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LYNPARZA® (olaparib) First-Line Maintenance Therapy Nearly Doubled the Time Without Disease Progression or Death in Phase 3 POLO Trial for Patients with Germline BRCA-Mutated Metastatic Pancreatic Cancer

22% of Patients Receiving LYNPARZA Remained Progression-Free After
Two Years vs. 10% on Placebo, Following Platinum-Based Chemotherapy

AstraZeneca and Merck’s LYNPARZA is the Only PARP Inhibitor to
Demonstrate Benefit in This Setting in a Phase 3 Trial

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #ASCO19–AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United
States and Canada, today announced detailed results from the Phase 3
POLO trial evaluating LYNPARZA tablets as a first-line maintenance
monotherapy for patients with germline BRCA-mutated (gBRCAm)
metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose
disease had not progressed following platinum-based chemotherapy. The
results of the trial will be featured today in a press briefing at the 55th
Annual Meeting of the American Society of Clinical Oncology (ASCO) in
Chicago and presented as a late-breaker oral presentation at 1:00 p.m.
CDT during the plenary session (Abstract #LBA4). The results will also
be published online simultaneously in the New England Journal of
Medicine
(NEJM).


Results from 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 47% (HR 0.53 [95% CI 0.35-0.82], p=0.004). The median PFS
for patients treated with LYNPARZA was 7.4 months compared to 3.8 months
for those on placebo, with more than twice as many patients remaining
progression free at both one year (34% on LYNPARZA vs. 15% on placebo)
and two years (22% vs. 10%) respectively.

 

Summary of PFSi,ii

 
      Lynparza (n=92)     Placebo (n=62)
Number of patients with event (%)iii     60 (65)     44 (71)
Median (in months)     7.4     3.8
Hazard ratio (95% CI)     0.53 (0.35-0.82)
P-value     P=0.004

i Blinded, independent central review
ii Median
duration of follow-up for progression was 9.1 months (range, 0 to 39.6)
and 3.8 months (range, 0 to 29.8) in the olaparib and placebo arms,
respectively

iii Analysis of the primary endpoint was
performed at 68% data maturity

José Baselga, executive vice president, Oncology R&D, AstraZeneca said,
These remarkable results raise new hope for a patient population that
has seen little progress over the last 20 years. The POLO trial showed
that at six months, more than twice as many patients taking LYNPARZA
were progression free compared to those on placebo. We are now working
with regulatory authorities to bring LYNPARZA to patients as quickly as
possible.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
We are encouraged by the results of the POLO trial which showed a
considerable reduction in risk of disease progression or death with
LYNPARZA for germline BRCA-mutated metastatic pancreatic cancer
patients who did not progress on chemotherapy. Currently, less than 3%
of metastatic pancreatic cancer patients survive more than five years
after diagnosis. The results of this trial reinforce Merck and
AstraZeneca’s commitment to develop innovative treatments for cancers
with few options.”

Dr. Hedy L. Kindler, MD, Co-Principal Investigator of the POLO trial and
professor of medicine, University of Chicago Medicine, said, “Despite
efforts to identify therapies, targeted or combination treatments to
improve patient outcomes, pancreatic cancer remains an area of high
unmet need. The results of the POLO trial may open the door to a new era
of personalized, biomarker-led care in metastatic pancreatic cancer and
reinforces the importance of knowing BRCA status at diagnosis.”

The safety and tolerability profile of LYNPARZA in the POLO trial was in
line with that observed in prior clinical trials. The most common
adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%),
abdominal pain (29%), diarrhea (29%), anemia (28%), decreased appetite
(25%) and constipation (23%). The most common ≥ grade 3 AEs were anemia
(11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain
(2%), vomiting (1%) and arthralgia (1%). Around 84% of patients on
LYNPARZA remained on the recommended starting dose, while 16% had a dose
reduction vs. 97% who remained on the recommended dose with placebo,
while 3% had a dose reduction. Additionally, 95% of patients on LYNPARZA
continued treatment without an AE-related discontinuation, while 5% had
an AE-related discontinuation vs. 98% who continued treatment without an
AE-related discontinuation and 2% that had an AE-related discontinuation
with placebo.

LYNPARZA is not currently approved by the U.S. Food and Drug
Administration (FDA) for gBRCAm pancreatic cancer.

LYNPARZA 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. Regulatory reviews are underway in other jurisdictions
for both ovarian cancer and breast cancer.

About POLO

POLO is a Phase 3 randomized, double-blinded, placebo-controlled,
multi-center study of LYNPARZA tablets (300 mg twice daily) as
maintenance monotherapy vs. placebo. The trial randomized 154 patients
with gBRCAm metastatic pancreatic cancer whose disease had not
progressed on first-line platinum-based chemotherapy. Patients were
randomized (3:2) to receive LYNPARZA or placebo until disease
progression. The primary endpoint was PFS and key secondary endpoints
include overall survival, time to second disease progression, overall
response rate, disease control rate and health-related quality of life.

About Pancreatic Cancer

Pancreatic cancer is the 12th most common cancer worldwide,
with 458,918 new cases in 2018 alone. With the worst survival rate of
all the most common cancers, it is the seventh leading cause of cancer
death, and less than 3% of patients with metastatic disease survive more
than five years after diagnosis. Early diagnosis of pancreatic cancer is
difficult, as often there are no symptoms until it is too late. Around
80% of patients are diagnosed at the metastatic stage.

There are two types of pancreatic cancer. Exocrine tumors, of which the
most common type is pancreatic ductal adenocarcinoma (PDAC), start in
the exocrine cells, where enzymes help to digest food. Neuroendocrine
tumors start in neuroendocrine cells, which produce hormones, such as
insulin, that control different functions of the body.

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 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.

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 the AstraZeneca and Merck Strategic Oncology Collaboration

In 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. 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 TwitterFacebookInstagram,
YouTube
and LinkedIn.

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“company”) includes “forward-looking statements” within the meaning of
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Reform Act of 1995. These statements are based upon the current beliefs
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respect to pipeline products that the products will receive the
necessary regulatory approvals or that they will prove to be
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Contacts

Media Contacts:
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(267) 305-3558

Michael Close
(267) 305-1211

Investor Contacts:
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