TIDMAZN
RNS Number : 1883O
AstraZeneca PLC
30 September 2019
30 September 2019 15:30 BST
Lynparza more than doubled the time without radiographic disease
progression in patients with BRCA1/2- or ATM-mutated metastatic
castration-resistant prostate cancer
AstraZeneca and MSD'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 MSD Inc., Kenilworth, N.J., US (MSD: known as
Merck & Co., Inc. inside 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 analyse 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 tumours, 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 tumours,
Lynparza is effective beyond just BRCA in tumours 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, MSD Research Laboratories,
said: "The results from the Phase III PROfound trial are a
testament to MSD 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 tumour and
how it could inform treatment decisions to better personalise 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 personalised care and precision medicine for metastatic
castration-resistant prostate cancer."
Summary of results(i)
Cohort A Cohort A+B (ii)
(BRCA1/2 or ATM) (Overall HRRm)
Lynparza pcNHA Lynparza pcNHA
n=162 n=83 n=256 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 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
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 anaemia (47%),
nausea (41%), fatigue/asthenia (41%), decreased appetite (30%) and
diarrhoea (21%). Grade 3 or above AEs were anaemia (22%), pulmonary
embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnoea (2%),
urinary tract infection (2%), decreased appetite (1%), diarrhoea
(1%) and backpain (1%). 16% of patients on Lynparza discontinued
treatment due to AEs.
AstraZeneca and MSD 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.
About PROfound
PROfound is a prospective, multicentre, randomised, open-label,
Phase III trial testing the efficacy and safety of Lynparza versus
new hormonal agents (e.g. abiraterone or enzalutamide) in patients
with mCRPC who have progressed on prior treatment with new hormonal
anticancer treatments and have a qualifying tumour mutation in one
of 15 genes involved in the HRR pathway, including among them
BRCA1/2, ATM and CDK12.
About metastatic castration-resistant prostate cancer
Prostate cancer is the second-most common cancer in men, with an
estimated 1.3 million new cases diagnosed worldwide in 2018 and is
associated with a significant mortality rate.(1) Development of
prostate cancer is often driven by male sex hormones called
androgens, including testosterone.(2) 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.(2) 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.(3) Of men
with no metastases at CRPC diagnosis, 33% are likely to develop
metastases within two years.(3) Despite an increase in the number
of available therapies for men with mCRPC, five-year survival
remains low.(3)
About 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).4(,5) The
inability to properly repair DNA damage leads to genomic
instability and contributes to cancer aetiology.(5) 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 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.(4)
About Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the
first targeted treatment to block DNA damage response (DDR) in
cells/tumours harbouring 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 tumour
types with defects and dependencies in the DDR pathway.
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 US, the EU, Japan and several other countries as 1st-line
maintenance treatment of BRCA-mutated advanced ovarian cancer
following response to platinum-based chemotherapy. It is also
approved in 43 countries, including the US and Japan, for germline
BRCA-mutated, 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 ovarian, breast and pancreatic cancers.
Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, is approved for advanced ovarian cancer and
metastatic breast cancer and has been used in over 25,000 patients
worldwide. Lynparza has the broadest and most advanced clinical
trial development programme of any PARP inhibitor, and AstraZeneca
and MSD are working together to understand how it may affect
multiple PARP-dependent tumours 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 the AstraZeneca and MSD 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-commercialise 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 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 haematology.
By harnessing the power of four scientific platforms -
Immuno-Oncology, Tumour 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 commercialisation 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 astrazeneca.com and follow us on
Twitter @AstraZeneca.
Media Relations
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References
1. Bray, F., Ferlay, et al. (2018). Global cancer statistics
2018: GLOBOCAN estimates of incidence and mortality worldwide for
36 cancers in 185 countries. CA: A Cancer Journal for Clinicians,
68(6), pp.394-424.
2. Cancer.Net. (2019). Treatment of metastatic
castration-resistant prostate cancer.
https://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer
[Accessed September 2019].
3. Cancer.Net. (2019). Prostate Cancer - Statistics. Available
at: www.cancer.net/cancer-types/prostate-cancer/statistics
[Accessed September 2019].
4. Li, X. and Heyer, W. (2008). Homologous recombination in DNA
repair and DNA damage tolerance. Cell Research, 18(1),
pp.99-113.
5. Ledermann, J., Drew, Y. and Kristeleit, R. (2016). Homologous
recombination deficiency and ovarian cancer. European Journal of
Cancer, 60, pp.49-58.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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