First PARP Inhibitor to Demonstrate Clinical
Benefit in Radiographic Progression-Free Survival in Combination
With New Hormonal Agent in This Setting
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the
United States and Canada, today announced positive results from the
Phase 3 PROpel trial, in which LYNPARZA in combination with
abiraterone and prednisone demonstrated a statistically significant
and clinically meaningful improvement in the primary endpoint of
radiographic progression-free survival (rPFS) versus abiraterone
plus prednisone as a first-line treatment for men with metastatic
castration-resistant prostate cancer (mCRPC) with or without
homologous recombination repair (HRR) gene mutations.
At a planned interim analysis, the Independent Data Monitoring
Committee concluded that the trial met the primary endpoint of rPFS
in men with mCRPC who had not received treatment in the first-line
setting, including new hormonal agents (NHAs) or chemotherapy. The
trial also showed a trend at this interim analysis towards improved
overall survival (OS). However, the OS data are still immature, and
the trial will continue to assess OS as a key secondary endpoint.
The safety and tolerability were consistent with the known profiles
of each medicine and will continue to be assessed.
Globally, prostate cancer is the second most common cancer in
men, with an estimated 1.4 million patients diagnosed worldwide in
2020. Approximately 10-20% of men with advanced prostate cancer are
estimated to develop CRPC within five years, and at least 84% of
these men may develop metastases at the time of CRPC diagnosis.
Susan Galbraith, executive vice president, oncology R&D,
AstraZeneca, said, “Today, men with metastatic castration-resistant
prostate cancer have limited options in the first-line setting, and
sadly often the disease progresses after initial treatment with
current standards of care. These exciting results demonstrate the
potential for LYNPARZA with abiraterone to become a new first-line
option for these patients regardless of their biomarker status and
may help reach a broad population of patients living with this
aggressive disease. We look forward to discussing the results with
global health authorities as soon as possible.”
Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories,
said, “We are encouraged by the PROpel results and the clinical
benefit LYNPARZA in combination with abiraterone demonstrated
versus abiraterone as a potential first-line treatment option for
men with metastatic castration-resistant prostate cancer. These
data build on Merck and AstraZeneca’s commitment to bring LYNPARZA
to earlier lines of treatment and to more patients with advanced
prostate cancer.”
The data will be presented at an upcoming medical meeting.
About PROpel PROpel is a randomized, double-blind,
multicenter Phase 3 trial testing the efficacy, safety and
tolerability of LYNPARZA versus placebo when given in addition to
abiraterone in men with mCRPC who had not received prior
chemotherapy or NHAs in the first-line setting. Patients in both
treatment groups also received either prednisone or prednisolone (5
mg twice daily). The primary endpoint is rPFS, and secondary
endpoints include OS and time to first subsequent anticancer
therapy or death.
The trial enrolled men with or without HRR gene mutations. They
may have previously been treated with docetaxel at a prior stage of
disease. The trial excluded men with prior treatment with
abiraterone. Treatment with any other NHA must have been stopped
one year or longer prior to randomization. Men must have an Eastern
Cooperative Oncology Group (ECOG) performance status of 0-1 and be
a candidate for abiraterone treatment with documented evidence of
progressive disease.
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.
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.
Venous Thromboembolic Events: Including pulmonary
embolism, 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.
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—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 compared to a ≥5% frequency for
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 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%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma Most common adverse reactions (Grades
1-4) in ≥10% of patients in clinical trials of 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 in clinical trials of 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 in clinical trials of 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 in clinical trials of 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.
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 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 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 Metastatic Castration-Resistant Prostate Cancer
Prostate cancer is the second most common cancer in men 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 men with advanced
prostate cancer are estimated to develop CRPC within five years,
and at least 84% of these men may develop metastases at the time of
CRPC diagnosis. Of men 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 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 For over 130 years, Merck, 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 in pursuit of our mission to save
and improve lives. We demonstrate our commitment to patients and
population health by increasing access to health care through
far-reaching policies, programs and partnerships. Today, Merck
continues to be at the forefront of research to prevent and treat
diseases that threaten people and animals – including cancer,
infectious diseases such as HIV and Ebola, and emerging animal
diseases – as we aspire to be the premier research-intensive
biopharmaceutical company in the world. For more information, visit
www.merck.com and connect with us on Twitter, Facebook, Instagram,
YouTube and LinkedIn.
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