TIDMAZN
RNS Number : 2291Y
AstraZeneca PLC
30 December 2019
30 December 2019 07:00 GMT
Lynparza approved in the US as a 1st-line maintenance
treatment
of germline BRCA-mutated metastatic pancreatic cancer
Lynparza reduced the risk of disease progression or death by 47%
in patients
whose disease had not progressed on at least 16 weeks of a
1st-line platinum-based chemotherapy regimen
Only PARP inhibitor approved in germline BRCA-mutated
metastatic pancreatic cancer
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 the
maintenance treatment of adult patients with deleterious or
suspected deleterious germline BRCA-mutated (gBRCAm) metastatic
pancreatic adenocarcinoma (pancreatic cancer) whose disease has not
progressed on at least 16 weeks of a 1st-line platinum-based
chemotherapy regimen. Patients will be selected for therapy based
on an FDA-approved companion diagnostic for Lynparza.
The approval follows the recommendation from the US FDA
Oncologic Drugs Advisory Committee (ODAC) on 17 December for
Lynparza in this indication, and was based on results from the
pivotal Phase III POLO trial published in The New England Journal
of Medicine and presented at the 2019 American Society of Clinical
Oncology Annual Meeting.
Results showed a statistically significant and clinically
meaningful improvement in progression-free survival, where Lynparza
nearly doubled the time patients with gBRCAm metastatic pancreatic
cancer lived without disease progression or death to a median of
7.4 months vs. 3.8 months on placebo. The safety and tolerability
profile of Lynparza in the POLO trial was in line with that
observed in prior clinical trials.
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "Patients with advanced pancreatic cancer historically
have faced poor outcomes due to the aggressive nature of the
disease and limited treatment advances over the last few decades.
Lynparza is now the only approved targeted medicine in
biomarker-selected patients with advanced pancreatic cancer."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "Lynparza embodies MSD's and AstraZeneca's commitment to
advance the treatment of challenging types of cancer, including
metastatic pancreatic cancer. The expanded approval of Lynparza
represents a significant milestone for patients and supports the
value of germline BRCA testing in patients with this disease."
Hedy L. Kindler, Co-Principal Investigator of the POLO trial and
Professor of Medicine, University of Chicago Medicine, said:
"Today's approval of olaparib based on the POLO results gives
clinicians an important 1st-line maintenance treatment option which
nearly doubled the progression-free survival benefit in patients
with germline BRCA-mutated metastatic pancreatic cancer."
Julie Fleshman, President and CEO, Pancreatic Cancer Action
Network, said: "Metastatic pancreatic cancer patients have been
waiting a long time for new therapy options for their devastating
disease. Today's approval of Lynparza provides an exciting new
treatment option for patients with germline BRCA-mutated metastatic
pancreatic cancer."
The Pancreatic Cancer Action Network (PanCAN) is a US-based
organisation that supports and advocates on behalf of the patients,
caregivers and communities affected by pancreatic cancer.
About pancreatic cancer
Pancreatic cancer is a deadly cancer with a high unmet medical
need. It is the 12th most commonly occurring cancer(2) and the 7th
leading cause of cancer death globally.(3) The disease has the
lowest survival rate of the most common cancers(4,5) and is the
only major cancer with a single-digit five-year survival rate
(2-9%) in nearly every country.(5) There were approximately 460,000
new cases worldwide in 2018(6.) As there are often no symptoms, or
symptoms may be non-specific in the early stages(7) , it is most
commonly diagnosed at an incurable stage.(8) Around 80% of
pancreatic cancer patients are diagnosed when the disease has
metastasised and for these the average survival is less than a
year.(9) Despite advances in treatment(10) , few improvements have
been made in diagnosis and treatment over the decades.(11,12)
Current treatment is surgery (for which approximately only 10-20%
of patients are eligible), chemotherapy and radiotherapy,
highlighting a critical unmet medical need for more effective
treatment options.(13)
About POLO
POLO is a Phase III randomised, double-blinded,
placebo-controlled, multi-centre trial of Lynparza tablets (300mg
twice daily) as maintenance monotherapy vs. placebo. The trial
randomised 154 patients with gBRCAm metastatic pancreatic cancer
whose disease had not progressed on 1st-line platinum-based
chemotherapy. Patients were randomised (3:2) to receive Lynparza or
placebo until disease progression. The primary endpoint was PFS and
key secondary endpoints included overall survival, time to second
disease progression, overall response rate and health-related
quality of life.(1)
The results showed a statistically significant and clinically
meaningful improvement in progression-free survival, where Lynparza
nearly doubled the time patients with gBRCAm metastatic pancreatic
cancer lived without disease progression or death to a median of
7.4 months vs. 3.8 months on placebo and reduced the risk of
disease progression or death by 47% (HR 0.53 [95% CI, 0.35-0.81],
p=0.0035). The benefit of maintenance with Lynparza was seen
consistently across a range of clinically meaningful endpoints. In
patients with measurable disease at baseline, 23% responded to
Lynparza vs.12% on placebo (odds ratio, 2.30; 95% CI, 0.89 to 6.76)
and had a median duration of treatment in excess of two years (24.9
months; 95% CI, 14.8 to could not be calculated) vs 3.7 months on
placebo (95% CI, 2.1 to could not be calculated). Overall survival
(OS), a secondary endpoint, at interim analysis was 18.9 months for
Lynparza vs. 18.1 months for placebo but did not reach statistical
significance (HR=0.90; p=0.68).
The safety and tolerability profile of Lynparza in the POLO
trial was in line with that observed in prior clinical trials. The
most common adverse reactions (ARs) >=10% were fatigue (60%),
nausea (45%), abdominal pain (34%), diarrhoea (29%), anaemia (27%),
decreased appetite (25%), constipation (23%), vomiting (20%), back
pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%),
dyspnoea (13%), nasopharyngitis (12%), neutropenia (12%), dysgeusia
(11%) and stomatitis (10%). Grade 3 or above ARs were anaemia
(11%), fatigue (5%), neutropenia (4%), decreased appetite (3%),
thrombocytopenia (3%), abdominal pain (2%), vomiting (1%) and
arthralgia (1%). ARs led to dose reduction in 23% of patients on
Lynparza while 6% of patients discontinued treatment.
Based on the results of POLO, the National Comprehensive Cancer
Network (NCCN) guidelines were updated in July 2019 to recommend
Lynparza as maintenance treatment for gBRCAm pancreatic
cancer.(14)
In the US, eligible metastatic pancreatic cancer patients will
be selected for therapy based on the FDA-approved companion
diagnostic, BRACAnalysis CDx, a genetic test that detects the
presence of a BRCA1 or BRCA2 gene mutation. BRACAnalysis CDx is
owned and commercialised by Myriad Genetics, Inc.
About BRCA mutations
BRCA1 and BRCA2 (breast cancer susceptibility genes 1/2) are
human genes that produce proteins responsible for repairing damaged
DNA and play an important role in maintaining the genetic stability
of cells. When either of these genes is mutated, or altered, such
that its protein product either is not made or does not function
correctly, DNA damage may not be repaired properly, and cells
become unstable. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.
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 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. 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, 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 investments 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.
About 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. Golan et al (2019). Maintenance Olaparib for Germline
BRCA-Mutated Metastatic Pancreatic Cancer. New England Journal of
Medicine.
2. World Cancer Research Fund International. Pancreatic cancer statistics. Available at: www.wcrf.org/dietandcancer/cancer-trends/pancreatic-cancer-statistics Accessed October 2019.
3. World Health Organization. IARC. (2019). Estimated number of
deaths in 2018, worldwide, both sexes, all ages. Website available
here. Accessed October 2019.
4. Pancreaticcancer.org.uk. Pancreatic cancer statistics. Available at: www.pancreaticcancer.org.uk/statistics/ Accessed October 2019.
5. Worldpancreaticcancerday.org. Available at:
www.worldpancreaticcancerday.org/about-pancreatic-cancer/ Accessed
October 2019.
6. World Health Organization. IARC. (2019). Estimated number of
new cases in 2018, worldwide, both sexes, all ages. Website
available here. Accessed October 2019.
7. Pancreaticcancer.org.uk. Signs and symptoms of pancreatic cancer. Available at: www.pancreaticcancer.org.uk/information-and-support/facts-about-pancreatic-cancer/signs-and-symptoms-of-pancreatic-cancer/ Accessed October 2019.
8. DaVee (2018). Pancreatic cancer screening in high-risk
individuals with germline genetic mutations. Gastrointestinal
Endoscopy. 87(6), pp.1443-1450.
9. Azar et al. (2019). Treatment and survival rates of stage IV
pancreatic cancer at VA hospitals: a nation-wide study. Journal of
Gastrointestinal Oncology, 10(4), pp.703-711.
10. Sheahan et al. (2018). Targeted therapies in the management
of locally advanced and metastatic pancreatic cancer: a systematic
review. Oncotarget. 9(30): 21613-21627.
11. Adamska et al. (2017). Pancreatic ductal adenocarcinoma:
current and evolving therapies. International Journal of Molecular
Science. 18(7): 1338.
12. Yongxing et al. (2017). Molecular subtyping of pancreatic
cancer: translating genomics and transcriptomics into the clinic.
Journal of Cancer. 8(4):513-522.
13. Stunt, A. (2016). Pancreatic cancer: GPs can help prognosis
by identifying early signs. Guidelines in Practice. Available at:
www.guidelinesinpractice.co.uk/cancer/pancreatic-cancer-gps-can-help-prognosis-by-identifying-early-signs/352855.article
Accessed October 2019.
14. NCCN. (2019). NCCN Guidelines for Patients | Pancreatic
Cancer. Nccn.org. Available at:
https://www.nccn.org/patients/guidelines/pancreatic/12/ Accessed
December 2019.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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