Merck and AstraZeneca’s LYNPARZA Reduced the
Risk of Disease Progression or Death by 51% in Men with Homologous
Recombination Repair (HRR) Gene Mutations First Positive
Phase 3 Trial Evaluating a Targeted Treatment in Biomarker-Selected
Prostate Cancer Patients
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the
United States and Canada, today presented detailed results from the
Phase 3 PROfound trial in 387 men with metastatic
castration-resistant prostate cancer (mCRPC) who have a mutation in
their homologous recombination repair (HRR) 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 mCRPC harboring
HRR-mutated (HRRm) genes in two cohorts: the primary endpoint was
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 men with HRRm genes (BRCA1/2,
ATM, CDK12 and 11 other HRRm genes).
Results showed a statistically-significant and
clinically-meaningful improvement with LYNPARZA in the primary
endpoint of radiographic progression-free survival (rPFS) in
BRCA1/2 or ATM-mutated tumors reducing the risk of disease
progression or death by a median of 7.4 months versus 3.6 months
for those receiving abiraterone or enzalutamide (HR 0.34 [95% CI,
0.25-0.47], p<0.0001). LYNPARZA reduced the risk of disease
progression or death by 66% 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% and improved rPFS to a median of 5.8
months vs. 3.5 months for those receiving abiraterone or
enzalutamide (HR 0.49 [95% CI, 0.38-0.63], p<0.0001).
Results were presented during the Presidential Symposium at the
2019 European Society of Medical Oncology (ESMO) congress in
Barcelona, Spain (LBA #12).
Dr. José Baselga, executive vice president, oncology R&D,
AstraZeneca, 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 3 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.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “The results from the Phase 3 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.”
In the key secondary endpoint of time to pain progression
(TTPP), median TTPP was not reached with LYNPARZA and was 9.92
months with abiraterone and enzalutamide in patients with BRCA1/2
or ATM mutations (HR 0.44 [95% CI, 0.22-0.91], p 0.0192).
Results also showed a trend at this interim analysis time point
for improvement in overall survival (OS), another key secondary
endpoint. LYNPARZA extended OS to a median of 18.5 months versus
15.1 months for abiraterone or enzalutamide in men with BRCA1/2 or
ATM-mutated tumors (HR 0.64 [95% CI, 0.43-0.97], p<0.0173), of
which 81% started on abiraterone or enzalutamide and, following
confirmed disease progression, then switched to LYNPARZA. At this
interim analysis, the OS endpoint did not meet statistical
significance. In an exploratory analysis, a similar trend in OS was
observed at this interim analysis in the HRRm population with a
median of 17.5 months for men treated with LYNPARZA vs. 14.3 months
for those receiving abiraterone or enzalutamide (HR 0.67 [95% CI,
0.49-0.93]).
The trial showed a confirmed overall response rate (ORR) a key
secondary endpoint of 33.3% for LYNPARZA vs. 2.3% for abiraterone
or enzalutamide in patients with BRCA1/2 or ATM mutations
(p<0.0001). In an exploratory analysis of patients in the
overall HRRm population, confirmed ORR was 21.7 % for LYNPARZA vs.
4.5% for patients receiving abiraterone or enzalutamide.
Summary of resultsi
Cohort A ii
(BRCA1/2 or ATM)
Cohort A+B iii, v.
(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 v.
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)v.
Time to pain progression iiii
Median, months
NR
9.92
Hazard ratio (95% CI)
0.44 (0.22-0.91)
p-value
0.0192
OS (interim) iv, v.
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)v.
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
secondary endpoint included in the formal testing 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 v. ORR and OS in Cohort A+B were exploratory
analyses and not multiplicity controlled
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% for LYNPARZA compared to
abiraterone or enzalutamide were anemia (47% vs.15%), nausea (41%
vs. 19%), fatigue and asthenia (41% vs. 32%), decreased appetite
(30% vs. 18%), and diarrhea (21% vs. 7%). Grade 3 or above AEs were
anemia (22% vs. 5%), fatigue and asthenia (3% vs. 5%), vomiting (2%
vs. 1%), dyspnea (2% vs. 0%), urinary tract infection (2% vs. 4%),
nausea (1% vs. 0%), decreased appetite (1% each), diarrhea (1% vs.
0%), and back pain (1% vs. 2%). AEs led to discontinuation of
treatment in 16% of patients on LYNPARZA vs. 9% on abiraterone and
enzalutamide.
AstraZeneca and Merck are also exploring additional trials in
prostate cancer, including the ongoing Phase 3 PROpel trial,
evaluating LYNPARZA as a first-line therapy in mCRPC for patients
with or without HRR mutations, in combination with abiraterone
acetate.
About PROfound
PROfound is a prospective, multi-center, randomized, open-label,
Phase 3 trial evaluating the efficacy and safety of LYNPARZA versus
enzalutamide or abiraterone in patients with metastatic
castration-resistant prostate cancer (mCRPC) who have progressed on
prior treatment with a new hormonal anticancer treatment and have a
qualifying tumor mutation in one of 15 genes involved in the
homologous recombination repair (HRR) pathway, among them BRCA 1/2
, ATM and CDK12.
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 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.
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. 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, five-year survival for men with mCRPC, remains low.
About Homologous Recombination Repair (HRR) Mutations
Homologous recombination repair (HRR) plays a significant role
in maintaining the genetic stability of cells and suppressing tumor
growth by repairing damaged DNA. Mutations, or defects, in
homologous recombination (HR) pathway genes – which include ataxia
telangiectasia mutated (ATM) and BRCA1/2 genes – increase the risk
for breast, ovarian, pancreatic, prostate and other cancers.
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.
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 and connect with us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
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Kenilworth, N.J., USA
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USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
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the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
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Risks and uncertainties include but are not limited to, general
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including interest rate and currency exchange rate fluctuations;
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