AstraZeneca and Merck (NYSE: MRK), known as MSD outside of the
United States and Canada, today announced that the U.S. Food and
Drug Administration (FDA) has informed AstraZeneca that the agency
will extend by three months the Prescription Drug User Fee Act
(PDUFA) date for the pending supplemental new drug application
(sNDA) for LYNPARZA in combination with abiraterone and prednisone
or prednisolone for the treatment of adult patients with metastatic
castration-resistant prostate cancer (mCRPC). The purpose of the
extension is to provide further time for the full review of the
submission. The companies will continue to work with the FDA to
facilitate the completion of the agency’s review.
The sNDA for LYNPARZA in combination with abiraterone and
prednisone or prednisolone is based on the Phase 3 PROpel trial,
results of which were published in NEJM Evidence in June 2022. The
application was granted priority review, and AstraZeneca and Merck
are committed to working with the FDA to bring this treatment
option to patients with mCRPC.
In November, the European Medicines Agency’s Committee for
Medicinal Products for Human Use adopted a positive opinion
recommending approval of LYNPARZA in combination with abiraterone
and prednisone or prednisolone in the European Union (EU) for the
treatment of adult patients with mCRPC for whom chemotherapy is not
clinically indicated. This combination is also undergoing
regulatory reviews in other countries.
Approved indications for LYNPARZA are not impacted by this
review period extension. Among these, LYNPARZA is approved in the
U.S. for patients with homologous recombination repair (HRR)
gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who
have progressed following prior treatment with enzalutamide or
abiraterone and in the EU, Japan and China for patients with
BRCA-mutated mCRPC who have progressed following prior therapy that
included a new hormonal agent (NHA). These approvals were based on
the data from the Phase 3 PROfound trial.
About PROpel
PROpel is a randomized, double-blind Phase 3 trial testing the
efficacy, safety and tolerability of LYNPARZA versus placebo when
given in addition to abiraterone and prednisone or prednisolone in
patients with mCRPC who had not received prior chemotherapy or NHAs
in the mCRPC setting. The major efficacy outcome was radiographic
progression-free survival as assessed by investigator per RECIST
v1.1 and Prostate Cancer Working Group (bone) criteria. Overall
survival was an additional efficacy outcome measure.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in approximately 1.5% of patients exposed
to LYNPARZA monotherapy, and the majority of events had a fatal
outcome. The median duration of therapy in patients who developed
MDS/AML was 2 years (range: <6 months to >10 years). All of
these patients had previous chemotherapy with platinum agents
and/or other DNA-damaging agents, including radiotherapy.
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 0.8% of patients exposed to
LYNPARZA monotherapy, 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.
Venous Thromboembolic Events (VTE): Including severe or
fatal pulmonary embolism (PE) occurred in patients treated with
LYNPARZA. VTE occurred in 7% of patients with metastatic
castration-resistant prostate cancer who received LYNPARZA plus
androgen deprivation therapy (ADT) compared to 3.1% of patients
receiving enzalutamide or abiraterone plus ADT in the PROfound
study. Patients receiving LYNPARZA and ADT had a 6% incidence of
pulmonary embolism compared to 0.8% of patients treated with ADT
plus either enzalutamide or abiraterone. Monitor patients for signs
and symptoms of venous thrombosis and pulmonary embolism, and treat
as medically appropriate, which may include long-term
anticoagulation as clinically indicated.
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
who received 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%), urinary
tract infection (13%), thrombocytopenia (11%), and stomatitis
(11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received 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—First-Line Maintenance Advanced Ovarian
Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients
treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared
to placebo/bevacizumab in the first-line maintenance setting
for PAOLA-1 were: nausea (53%), fatigue (including asthenia)
(53%), anemia (41%), lymphopenia (24%), vomiting (22%), and
leukopenia (18%). In addition, the most common adverse reactions
(≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of
the frequency compared with the placebo/bevacizumab arm were:
diarrhea (18%), neutropenia (18%), urinary tract infection (15%),
and headache (14%).
In addition, venous thromboembolic events occurred more commonly
in patients receiving LYNPARZA/bevacizumab (5%) than in those
receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients for LYNPARZA in combination with bevacizumab in the
first-line maintenance setting for PAOLA-1 were:
decrease in hemoglobin (79%), decrease in lymphocytes (63%),
increase in serum creatinine (61%), decrease in leukocytes (59%),
decrease in absolute neutrophil count (35%), and decrease in
platelets (35%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received 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 who received 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—Adjuvant Treatment of gBRCAm,
HER2-Negative, High-Risk Early Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the adjuvant setting for
OlympiA were: nausea (57%), fatigue (including asthenia)
(42%), anemia (24%), vomiting (23%), headache (20%), diarrhea
(18%), leukopenia (17%), neutropenia (16%), decreased appetite
(13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the adjuvant setting for
OlympiA were: decrease in lymphocytes (77%), increase in
mean corpuscular volume (67%), decrease in hemoglobin (65%),
decrease in leukocytes (64%), and decrease in absolute neutrophil
count (39%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA in the metastatic setting for
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 who received
LYNPARZA in the metastatic setting for 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%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the first-line maintenance setting
for POLO were: fatigue (60%), nausea (45%), abdominal pain
(34%), diarrhea (29%), anemia (27%), decreased appetite (25%),
constipation (23%), vomiting (20%), back pain (19%), arthralgia
(15%), rash (15%), thrombocytopenia (14%), dyspnea (13%),
neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and
stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the first-line maintenance
setting for POLO were: increase in serum creatinine
(99%), decrease in hemoglobin (86%), increase in mean corpuscular
volume (71%), decrease in lymphocytes (61%), decrease in platelets
(56%), decrease in leukocytes (50%), and decrease in absolute
neutrophil count (25%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic
Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA for PROfound were: anemia (46%),
fatigue (including asthenia) (41%), nausea (41%), decreased
appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia
(12%), cough (11%), and dyspnea (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA for PROfound were: decrease
in hemoglobin (98%), decrease in lymphocytes (62%), decrease in
leukocytes (53%), and decrease in absolute neutrophil count
(34%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA with
other myelosuppressive anticancer agents, including DNA-damaging
agents, indicate a potentiation and prolongation of
myelosuppressive toxicity.
CYP3A Inhibitors: Avoid coadministration of strong or
moderate CYP3A inhibitors when using LYNPARZA. If a strong or
moderate CYP3A inhibitor must be coadministered, reduce the dose of
LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice,
Seville oranges, and Seville orange juice during LYNPARZA
treatment.
CYP3A Inducers: Avoid coadministration of strong or
moderate CYP3A inducers when using 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 dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA 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 for LYNPARZA in the United States
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 for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer
in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of
adult patients with advanced epithelial ovarian, fallopian tube or
primary peritoneal cancer who are in complete or partial response
to first-line platinum-based chemotherapy and whose cancer is
associated with homologous recombination deficiency (HRD)-positive
status defined by either:
- a deleterious or suspected deleterious BRCA mutation,
and/or
- genomic instability
Select patients 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.
Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early
Breast Cancer
For the adjuvant treatment of adult patients with deleterious or
suspected deleterious gBRCAm, human epidermal growth factor
receptor 2 (HER2)-negative high-risk early breast cancer who have
been treated with neoadjuvant or adjuvant chemotherapy. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
gBRCAm, HER2-Negative Metastatic Breast Cancer
For the treatment of adult 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.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
HRR Gene-mutated Metastatic Castration-Resistant Prostate
Cancer
For the treatment of adult patients with deleterious or
suspected deleterious germline or somatic homologous recombination
repair (HRR) gene-mutated metastatic castration-resistant prostate
cancer (mCRPC) who have progressed following prior treatment with
enzalutamide or abiraterone. Select patients for therapy based on
an FDA-approved companion diagnostic for LYNPARZA.
Please see complete Prescribing Information,
including 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 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 metastatic castration-resistant prostate cancer
Prostate cancer is the second most common cancer in male
patients globally and is associated with a significant mortality
rate. Development of prostate cancer is often driven by male sex
hormones called androgens, including testosterone. In patients with
mCRPC, their prostate cancer grows and spreads to other parts of
the body despite the use of androgen-deprivation therapy to block
the action of male sex hormones. Approximately 10-20% of patients
with prostate cancer will develop castration-resistant prostate
cancer (CRPC) within five years, with at least 84% of these
patients presenting with metastases at the time of CRPC diagnosis.
Of patients with no metastases at CRPC diagnosis, 33% are likely to
develop metastases within two years.
About the AstraZeneca and Merck strategic oncology
collaboration
In July 2017, AstraZeneca and Merck, known as MSD outside of the
United States and Canada, announced a global strategic oncology
collaboration to co-develop and co-commercialize certain oncology
products including LYNPARZA, the world’s first PARP inhibitor, for
multiple cancer types. Working together, the companies will develop
these products in combination with other potential new medicines
and as monotherapies. Independently, the companies will develop
these oncology products 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
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. 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., Rahway,
N.J., USA
This news release of Merck & Co., Inc., Rahway, 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 candidates that
the candidates 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 the global outbreak of novel coronavirus disease
(COVID-19); 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 instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s Annual
Report on Form 10-K for the year ended December 31, 2021 and the
company’s other filings with the Securities and Exchange Commission
(SEC) available at the SEC’s Internet site (www.sec.gov).
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