LYNPARZA is the First and Only PARP
Inhibitor to Demonstrate Activity in Combination with
Standard-of-Care Treatment in Prostate Cancer
AstraZeneca and Merck Presented Results of
Study 08 at 2018 ASCO Annual Meeting with Simultaneous Publication
in The Lancet Oncology
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the
United States and Canada, today presented data which showed
clinical improvement in median radiologic progression-free survival
(rPFS) with LYNPARZA® (olaparib) in combination with abiraterone
compared to abiraterone monotherapy, a current standard of care, in
metastatic castration-resistant prostate cancer (mCRPC). LYNPARZA
is being jointly developed and commercialized by AstraZeneca and
Merck.
The results of Study 08, a randomized, double-blinded,
multi-center Phase 2 trial, comparing LYNPARZA in combination with
abiraterone (n=71) to abiraterone monotherapy (n=71) in patients
with previously-treated mCRPC, regardless of homologous
recombination repair (HRR) mutation status, were presented at the
2018 American Society of Clinical Oncology (ASCO) Annual Meeting as
a “Best of ASCO presentation” and were published online today in
The Lancet Oncology. The primary endpoint was rPFS. Secondary
endpoints included time to second progression or death (PFS2),
overall survival (OS) and health-related quality of life.
LYNPARZA is not FDA-approved for prostate cancer. LYNPARZA is
indicated for the treatment of advanced ovarian cancer patients
with a gBRCA mutation previously treated with three or more lines
of chemotherapy; for the maintenance treatment of recurrent ovarian
cancer in response to platinum-based chemotherapy regardless of
BRCA mutation status; and for the treatment of gBRCA HER2-negative
metastatic breast cancer after chemotherapy and prior endocrine
therapy, if appropriate. Physicians should select advanced ovarian
cancer and metastatic breast cancer patients for therapy based on a
FDA-approved companion diagnostic. Please see Indications for
LYNPARZA® (olaparib) 100 mg in the U.S.
below.
Noel Clarke, professor of urological oncology, Christie NHS
Foundation Trust, Manchester, United Kingdom, said, “This is the
first time we have seen an improvement with the use of a PARP
inhibitor in combination with abiraterone in patients with
metastatic castration-resistant prostate cancer, and this effect
may be independent of HRR status. The data suggest this therapeutic
combination may be a promising new treatment approach for this
aggressive disease.”
Sean Bohen, executive vice president, global medicines
development and chief medical officer at AstraZeneca, said, “A
previous trial demonstrated improvements in response rates with
LYNPARZA monotherapy in metastatic castration-resistant patients
with HRR mutations. The Study 08 combination data suggest that,
regardless of their mutation status, men with metastatic
castration-resistant prostate cancer may potentially benefit from
LYNPARZA in combination with abiraterone.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “There is a significant unmet medical need for
patients with metastatic castration-resistant prostate cancer as
they are a high-risk group with limited treatment options. LYNPARZA
is the first PARP inhibitor to demonstrate activity in combination
with standard-of-care treatment in prostate cancer. These data from
Study 08 represent another important milestone in the clinical
development of LYNPARZA.”
Median rPFS was 13.8 months with LYNPARZA and abiraterone
compared to 8.2 months with abiraterone alone (HR=0.65 [95% CI,
0.44-0.97]; p=0.034). Median PFS2 was 23.3 months versus 18.5
months (HR=0.79 [95% CI, 0.51-1.21]). Median OS was 22.7 months
with combination treatment versus 20.9 months with abiraterone
alone (HR=0.91; [95% CI, 0.60-1.38]). Pre-specified exploratory
subgroup analyses demonstrated an rPFS improvement in patients
regardless of HRR status (see Table 1). Study 08 was not powered
for subgroup analyses, PFS2 and OS. HRR mutation status was not
known for all patients.
Table 1: rPFS by HRR status
Median rPFS
(months)
HR
95% CI
LYNPARZA +
abiraterone
abiraterone
Overall (n=142)
13.8
8.2 0.65
0.44-0.97
HRR-mutation (n=21)
17.8
6.5 0.74
0.26-2.12 Wild-type HRR (n=35)
15.0 9.7
0.52 0.24-1.15
Partially-characterized HRR status
(n=86)*
13.1
6.4 0.67
0.40-1.13
*Those whose plasma and blood samples both tested negative for
HRR mutations, but for whom no valid tumor test result was
available
The safety of LYNPARZA in combination with abiraterone was also
reported, as was the safety of abiraterone monotherapy. Grade ≥3
adverse events (AEs), serious AEs and treatment discontinuations
due to AEs were more frequent with combination treatment than
abiraterone alone (54% vs 28%; 34% vs 18%; 30% vs 10%,
respectively). The most common grade ≥3 AEs in the combination arm
were anemia (21%), pneumonia (6%) and myocardial infarction (6%).
Serious cardiovascular events occurred in seven patients in the
combination group and one patient in the abiraterone group.
LYNPARZA is associated with a number of serious, potentially fatal
risks, including MDS-AML, pneumonitis and embryo-fetal toxicity.
Please see Important Safety Information for LYNPARZA®
(olaparib) tablets 100 mg below.
In addition to Study 08, other studies are underway to explore
the potential of LYNPARZA as a monotherapy for HRR-mutated mCRPC,
including PROfound, which is testing LYNPARZA monotherapy versus
enzalutamide or abiraterone in patients with previously-untreated
mCRPC. Additional trials are planned to explore LYNPARZA in
combination for the treatment of mCRPC regardless of HRR status.
LYNPARZA was granted Breakthrough Therapy Designation by the U.S.
Food and Drug Administration in 2016 for the treatment of
BRCA-mutated or ataxia telangiectasia mutated (ATM) gene-mutated
mCRPC.
LYNPARZA is a first-in-class PARP inhibitor approved in the U.S.
for certain patients with recurrent ovarian and metastatic breast
cancer and has treated nearly 5,500 patients since 2014. LYNPARZA
has a broad clinical development program, and AstraZeneca and Merck
are working together to deliver LYNPARZA as quickly as possible to
more patients across multiple cancer types, including prostate and
pancreatic cancers.
Indications for LYNPARZA® (olaparib) 100 mg in
the U.S.
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated:
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.
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.
In patients with deleterious or suspected deleterious gBRCAm,
human epidermal growth factor receptor 2 (HER2)-negative metastatic
breast cancer who have previously 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 treatment. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
Important Safety Information for LYNPARZA®
(olaparib) tablets 100 mg
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 (olaparib) 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—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA in the maintenance setting
for SOLO-2: 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%), and decreased appetite
(21%).
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 (olaparib) for advanced gBRCAm
ovarian cancer after 3 or more lines of chemotherapy (pooled
from 6 studies) were: fatigue (including 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%), increase in mean corpuscular volume (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 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 (olaparib). 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 hepatic impairment (Child-Pugh
classification A). There are no data in patients with moderate or
severe hepatic impairment.
Renal Impairment: No adjustment to the starting dose is
necessary in patients with mild renal impairment (CLcr=51-80
mL/min). 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).
About Study 08
Study 08 was a global, randomized, double-blinded, multi-center
Phase 2 trial of 142 patients, assessing the efficacy and safety of
LYNPARZA tablets (300 mg twice daily) and abiraterone tablets (4 x
250 mg once daily) (n=71) compared to matched placebo and
abiraterone tablets (4 x 250 mg once daily) (n=71) in patients
regardless of HRR status. Prednisone/prednisolone (5 mg twice
daily) was administered to patients in both treatment arms.
Patients in Study 08 had previously received docetaxel for
mCRPC. Prior to enrollment, patients had received no more than two
lines of chemotherapy.
The primary endpoint was radiologic progression-free survival
(rPFS) (time from randomization to radiologic progression or
death). rPFS is increasingly used in clinical trials of mCRPC as a
clinically-meaningful endpoint focusing on the impact of treatment
on disease progression to areas where spread of prostate cancer is
common, notably soft tissue and bone.
Secondary endpoints included time to second progression or death
(PFS2), overall survival (OS) and health-related quality of
life.
About Metastatic Castration-Resistant Prostate Cancer
(mCRPC)
Prostate cancer is the second most common cancer in men, with an
estimated 1.6 million new cases diagnosed worldwide in 2015, and is
associated with a significant mortality rate. Development of
prostate cancer is often driven by male sex hormones called
androgens, including testosterone. Metastatic castration-resistant
prostate cancer (mCRPC) occurs when 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 percent of men with advanced prostate
cancer will develop mCRPC within five years, and at least 84
percent of these will have metastases at the time of mCRPC
diagnosis. Of men with no metastases at mCRPC diagnosis, 33 percent
are likely to develop metastases within two years. Despite an
increase in the number of available therapies for men with mCRPC,
five-year survival is only 28 percent.
About LYNPARZA® (olaparib)
LYNPARZA was the 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. Specifically, in vitro studies have shown that
LYNPARZA-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complexes,
resulting in DNA damage and cancer cell death.
LYNPARZA is being tested in a range of DDR-deficient tumor
types.
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 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
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 2017
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see complete Prescribing Information
for LYNPARZA (olaparib), including Patient Information
(Medication Guide)
View source
version on businesswire.com: https://www.businesswire.com/news/home/20180604006294/en/
MerckMedia:Pamela Eisele, 267-305-3558Michael Close,
267-305-1211orInvestors:Teri Loxam, 908-740-1986Michael DeCarbo,
908-740-1807
Merck (NYSE:MRK)
Historical Stock Chart
From Mar 2024 to Apr 2024
Merck (NYSE:MRK)
Historical Stock Chart
From Apr 2023 to Apr 2024