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 the 2018 ASCO Annual Meeting with simultaneous
publication in The Lancet Oncology
AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US
(Merck: known as MSD outside the US 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). Olaparib is being jointly developed and
commercialized by AstraZeneca and Merck.
The results of Study 08, a randomized, double-blinded,
multi-center Phase II trial, comparing olaparib 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 in
Chicago, IL, June 1-5, 2018, 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.
Olaparib is not FDA-approved for prostate cancer. Olaparib 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 Complete Indications
below.
Noel Clarke, Professor of Urological Oncology, Christie NHS
Foundation Trust, Manchester, UK, 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
olaparib monotherapy in metastatic castration-resistant patients
with HRR mutations. The Study 08 combination data suggests that,
regardless of their mutation status, men with metastatic
castration-resistant prostate cancer may potentially benefit from
olaparib in combination with abiraterone.”
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. Olaparib 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 olaparib.”
Median rPFS was 13.8 months with olaparib 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 vs 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
olaparib +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 olaparib 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% and 28%; 34% and 18%; 30% and 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.
Olaparib is associated with a number of serious, potentially fatal
risks, including MDS-AML, pneumonitis, and embryo-fetal toxicity.
Please see Important Safety Information below.
In addition to Study 08, other studies are underway to explore
the potential of olaparib as a monotherapy for HRR-mutated mCRPC,
including PROfound, which is testing olaparib monotherapy vs.
enzalutamide or abiraterone in patients with previously-untreated
mCRPC. Additional trials are planned to explore olaparib in
combination for the treatment of mCRPC regardless of HRR status.
Olaparib was granted Breakthrough Therapy Designation by the US
Food and Drug Administration in 2016 for the treatment of
BRCA-mutated or ATM gene-mutated mCRPC.
Olaparib is a first-in-class PARP inhibitor approved in the US
for certain patients with recurrent ovarian and metastatic breast
cancer and has treated nearly 5,500 patients since 2014. Olaparib
has a broad clinical-development program and AstraZeneca and Merck
are working together to deliver olaparib as quickly as possible to
more patients across multiple cancer types, including prostate and
pancreatic cancers.
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 Study 08
Study 08 was a global, randomized, double-blinded, multi-center
Phase II trial of 142 patients, assessing the efficacy and safety
of olaparib tablets (300 mg twice daily) and abiraterone tablets (4
x 250 mg once daily) (n=71) compared to matched placebo and
abiraterone (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 radiological 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 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% of men with advanced prostate cancer
will develop mCRPC within five years, and at least 84% of these
will have metastases at the time of mCRPC diagnosis. Of men with no
metastases at mCRPC diagnosis, 33% 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%.
About LYNPARZA® (olaparib)
Olaparib 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 olaparib-induced cytotoxicity
may involve inhibition of PARP enzymatic activity and increased
formation of PARP-DNA complexes, resulting in DNA damage and cancer
cell death.
Olaparib 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 one of AstraZeneca’s Four
Growth Platforms 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, DDR 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. The Company also is selectively active
in the areas of autoimmunity, neuroscience and infection.
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-20422 Last Updated 6/18
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