KENILWORTH, N.J.--(BUSINESS WIRE)--AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada), today presented full results from the Phase 3 SOLO3 trial which evaluated LYNPARZA, compared to chemotherapy, for the treatment of platinum-sensitive relapsed patients with germline BRCA1/2-mutated (gBRCAm) advanced ovarian cancer, who have received two more prior lines of chemotherapy. The results were presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
The results from the trial showed a statistically-significant and clinically-meaningful improvement in objective response rate (ORR) in the LYNPARZA arm compared to the chemotherapy arm (ORR; 72.2% for LYNPARZA vs 51.4% for chemotherapy; 95% CI: 1.40 to 4.58; p=0.002).
The key secondary endpoint of progression-free survival (PFS) was also significantly increased in the LYNPARZA arm (13.4 months) compared to the chemotherapy arm (9.2 months; PFS HR 0.62 [p=0.013]).
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Summary of endpoints[i] |
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LYNPARZA |
Chemotherapy | |||||
| ORR (primary endpoint) | ||||||
| Number of patients | 151 | 72 | ||||
| Number of patients with response (%) | 109 (72.2%) | 37 (51.4%) | ||||
| Odds ratio (95% CI) | 2.53 (1.40, 4.58) | |||||
| p-value | 0.002 | |||||
| PFS (key secondary endpoint)[ii] | ||||||
| Number of patients | 178 | 88 | ||||
| Number of patients with event (%) | 110 (61.8%) | 49 (55.7%) | ||||
| Hazard ratio (95% CI) | 0.62 (0.43, 0.91) | |||||
| Median in months | 13.4 | 9.2 | ||||
| p-value | 0.013 | |||||
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iAssessed by blinded independent central review |
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iiAnalysis was done at 64.5% maturity |
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José Baselga, executive vice president, Oncology R&D, AstraZeneca, said, “This trial shows that LYNPARZA has the potential to provide a much-needed improvement and alternative over standard-of-care chemotherapy for certain patients with relapsed BRCA-mutated advanced ovarian cancer. This is the fourth positive Phase 2 or Phase 3 trial in advanced ovarian cancer for LYNPARZA across multiple lines of therapy. We look forward to discussing these results with regulatory authorities.”
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “LYNPARZA is the first and only PARP inhibitor to demonstrate efficacy versus chemotherapy in relapsed BRCA-mutated advanced ovarian cancer following two or more prior lines of chemotherapy. The positive SOLO3 results reaffirm AstraZeneca and Merck’s ongoing commitment to explore potential treatment options beyond standard-of-care for BRCA-mutated patients with advanced stage disease.”
The safety and tolerability profile of LYNPARZA in SOLO3 was consistent with previous trials. The most common adverse events (AEs) ≥ 20% were nausea (64.6%), fatigue/asthenia (52.2%), anemia (51.1%), vomiting (38.2%), diarrhea (28.1%) and abdominal pain (21.3%). The most common ≥ Grade 3 AEs were anemia (21.3%), neutropenia (9.6%), fatigue/asthenia (4.5%) and thrombocytopenia (3.9%). AEs led to dose interruption in 48% percent of patients on LYNPARZA vs. 42% in the chemotherapy arm, while 7% of patients discontinued treatment vs. 20% in the chemotherapy arm.
LYNPARZA is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the U.S. as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the U.S., countries in the EU and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for both ovarian cancer and breast cancer.
About SOLO3
SOLO3 is a Phase 3 randomized, open-label,
controlled, multi-center trial to evaluate the efficacy and safety of
LYNPARZA tablets following two or more prior lines of chemotherapy. The
trial randomized 266 patients with a deleterious or suspected
deleterious BRCA1 or BRCA2 mutation. Eligible patients
were randomized (2:1) to receive LYNPARZA 300mg tablets twice daily or
physician’s choice single-agent chemotherapy (paclitaxel, topotecan,
pegylated liposomal doxorubicin or gemcitabine). The primary endpoint
was overall response rate (ORR) by blinded independent central review
and key secondary endpoints included progression-free survival (PFS),
time to second disease progression or death and overall survival.
About Ovarian Cancer
Ovarian cancer is a leading cause of
cancer death in women worldwide, with a five-year survival rate of 19%.
In 2018, there were over 295,000 new cases diagnosed and around 185,000
deaths. Over 70% of women with ovarian cancer have advanced disease at
the time of diagnosis, with up to 80% at risk of recurrence after
initial treatment. Effective treatments are needed in later lines of
therapy as patients typically obtain limited benefit after two prior
lines of chemotherapy.
About BRCA
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 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.
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—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—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%).
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 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 adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min) but patients should be monitored closely for toxicity. 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:
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 with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal cancer
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
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 click here for complete Prescribing Information, including Patient Information (Medication Guide).
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
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