthralgia (22% vs. 24%). Overall Grade 3 or above (AEs) were
57% for LYNPARZA added to bevacizumab and 51% for bevacizumab
alone. Grade 3 or above AEs were hypertension (19% vs. 30%), anemia
(17% vs. 0.4%), lymphopenia (7% vs. 1%), fatigue (5% vs. 2%),
neutropenia (6% vs 3%), nausea (2% vs. 1%), diarrhea (2% each),
leukopenia (2% vs. 1%), vomiting (2% each) and abdominal pain (1%
vs. 2% AEs led to dose interruption in 54% of patients on LYNPARZA
plus bevacizumab vs. 24% on bevacizumab alone, while 20% of
patients on LYNPARZA plus bevacizumab discontinued treatment vs. 6%
on bevacizumab alone.
LYNPARZA, which is being jointly developed and commercialized by
Merck and AstraZeneca, is currently approved in 64 countries,
including those in the EU, for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer regardless of BRCA
status. It is approved in the U.S. as first-line maintenance
treatment in BRCAm advanced ovarian cancer following response to
platinum-based chemotherapy. It is also approved in 38 countries,
including the U.S., countries in the EU, and Japan, for germline
BRCAm HER2-negative metastatic breast cancer previously treated
with chemotherapy; in the EU this includes locally advanced breast
cancer. LYNPARZA has been used to treat over 25,000 patients
worldwide.
LYNPARZA is the only PARP inhibitor with positive Phase 3 trials
in four different cancer types.
About PAOLA-1
PAOLA-1 is a double-blind Phase 3 trial evaluating the efficacy
and safety of LYNPARZA added to SoC bevacizumab vs. bevacizumab
alone, as a first-line maintenance treatment for newly-diagnosed
advanced FIGO Stage III-IV high grade serous or endometroid
ovarian, fallopian tube, or peritoneal cancer patients who had a
complete or partial response to first-line treatment with
platinum-based chemotherapy and bevacizumab. The intent-to-treat*
population refers to all patients randomized in the trial.
PAOLA-1 is an ENGOT (European Network of Gynaecological
Oncological Trial groups) trial, sponsored by ARCAGY Research
(Association de Recherche sur les CAncers dont GYnécologiques) on
behalf of GINECO (Groupe d’Investigateurs National des Etudes des
Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group
specialising in clinical and translational research in patients’
cancers and a member of the GCIG (Gynecologic Cancer
InterGroup).
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—First-Line Maintenance BRCAm Advanced
Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
in clinical trials of LYNPARZA in the first-line maintenance
setting for SOLO-1 were: nausea (77%), fatigue (67%),
abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%),
constipation (28%), upper respiratory tract infection/influenza/
nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased
appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia
(17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia
(11%), and stomatitis (11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the first-line
maintenance setting for SOLO-1 were: decrease in hemoglobin
(87%), increase in mean corpuscular volume (87%), decrease in
leukocytes (70%), decrease in lymphocytes (67%), decrease in
absolute neutrophil count (51%), decrease in platelets (35%), and
increase in serum creatinine (34%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA in the maintenance setting
for SOLO-2 were: 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%),
decreased appetite (21%), and dyspepsia (20%).
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/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%), mean corpuscular volume elevation (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 metastatic 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 or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients
with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No adjustment to the starting dose is
necessary in patients with mild renal impairment (CLcr=51-80
mL/min), but patients should be monitored closely for toxicity. 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:
First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious germline or somatic BRCA-mutated (gBRCAm
or sBRCAm) advanced epithelial ovarian, fallopian tube or primary
peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal
cancer for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
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.
Advanced gBRCAm ovarian cancer
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.
gBRCAm, HER2-negative metastatic breast cancer
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 click here for complete Prescribing Information,
including Patient Information (Medication Guide).
About LYNPARZA® (olaparib)
LYNPARZA is a 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. Inhibition of PARP with LYNPARZA leads to the
trapping of PARP bound to DNA single-strand breaks, stalling of
replication forks, their collapse and the generation of DNA
double-strand breaks and cancer cell death. LYNPARZA is being
tested in a range of tumor types with defects and dependencies in
the DDR.
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 as a
monotherapy and in combination across multiple cancer types.
About Ovarian Cancer
Ovarian cancer the eighth most common cause of death from cancer
in women worldwide, with a five-year survival rate of approximately
19%. In 2018, there were nearly 300,000 new cases diagnosed and
around 185,000 deaths.
About Homologous Recombination Deficiency (HRD)
Homologous recombination deficiencies (HRDs), including BRCA,
cause genomic instability which can be detected using assays such
as the Myriad My Choice HRD test. BRCA mutations are just one of
many homologous recombination repair deficiencies which are found
in up to half of newly diagnosed advanced ovarian cancer
patients.
About GINECO
GINECO (Groupe d’Investigateurs Nationaux pour l’Étude des
Cancers Ovariens et du sein) is the French Cooperative Group in
Oncology labelled by INCA (Institut National du Cancer or French
NCI) developing and conducting gynaecological and metastatic breast
cancer clinical trials at the national and international level.
Founded in 1993, the GINECO group is member of international
consortia such as ENGOT and GCIG.
About ENGOT
ENGOT (European Network for Gynaecological Oncological Trial
groups) is a research network of the European Society of
Gynaecological Oncology (ESGO). Founded in 2007, ENGOT includes 21
cooperative groups from 25 European countries.
About GCIG
The GCIG (Gynecological Cancer InterGroup) aims to promote and
facilitate high quality clinical trials in order to improve
outcomes for women with gynaecological cancer. Founded in 1998,
GCIG includes 23 cooperative groups from 28 countries
worldwide.
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. Working together, the companies will develop
LYNPARZA and selumetinib in combination with other potential new
medicines and as monotherapies. Independently, the companies will
develop LYNPARZA and selumetinib in combination with their
respective PD-L1 and PD-1 medicines.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
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The company undertakes no obligation to publicly update any
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future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
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Annual Report on Form 10-K and the company’s other filings with the
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