Only PARP inhibitor to improve overall survival
vs. new hormonal agent treatments for this advanced prostate cancer
population with high unmet needs
AstraZeneca and Merck (NYSE: MRK), known as MSD outside the
United States and Canada, today announced further positive results
from the Phase III PROfound trial of LYNPARZA (olaparib) in men
with metastatic castration-resistant prostate cancer (mCRPC) who
have a homologous recombination repair gene mutation (HRRm) and
have progressed on prior treatment with new hormonal agent (NHA)
treatments (i.e., abiraterone or enzalutamide).
Results from the trial showed a statistically significant and
clinically meaningful improvement in the key secondary endpoint of
overall survival (OS) with LYNPARZA versus enzalutamide or
abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene
mutations, a subpopulation of HRR gene mutations.
The Phase III PROfound trial had met its primary endpoint in
August 2019, showing significantly improved radiographic
progression-free survival (rPFS) in men with mutations in BRCA1/2
or ATM genes, and had met a key secondary endpoint of rPFS in the
overall HRRm population.
José Baselga, Executive Vice President, Oncology R&D, said:
“Overall survival in metastatic castration-resistant prostate
cancer has remained extremely challenging to achieve. We are
thrilled by these results for LYNPARZA and we are working with
regulatory authorities to bring this medicine to patients as soon
as possible.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “LYNPARZA has demonstrated significant clinical benefit
across key endpoints in PROfound, including overall survival for
patients with BRCA or ATM mutations, and this reinforces its
potential to change the treatment standard for patients with
metastatic castration-resistant prostate cancer. These data further
support Merck and AstraZeneca’s commitment to uncovering the ways
in which LYNPARZA can help patients impacted by cancer.”
The safety and tolerability profile of LYNPARZA was generally
consistent with previous trials. The data will be presented at a
forthcoming medical meeting.
LYNPARZA was granted a Priority Review in the US for patients
with HRRm mCRPC in January 2020. LYNPARZA is not approved in mCRPC,
but an application is currently under regulatory review.
AstraZeneca and Merck are exploring additional trials in prostate
cancer, including the ongoing Phase III PROpel trial, with first
data expected in 2021, testing LYNPARZA as a 1st-line medicine for
patients with mCRPC in combination with abiraterone acetate versus
abiraterone acetate alone.
LYNPARZA is currently approved for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer regardless of BRCA
status and as 1st-line maintenance treatment in BRCAm advanced
ovarian cancer following response to platinum-based chemotherapy.
It is also approved for germline BRCAm HER2-negative metastatic
breast cancer previously treated with chemotherapy and for the
maintenance treatment of germline BRCAm advanced pancreatic cancer
following 1st-line platinum-based chemotherapy. For 1st-line
maintenance in advanced ovarian cancer, the metastatic breast
cancer setting and maintenance in advanced pancreatic cancer,
physicians should select patients for therapy based on an
FDA-approved companion diagnostic for LYNPARZA.
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%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients
in clinical trials of LYNPARZA in the first-line maintenance
setting for POLO were: fatigue (60%), nausea (45%),
abdominal pain (34%), diarrhea (29%), anemia (27%), decreased
appetite (25%), constipation (23%), vomiting (20%), back pain
(19%), arthralgia (15%), rash (15%), thrombocytopenia (14%),
dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia
(11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the first-line
maintenance setting for POLO were: increase in serum
creatinine (99%), decrease in hemoglobin (86%), increase in mean
corpuscular volume (71%), decrease in lymphocytes (61%), decrease
in platelets (56%), decrease in leukocytes (50%), and decrease in
absolute neutrophil count (25%).
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 dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA 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 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.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
Please see complete Prescribing Information, including
Patient Information (Medication Guide).
– ENDS –
NOTES TO EDITORS
About PROfound
PROfound is a prospective, multi-center, randomized, open-label,
Phase III trial evaluating the efficacy and safety of LYNPARZA 300
mg (two 150 mg tablets) twice daily versus enzalutamide or
abiraterone in patients with mCRPC who have progressed on prior
treatment with a new hormonal agent (NHA) treatments and have a
qualifying tumor mutation in one of 15 genes involved in the
homologous recombination repair (HRR) pathway, including among them
BRCA1/2, ATM and CDK12.
The trial was designed to analyze patients with HRRm genes in
two cohorts; the primary endpoint was rPFS in those with mutations
in BRCA1/2 or ATM genes and then, if LYNPARZA showed clinical
benefit, a formal analysis was performed of the overall trial
population of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11
other HRRm genes; key secondary endpoint).
About LYNPARZA® (olaparib)
LYNPARZA® (olaparib) is a
first-in-class PARP inhibitor and the first targeted treatment to
block DNA damage response (DDR) in cells/tumors harboring a
deficiency in homologous recombination repair, such as BRCA1/2
mutation. 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 PARP-dependent tumor types with defects and dependencies in the
DDR pathway.
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.
LYNPARZA is the foundation of AstraZeneca’s industry-leading
portfolio of potential new medicines targeting DDR mechanisms in
cancer cells.
About Metastatic Castration-Resistant Prostate Cancer
(mCRPC)
Prostate cancer is the second-most common cancer in men. An
estimated 191,930 men in the United States will be diagnosed with
prostate cancer in 2020. Development of prostate cancer is often
driven by male sex hormones called androgens, including
testosterone. 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 CRPC
within five years, and at least 84% of these men will have
metastases at the time of CRPC diagnosis. Of men with no metastases
at CRPC 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 low and extending survival
remains a key goal for treating these men.
About Homologous Recombination Repair (HRR) Mutations
HRR mutations occur in approximately 20-30% of metastatic
castration-resistant prostate cancer patients. HRR genes allow for
accurate repair of damaged DNA in normal cells. HRR deficiency
(HRD) means the DNA damage cannot be repaired and can result in
normal cell death. This is different in cancer cells, where a
mutation in HRR pathways leads to abnormal cell growth and
therefore cancer. HRD is a well-documented target for PARP
inhibitors, such as LYNPARZA. Deficiency in HRR leads to a
compromised ability to repair damaged DNA and is a feature of
cancer cells that is a target for PARP inhibitors, such as
LYNPARZA. PARP inhibitors block a rescue DNA damage repair
mechanism by trapping of PARP bound to DNA single-strand breaks
which leads to replication fork stalling causing their collapse and
the generation of DNA double-strand breaks, which in turn lead to
cancer cell death.
About the AstraZeneca and Merck Strategic Oncology
Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth,
NJ, US, known as MSD outside the US and Canada, announced a global
strategic oncology collaboration to co-develop and co-commercialize
LYNPARZA, the world’s first PARP inhibitor, for multiple cancer
types. Working together, the companies will develop LYNPARZA in
combination with other potential new medicines and as
monotherapies. Independently, the companies will develop LYNPARZA
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 six new
medicines launched between 2014 and 2020, and a broad pipeline of
small molecules and biologics in development, the Company is
committed to advance oncology as a key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to AstraZeneca’s main capabilities, the Company is
actively pursuing innovative partnerships and investment that
accelerate the delivery of our strategy, as illustrated by the
investment in Acerta Pharma in haematology.
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 personalised 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 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.
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