Solo-1 Phase III Trial Demonstrates Lynparza Maintenance Therapy Cut the Risk of Disease Progression or Death by 70% in Patients with Newly-Diagnosed, Advanced BRCA-Mutated Ovarian Cancer

60% of patients receiving LYNPARZA remained progression-free at
three years compared to 27% on placebo following platinum-based
chemotherapy

LYNPARZA is the only PARP inhibitor to demonstrate an improvement
in progression-free survival as 1
st-line
maintenance treatment for advanced ovarian cancer

WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., (Merck: known as
MSD outside the US and Canada) today announced detailed results from the
Phase III SOLO-1 trial testing LYNPARZA® (olaparib) 300 mg
tablets twice-daily as a maintenance treatment for patients with newly
diagnosed advanced BRCA-mutated (BRCAm) ovarian cancer who
were in complete or partial response following 1st-line standard
platinum-based chemotherapy.

Results of the trial confirm the statistically significant and
clinically meaningful improvement in progression-free survival (PFS) for
LYNPARZA compared to placebo, reducing the risk of disease progression
or death by 70% (HR 0.30 [95% CI 0.23-0.41], P<0.001). With median 41
months of follow-up, the median PFS for patients treated with LYNPARZA
was not reached compared to 13.8 months for patients treated with
placebo. Of those receiving LYNPARZA, 60% remained progression-free at
36 months, compared to 27% of women in the placebo arm. The data were
presented at the Presidential Symposium of the ESMO 2018 Congress
(European Society for Medical Oncology) in Munich, Germany, and
published simultaneously online in the New England Journal of Medicine
(NEJM).

Summary of Progression Free Survival as Assessed by
Investigators
1,2

 

        Lynparza (n=260)       Placebo (n=131)
Number of patients with event (%)3       102 (39)       96 (73)
Median (in months)       Not reached       13.8
Hazard ratio (95% CI)       0.30 (0.23-0.41)
P-value       p<0.001
1   Investigator-assessed
2 Median (interquartile range) duration of follow-up 40.7 months
(34.9–42.9) for olaparib and 41.2 months (32.2–41.6) for placebo
3 Analysis was done at 50.6% maturity
 

Sean Bohen, Executive Vice President, Global Medicines Development and
Chief Medical Officer, AstraZeneca said: “There is currently a
significant unmet need in the treatment of advanced ovarian cancer
because 70% of women relapse within the first three years after their
initial treatment. The remarkable results of the SOLO-1 trial, which
showed that 60% of women with newly diagnosed, advanced BRCA-mutated
ovarian cancer remained progression-free at three years, highlight the
potential of LYNPARZA as a maintenance therapy in the 1st-line
setting.”

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories, said:
Our collective goal in oncology research is to improve long-term
outcomes for people living with cancer. Based on the SOLO-1 trial
results, LYNPARZA is the only PARP inhibitor to have demonstrated a
significant and clinically meaningful improvement in reducing the risk
of progression for newly diagnosed patients with advanced BRCA-mutated
ovarian cancer following platinum-based chemotherapy. We are working
with regulatory authorities as quickly as possible to seek approval of
LYNPARZA for these patients.”

Kathleen Moore, Co-Principal Investigator of the SOLO-1 trial and
Associate Director for Clinical Research, Stephenson Cancer Center at
The University of Oklahoma, Oklahoma City, Oklahoma, said: “Women with
ovarian cancer are often diagnosed with advanced disease, which
unfortunately is associated with poor long-term survival rates. The
newly diagnosed setting is our best opportunity to achieve a sustained
remission, since once a patient’s ovarian cancer recurs, it is typically
incurable. The SOLO-1 results demonstrate the potential of LYNPARZA
maintenance therapy earlier in the treatment pathway and reinforce the
importance of identifying a patient’s BRCA mutation status at the
time of diagnosis—these results could change the way we treat women with
advanced BRCA-mutated ovarian cancer.”

The SOLO-1 safety profile was in line with that observed in prior
clinical trials. The most common adverse events (AEs) ≥20% in patients
taking LYNPARZA in the trial were nausea (77%), fatigue/asthenia (63%),
vomiting (40%), anemia (39%), diarrhea (34%), constipation (28%),
dysgeusia (26%), arthralgia (25%), abdominal pain (25%), neutropenia
(23%), headache (23%), dizziness (20%) and decreased appetite (20%). The
most common Grade ≥3 adverse reactions were anemia (22%) and neutropenia
(9%).1 Seventy-two percent of patients on LYNPARZA remained
on the recommended starting dose. Additionally, 88% of patients on
LYNPARZA continued treatment without an AE-related discontinuation.
Further, 48% of patients on LYNPARZA did not have a dose interruption as
a result of an AE.

Per SOLO-1 protocol guidelines, patients who demonstrated a complete
response (no radiological evidence of disease) at 2 years stopped
treatment with LYNPARZA; patients who demonstrated a partial response
and who in the opinion of the treating physician can derive further
benefit from continuous treatment, were treated beyond 2 years.

AstraZeneca and Merck are exploring additional trials in ovarian cancer,
including the ongoing GINECO/ENGOTov25 Phase III trial, PAOLA-1. This
trial is testing the effect of LYNPARZA in combination with
bevacizumab as a maintenance treatment for patients with newly diagnosed
advanced ovarian cancer, regardless of their BRCA status. Results
are expected during the second half of 2019.

LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor
approved in the US 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.

LYNPARZA is not currently FDA-approved for advanced BRCA-mutated
ovarian cancer treatment in the first-line maintenance setting. LYNPARZA
is indicated for the maintenance treatment of recurrent ovarian cancer
in response to platinum-based chemotherapy regardless of BRCA
mutation status, and for the treatment of advanced ovarian cancer
patients with a germline BRCA-mutation previously treated with
three or more lines of chemotherapy.7 Physicians should
select advanced ovarian cancer patients for therapy based on an
FDA-approved companion diagnostic. Please see complete indications below.

IMPORTANT SAFETY INFORMATION

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
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 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. 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).

INDICATIONS

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 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 see complete Prescribing
Information
, including Patient Information (Medication Guide).

NOTES TO EDITORS

About the SOLO-1 Phase III Trial

SOLO-1 is a Phase III randomized, double-blind, placebo-controlled,
multi-center trial to evaluate the efficacy and safety of LYNPARZA
tablets (300 mg twice-daily) as maintenance monotherapy compared with
placebo, in newly diagnosed patients with advanced BRCAm ovarian
cancer following platinum-based chemotherapy. The trial randomized 391
patients with a deleterious or suspected deleterious BRCA1 or BRCA2
mutation who were in clinical complete or partial response following
platinum-based chemotherapy. Patients were randomized (2:1) to receive
LYNPARZA or placebo for up to two years or until disease progression (at
the investigator’s discretion)., The primary endpoint was
investigator-assessed progression free survival and key secondary
endpoints included time to second disease progression or death, time to
first subsequent treatment and overall survival.

About Ovarian Cancer

Approximately 20,000 women in the United States are diagnosed with
ovarian cancer (including ovarian, fallopian tube and primary peritoneal
cancers) each year. Among women in the United States, it is the ninth
most common cancer and the fifth leading cause of cancer death.

The risk of developing ovarian cancer is increased in women with
specific inherited genetic abnormalities, including BRCA
mutations.

AstraZeneca is committed to the continued development of our R&D
portfolio for ovarian cancer, with a focus on improved care for all
patients.

About BRCA Mutations

BRCA1 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 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, 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 in
monotherapy and in combination across multiple cancer types. LYNPARZA is
being tested in a range of DDR-deficient tumor types and is the
foundation of AstraZeneca’s industry-leading portfolio of compounds
targeting DDR mechanisms in cancer cells.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US,
known as MSD outside the United States and Canada, announced a global
strategic oncology collaboration to co-develop and co-commercialize
olaparib, the world’s first PARP inhibitor, and potential new medicine
selumetinib, a MEK inhibitor, for multiple cancer types. Working
together, the companies will develop olaparib and selumetinib in
combination with other potential new medicines and as monotherapies.
Independently, the companies will develop olaparib and selumetinib in
combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly-growing portfolio of new medicines that has the potential to
transform patients’ lives and the Company’s future. With at least six
new medicines to be launched between 2014 and 2020, and a broad pipeline
of small molecules and biologics in development, we are committed to
advance Oncology as a growth driver for AstraZeneca focused on lung,
ovarian, breast and blood cancers. In addition to our core capabilities,
we actively pursue innovative partnerships and investments that
accelerate the delivery of our strategy, as illustrated by our
investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology,
Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug
Conjugates – and by championing the development of personalized
combinations, AstraZeneca has the vision to redefine cancer treatment
and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in three
main therapy areas – Oncology, Cardiovascular, Renal & Metabolism and
Respiratory. AstraZeneca operates in over 100 countries and its
innovative medicines are used by millions of patients worldwide. For
more information, please visit www.astrazeneca-us.com
and follow us on Twitter @AstraZenecaUS.

US-22729 Last Updated 10/18

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