TIDMAZN
RNS Number : 4537N
AstraZeneca PLC
20 May 2020
20 May 2020 07:00 BST
Lynparza approved in the US for HRR gene-mutated
metastatic castration-resistant prostate cancer
Only PARP inhibitor to improve overall survival vs. enzalutamide
or
abiraterone in a biomarker-based subset of prostate cancer
patients
with BRCA1/2 or ATM mutations
A pproximately 20-30% of men with metastatic
castration-resistant
prostate cancer have an HRR gene mutation
AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as
Merck & Co., Inc. inside the US and Canada) today announced
that Lynparza (olaparib) has been approved in the US for patients
with homologous recombination repair (HRR) gene-mutated metastatic
castration-resistant prostate cancer (mCRPC).
The approval by the US Food and Drug Administration (FDA) was
based on results from the Phase III PROfound trial , which were
published in The New England Journal of Medicine.
Prostate cancer is the second-most common cancer in men and
despite an increase in the number of available therapies for men
with mCRPC, five-year survival remains low. HRR gene mutations
occur in approximately 20-30% of patients with mCRPC.
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: "Prostate cancer
has lagged behind other solid tumours in the era of precision
medicine. I am thrilled by the approval of Lynparza which now
brings a molecularly targeted treatment to men with HRR
gene-mutated metastatic castration-resistant prostate cancer in the
US. The PROfound trial was an international effort and I want to
thank the patients, their families, the investigators and their
teams involved in making it possible."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "Today marks the first approval for Lynparza in
prostate cancer. In the PROfound trial, Lynparza more than doubled
the median radiographic progression-free survival and is the only
PARP inhibitor to improve overall survival, versus enzalutamide or
abiraterone for men with BRCA or ATM mutations. These results
further establish that genomic testing for HRR mutations should be
a critical step for the diagnosis and determination of treatment
options for men with advanced prostate cancer."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said, "Lynparza is the only PARP inhibitor approved with Phase III
data for men with HRR gene-mutated metastatic castration-resistant
prostate cancer. This approval highlights the importance of genomic
testing to help identify treatment options for men in this patient
population. We are proud to work in collaboration with AstraZeneca
toward our overall goal of improving outcomes for patients."
The primary endpoint of the trial was radiographic
progression-free survival (rPFS) in men with BRCA1/2 or ATM gene
mutations, a subpopulation of HRR gene mutations. Results showed
Lynparza reduced the risk of disease progression or death by 66%
(equal to a hazard ratio of 0.34; p-value <0.0001) and improved
rPFS to a median of 7.4 months versus 3.6 months with enzalutamide
or abiraterone.
Lynparza also showed an rPFS benefit in the overall HRR
gene-mutated trial population, a key secondary endpoint, and
reduced the risk of disease progression or death by 51% (equal to a
hazard ratio of 0.49; p-value <0.0001) and improved rPFS to a
median of 5.8 months versus 3.5 months with enzalutamide or
abiraterone.
Additional results from the PROfound trial announced on 24 April
2020 demonstrated 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 and BRCA1/2 or ATM gene mutations. Results showed
Lynparza reduced the risk of death by 31% (equal to a hazard ratio
of 0.69; p-value=0.0175) and improved OS to a median of 19.0 months
versus 14.6 months with enzalutamide or abiraterone.
The full indication is for the treatment of adult patients with
deleterious or suspected deleterious germline or somatic HRR
gene-mutated mCRPC who have progressed following prior treatment
with enzalutamide or abiraterone. Patients are to be selected for
treatment based on an FDA-approved companion diagnostic test for
Lynparza.
Lynparza is currently under regulatory review in the EU and
other jurisdictions as a treatment for men with HRR gene-mutated
mCRPC.
AstraZeneca and MSD are testing Lynparza in additional trials in
metastatic prostate cancer including the ongoing Phase III PROpel
trial as a 1st-line treatment in combination with abiraterone
acetate for patients with mCRPC versus abiraterone acetate
alone.
Financial considerations
Following this approval for Lynparza in the US, AstraZeneca will
receive a regulatory milestone payment from MSD of $35m,
anticipated to be booked as Collaboration Revenue by the Company
during the second quarter of 2020.
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)
HRR gene mutations
HRR gene mutations occur in approximately 20-30% of patients
with mCRPC.(4,) HRR genes allow for accurate repair of damaged DNA
in normal cells.(5,6) HRR deficiency (HRD) interferes with normal
cell DNA repair mechanisms and can result in normal cell death.(6)
This is different in cancer cells, where a mutation in HRR pathways
leads to abnormal cell growth and therefore cancer.(6) The
inability to properly repair DNA damage leads to genomic
instability and contributes to cancer aetiology.(6) HRD is a
well-documented target for PARP inhibitors, such as Lynparza. PARP
inhibitors block a rescue DNA damage repair mechanism by trapping
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.(6)
PROfound
PROfound is a prospective, multicentre, randomised, open-label,
Phase III trial testing the efficacy and safety of Lynparza versus
enzalutamide or abiraterone in patients with mCRPC who have
progressed on prior treatment with enzalutamide or abiraterone and
have a qualifying tumour mutation in BRCA1/2, ATM or one of 12
other genes involved in the HRR pathway.
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).
In the US, patients are selected for treatment with Lynparza
based on the following FDA-approved companion diagnostics:
-- FoundationOne CDX: to identify patients with HRR-gene
alterations in prostate tumour tissue. FoundationOne is a
registered trademark of Foundation Medicine, Inc.
-- BRACAnalysis CDX: a germline test to identify patients with
BRCA1 and BRCA2 gene mutations. Myriad Genetics, Inc. owns and
commercialises BRACAnalysis CDX.
Lynparza
Lynparza 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 a number of countries,
including those in the EU, for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer. 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 the US, Japan, and a number of other countries for
germline BRCA-mutated, HER2-negative, metastatic breast cancer,
previously treated with chemotherapy; in the EU, this includes
locally advanced breast cancer. Lynparza is approved in the US and
several other countries for the treatment of germline BRCA-mutated
metastatic pancreatic cancer. Regulatory reviews are underway in
several jurisdictions for ovarian, breast, pancreatic and prostate
cancers.
Lynparza , which is being jointly developed and commercialised
by AstraZeneca and MSD, has been used to treat over 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 Koselugo, a kinase
inhibitor, for multiple cancer types. Working together, the
companies will develop Lynparza and Koselugo in combination with
other potential new medicines and as monotherapies. Independently,
the companies will develop Lynparza and Koselugo 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 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, 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 & Metabolism, and Respiratory
& Immunology. Based in Cambridge, UK, 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 .
Contacts
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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 [Accessed: November 2019].
3. Kirby, M., 2011. Characterising the castration-resistant
prostate cancer population: a systematic review. International
Journal of Clinical Practice, 65(11), pp.1180-1192.
4. Mateo, J, et al (2015). DNA-repair defects and olaparib in
metastatic prostate cancer. New England Journal of Medicine,
373(18), pp.1697 - 1708.
5. Li et al. (2008). Homologous recombination in DNA repair and
DNA damage tolerance. Cell Research, 18(1), pp.99-113.
6. 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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