What can we help you find?

June 4, 2018 4:00 pm ET

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)

Merck
Media:
Pamela Eisele, 267-305-3558
Michael Close, 267-305-1211
or
Investors:
Teri Loxam, 908-740-1986
Michael DeCarbo, 908-740-1807