AstraZeneca and Merck’s LYNPARZA Increased
the Median Time Without Disease Progression or Death by 4.2 Months
Versus Physician’s Choice of Chemotherapy Following Two or More
Prior Lines of Chemotherapy
AstraZeneca and Merck’s LYNPARZA is the
First and Only PARP Inhibitor to Demonstrate Efficacy Versus
Chemotherapy in This Setting
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the
United States and Canada), today presented full results from the
Phase 3 SOLO3 trial which evaluated LYNPARZA, compared to
chemotherapy, for the treatment of platinum-sensitive relapsed
patients with germline BRCA1/2-mutated (gBRCAm) advanced ovarian
cancer, who have received two more prior lines of chemotherapy. The
results were presented at the 55th Annual Meeting of the American
Society of Clinical Oncology (ASCO) in Chicago.
The results from the trial showed a statistically-significant
and clinically-meaningful improvement in objective response rate
(ORR) in the LYNPARZA arm compared to the chemotherapy arm (ORR;
72.2% for LYNPARZA vs 51.4% for chemotherapy; 95% CI: 1.40 to 4.58;
p=0.002).
The key secondary endpoint of progression-free survival (PFS)
was also significantly increased in the LYNPARZA arm (13.4 months)
compared to the chemotherapy arm (9.2 months; PFS HR 0.62
[p=0.013]).
Summary of endpoints[i]
LYNPARZA(300 mg bd)
Chemotherapy
ORR (primary endpoint)
Number of patients 151 72
Number of patients with response (%) 109 (72.2%)
37 (51.4%) Odds ratio (95% CI) 2.53
(1.40, 4.58) p-value 0.002
PFS (key secondary
endpoint)[ii] Number of patients
178 88 Number of patients with event
(%) 110 (61.8%) 49 (55.7%) Hazard ratio
(95% CI) 0.62 (0.43, 0.91) Median in months
13.4 9.2 p-value 0.013
iAssessed by blinded independent central
review
iiAnalysis was done at 64.5% maturity
José Baselga, executive vice president, Oncology R&D,
AstraZeneca, said, “This trial shows that LYNPARZA has the
potential to provide a much-needed improvement and alternative over
standard-of-care chemotherapy for certain patients with relapsed
BRCA-mutated advanced ovarian cancer. This is the fourth positive
Phase 2 or Phase 3 trial in advanced ovarian cancer for LYNPARZA
across multiple lines of therapy. We look forward to discussing
these results with regulatory authorities.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “LYNPARZA is the first and only PARP inhibitor
to demonstrate efficacy versus chemotherapy in relapsed
BRCA-mutated advanced ovarian cancer following two or more prior
lines of chemotherapy. The positive SOLO3 results reaffirm
AstraZeneca and Merck’s ongoing commitment to explore potential
treatment options beyond standard-of-care for BRCA-mutated patients
with advanced stage disease.”
The safety and tolerability profile of LYNPARZA in SOLO3 was
consistent with previous trials. The most common adverse events
(AEs) ≥ 20% were nausea (64.6%), fatigue/asthenia (52.2%), anemia
(51.1%), vomiting (38.2%), diarrhea (28.1%) and abdominal pain
(21.3%). The most common ≥ Grade 3 AEs were anemia (21.3%),
neutropenia (9.6%), fatigue/asthenia (4.5%) and thrombocytopenia
(3.9%). AEs led to dose interruption in 48% percent of patients on
LYNPARZA vs. 42% in the chemotherapy arm, while 7% of patients
discontinued treatment vs. 20% in the chemotherapy arm.
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 SOLO3SOLO3 is a Phase 3 randomized, open-label,
controlled, multi-center trial to evaluate the efficacy and safety
of LYNPARZA tablets following two or more prior lines of
chemotherapy. The trial randomized 266 patients with a deleterious
or suspected deleterious BRCA1 or BRCA2 mutation. Eligible patients
were randomized (2:1) to receive LYNPARZA 300mg tablets twice daily
or physician’s choice single-agent chemotherapy (paclitaxel,
topotecan, pegylated liposomal doxorubicin or gemcitabine). The
primary endpoint was overall response rate (ORR) by blinded
independent central review and key secondary endpoints included
progression-free survival (PFS), time to second disease progression
or death and overall survival.
About Ovarian CancerOvarian cancer is a leading cause of
cancer death in women worldwide, with a five-year survival rate of
19%. In 2018, there were over 295,000 new cases diagnosed and
around 185,000 deaths. Over 70% of women with ovarian cancer have
advanced disease at the time of diagnosis, with up to 80% at risk
of recurrence after initial treatment. Effective treatments are
needed in later lines of therapy as patients typically obtain
limited benefit after two prior lines of chemotherapy.
About BRCABRCA1 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
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—First-Line Maintenance BRCAm Advanced
Ovarian CancerMost 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
CancerMost 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 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/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
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 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 CancerFor
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 CancerFor 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 cancerFor 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 cancerIn 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
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. 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 CancerOur 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 MerckFor 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
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