TIDMAZN
RNS Number : 2849A
AstraZeneca PLC
20 January 2020
20 January 2020 07:00 GMT
Lynparza regulatory submission granted Priority Review in the
US
for HRR-mutated metastatic castration-resistant prostate
cancer
Submission based on PROfound, the 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 announced
that a supplemental New Drug Application for Lynparza (olaparib)
has been accepted and granted Priority Review in the US for
patients with metastatic castration-resistant prostate cancer
(mCRPC) and deleterious or suspected deleterious germline or
somatic homologous recombination repair (HRR) gene mutations, who
have progressed following prior treatment with a new hormonal
agent.
A Prescription Drug User Fee Act (PDUFA) date is set for the
second quarter of 2020.
The Priority Review by the US Food and Drug Administration (FDA)
is based on results from the Phase III PROfound trial, which were
presented during the Presidential Symposium at the 2019 European
Society of Medical Oncology congress.
Results of the PROfound trial showed Lynparza significantly
reduced the risk of disease progression or death by 66% based on a
hazard ratio of 0.34 (p<0.0001) vs. abiraterone or enzalutamide
in patients with BRCA1/2 or ATM-mutated mCRPC, the primary endpoint
of the trial.
The trial also showed that Lynparza reduced the risk of disease
progression or death by 51% based on a hazard ratio of 0.49
(p<0.0001) vs. abiraterone or enzalutamide in the overall trial
population of patients with HRR-mutated (HRRm) mCRPC (those with
mutations in the genes for BRCA1/2, ATM, CDK12 or 11 other HRRm
genes; key secondary endpoint). The safety and tolerability profile
of Lynparza in the PROfound trial was in line with that observed in
previous clinical trials.
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)
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.
The trial was designed to analyse patients with 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
patients 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
patients with BRCA1/2- or ATM-mutated mCRPC lived without disease
progression to a median of 7.4 months vs. 3.6 months for those
treated with abiraterone or enzalutamide and reduced the risk of
disease progression or death by 66% (HR 0.34 [95% CI, 0.25-0.47],
p<0.0001). 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). PROfound
is the first positive Phase III trial testing a targeted treatment
in biomarker-selected prostate cancer patients.
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%). The most common Grade 3 or above AEs >=1% were
anaemia (22%), fatigue/asthenia (3%), vomiting (2%), dyspnoea (2%),
urinary tract infection (2%), pulmonary embolism (2%), decreased
appetite (1%), diarrhoea (1%), backpain (1%) and nausea (%). 16% of
patients on Lynparza discontinued treatment due to AEs.
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)
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, 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 65 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, China 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 44 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. It is approved in the US as a
1st-line maintenance treatment for germline BRCA-mutated metastatic
pancreatic cancer. Regulatory reviews are underway in other
jurisdictions for ovarian, breast, pancreatic and prostate
cancers.
Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, is approved for the treatment of advanced
ovarian cancer, metastatic breast cancer and metastatic pancreatic
cancer and has been used to treat more than 30,000 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.
The AstraZeneca and MSD 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-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.
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, 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, 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.
AstraZeneca
AstraZeneca (LSE/STO/NYSE: AZN) 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, 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 the Company on Twitter @AstraZeneca.
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References
1. Bray 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. www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer Last Accessed: November 2019.
3. Cancer.Net. (2019). Prostate Cancer - Statistics. Available at: www.cancer.net/cancer-types/prostate-cancer/statistics Last Accessed: November 2019.
4. Li et al. (2008). Homologous recombination in DNA repair and
DNA damage tolerance. Cell Research, 18(1), pp.99-113.
5. Ledermann et al. (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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