AstraZeneca and Merck’s LYNPARZA reduced the
risk of disease progression or death by 51% in men with homologous
recombination repair (HRR) gene mutations
First positive Phase III trial testing a
targeted treatment in biomarker-selected prostate cancer
patients
AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US
(Merck: known as MSD outside the US and Canada) today presented
detailed results from the Phase III PROfound trial in 387 men with
metastatic castration-resistant prostate cancer (mCRPC) who have a
mutation in their homologous recombination repair (HRRm) genes and
whose disease had progressed on prior treatment with new hormonal
agent (NHA) treatments (e.g. abiraterone or enzalutamide).
The trial was designed to analyze men with HRRm genes in two
cohorts: the primary endpoint was in those with mutations in
BRCA1/2 or ATM genes and then, if LYNPARZA® (olaparib) showed
clinical benefit, a formal analysis was performed of the overall
trial population of men with HRRm genes (BRCA1/2, ATM, CDK12 and 11
other HRRm genes; key secondary endpoint).
Results showed a statistically
significant and clinically meaningful improvement with LYNPARZA in
the primary endpoint of radiographic progression-free survival
(rPFS), improving the time men with BRCA1/2- or ATM-mutated mCRPC
lived without disease progression or death to a median of 7.4
months vs. 3.6 months for those treated with abiraterone or
enzalutamide. LYNPARZA reduced the risk of disease progression or
death by 66% (equal to a hazard ratio of 0.34) for these
men.
The trial also met the key secondary endpoint of rPFS in the
overall HRRm population, where LYNPARZA reduced the risk of disease
progression or death by 51% (equal to a hazard ratio of 0.49) and
improved rPFS to a median of 5.8 months vs. 3.5 months for
abiraterone or enzalutamide.
The results were presented during the Presidential Symposium at
the 2019 European Society of Medical Oncology (ESMO) congress in
Barcelona, Spain (Abstract #LBA12_PR).
Results also showed a trend at this interim analysis time point
for improvement in overall survival (OS), another key secondary
endpoint, in the two groups. LYNPARZA extended OS to 18.5 months
vs. 15.1 months for abiraterone or enzalutamide in men with
BRCA1/2- or ATM-mutated tumors, despite that at this interim
analysis 81% of patients on NHA crossed over to LYNPARZA at
progression. A similar trend in OS was observed at this interim
analysis in the overall HRRm population with a median of 17.5
months’ OS for men treated with LYNPARZA vs. 14.3 months for
abiraterone or enzalutamide (analysis at 41% data maturity).
José Baselga, Executive Vice President, Oncology R&D, said:
“Results from PROfound demonstrate that, in addition to providing
substantial benefit as a precision medicine for men with metastatic
castration-resistant prostate cancer with BRCA-mutated tumors,
LYNPARZA is effective beyond just BRCA in tumors with mutations in
other genes associated with homologous recombination repair.
PROfound validates the concept of PARP sensitivity across multiple
genes associated with homologous recombination repair in this
disease and marks the first positive Phase III trial using a
molecular biomarker to identify men for targeted treatment for
metastatic castration-resistant prostate cancer. We are working
with global health authorities to bring LYNPARZA to these patients
as quickly as possible.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “The results from the Phase III PROfound trial are a
testament to Merck and AstraZeneca’s lasting commitment to patients
with cancer. The trial met the primary endpoint in men with
metastatic castration-resistant prostate cancer that progressed on
prior hormonal therapy, a notoriously difficult-to-treat disease.
The benefit seen in patients beyond just those with BRCA mutations
underscores the potential value of genomic testing in prostate
cancer.”
Maha Hussain, one of the
principal investigators of the PROfound trial and Deputy Director
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern
University, said: “We have seen advances in the treatment over the last 15 years for men with
metastatic castration-resistant prostate cancer. However, to date
treatments for this state of disease continue to use ‘one size fits
all’ approaches overlooking the genomic make-up of the tumor and
how it could inform treatment decisions to better personalize care
and impact outcomes. I am thrilled by the PROfound results and
LYNPARZA’s clinically meaningful benefit which offers the potential
of a molecularly targeted treatment for this patient population
with advanced disease. I am confident we are now entering a new era
of personalized care and precision medicine for metastatic
castration-resistant prostate cancer.”
Summary of resultsi
Cohort A
(BRCA1/2 or ATM)
Cohort A+B ii
(Overall HRRm)
LYNPARZA
n=162
pcNHA
n=83
LYNPARZA
n=256
pcNHA
n=131
rPFS
Median, months
7.4
3.6
5.8
3.5
% progression-free at 6 months
59.8
22.6
49.7
23.7
% progression-free at 12 months
28.1
9.4
22.1
13.5
Hazard ratio (95% CI)
0.34 (0.25-0.47)
0.49 (0.38-0.63)
p-value
<0.0001
<0.0001
Confirmed ORR
Patients with response (%)
33.3
2.3
21.7
4.5
Odds ratio (95% CI)
20.86 (4.18-379.18)
5.93 (2.01-25.40)
p-value
<0.0001
0.0006 (nominal)
Time to pain progression iii
Median, months
NR
9.92
Hazard ratio (95% CI)
0.44 (0.22-0.91)
p-value
0.0192
OS (interim) iv
Median, months
18.5
15.1
17.5
14.3
Hazard ratio (95% CI)
0.64 (0.43-0.97)
0.67 (0.49-0.93)
p-value
0.0173
0.0063 (nominal)
NR, not reached; ORR,
objective response rate; pc, physician’s choice i Assessed by blinded independent central
review (BICR) ii
Cohort B included patients with
any 1 of 12 other HRR mutations iii Time to pain progression in Cohort A was a
key secondary endpoint included in the formal hierarchy
iv Interim analysis was done at 38% (Cohort A)
and 41% (Cohort A+B) data maturity; Alpha spend at interim was
0.01; statistical significance not reached
The safety and tolerability profile of LYNPARZA in the PROfound
trial was in line with that observed in prior clinical trials. The
most common adverse events (AEs) ≥20% were anemia (47%), nausea
(41%), fatigue/asthenia (41%), decreased appetite (30%) and
diarrhea (21%). Grade 3 or above AEs were anemia (22%), pulmonary
embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnea (2%),
urinary tract infection (2%), decreased appetite (1%), diarrhea
(1%) and back pain (1%). 16% of patients on LYNPARZA discontinued
treatment due to AEs.
AstraZeneca and Merck are also exploring additional trials in
prostate cancer, including the ongoing Phase III PROpel trial,
testing LYNPARZA as a 1st-line therapy in mCRPC, in combination
with abiraterone.
LYNPARZA is currently approved for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer regardless of BRCA
status. It is approved 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. For
1st-line maintenance in advanced ovarian cancer and the metastatic
breast cancer setting, physicians should select patients for
therapy based on an FDA-approved companion diagnostic. LYNPARZA is
not approved in metastatic pancreatic cancer, but an application is
currently under regulatory review.
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 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 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 testing the efficacy and safety of LYNPARZA 300 mg
(two 150 mg tablets) twice daily versus new hormonal agents (e.g.,
abiraterone or enzalutamide) in patients with metastatic
castration-resistant prostate cancer (mCRPC) who have progressed on
prior treatment with new hormonal anticancer 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.
About Metastatic Castration-Resistant Prostate Cancer
(mCRPC)
Prostate cancer is the second-most common cancer in men. An
estimated 174,650 men in the United States will be diagnosed with
prostate cancer in 2019. 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 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 remains low.
About Homologous Recombination Repair (HRR) Gene
Mutations
HRR is a DNA repair process that allows for high-fidelity,
error-free repair of damaged DNA, in the form of double-strand
breaks and inter-strand crosslinks (amongst others). The inability
to properly repair DNA damage leads to genomic instability and
contributes to cancer etiology. 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
olaparib. PARP inhibitors block DNA damage repair 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 LYNPARZA
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 (HRR), such as
mutations in BRCA1 and/or BRCA2. 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.
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 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.
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 therapy areas - Oncology, Cardiovascular, Renal and
Metabolism (CVRM), and Respiratory. AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit www.astrazeneca-us.com and follow
us on Twitter @AstraZenecaUS.
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