TIDMAZN
RNS Number : 2333X
AstraZeneca PLC
17 December 2019
17 December 2019 18:00 GMT
Lynparza recommended by FDA advisory committee for 1st-line
maintenance treatment of germline BRCA-mutated metastatic
pancreatic cancer
ODAC voted that Lynparza demonstrated a clinically meaningful
and favourable
risk-benefit profile for patients based on Phase III POLO trial
results
AstraZeneca and MSD Inc., Kenilworth, NJ, US (MSD: known as
Merck & Co., Inc. inside the US and Canada) today announced
that the US Food and Drug Administration (FDA) Oncologic Drugs
Advisory Committee (ODAC) voted 7 to 5 to recommend Lynparza
(olaparib) as a 1st-line maintenance monotherapy for patients with
germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the
pancreas (pancreatic cancer), whose disease has not progressed
following 1st-line platinum-based chemotherapy.
In August 2019, the FDA accepted the supplemental New Drug
Application (sNDA) for Lynparza for this indication with Priority
Review and set a Prescription Drug User Fee Act (PDUFA) date for
the fourth quarter of 2019.
José Baselga, Executive Vice President, Oncology R&D, said:
"We are pleased with the ODAC's recommendation for Lynparza and the
potential to bring a personalised, biomarker-targeted medicine to
patients with germline BRCA-mutated metastatic pancreatic cancer.
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. We look
forward to working with the FDA as it completes the review of our
application."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "We are encouraged by the ODAC's favourable vote for Lynparza
as a 1st-line maintenance therapy in germline BRCA-mutated
metastatic pancreatic cancer. This recommendation is a significant
step towards reaching our goal to help patients with this deadly
disease."
The sNDA submission was based on the positive results from the
Phase III POLO trial published in The New England Journal of
Medicine and presented at the 2019 American Society of Clinical
Oncology Annual Meeting. The results showed a statistically
significant and clinically meaningful improvement in
progression-free survival and reduced the risk of disease
progression or death by 47% based on a hazard ratio of 0.53
(p=0.0038). 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 benefit of maintenance with Lynparza was seen consistently
across a range of clinically meaningful endpoints. At each time
point, from six months onwards, more than twice as many patients
treated with Lynparza showed no disease progression vs. those on
placebo. In patients with measurable disease at baseline, 23%
responded to Lynparza vs.12% on placebo and had a median duration
of treatment in excess of two years (24.9 months) vs 3.7 months on
placebo. 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 Phase III POLO
trial was in line with that observed in prior clinical trials.
The ODAC provides the FDA with independent, expert advice and
recommendations on marketed and potential new medicines for use in
the treatment of cancer. The FDA will consider the vote as it
reviews the submission and is not bound by the Committee's
recommendation.
In addition to the US, Lynparza is currently under regulatory
review in the EU, Canada and other jurisdictions as a 1st-line
maintenance treatment for patients with gBRCAm metastatic
pancreatic cancer.
Pancreatic cancer is a rare, life-threatening disease that
accounts for about 3% of all cancers in the US. The FDA granted
Lynparza Orphan Drug Designation in October 2018, which is for
medicines intended to treat, diagnose or prevent rare diseases or
disorders that affect fewer than 200,000 people in the US.
Lynparza was the first PARP inhibitor to be approved and has
been used in over 25,000 patients worldwide. Lynparza is currently
approved in 65 countries including the US 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 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.
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, 0.35-0.82],
p=0.004). The benefit of maintenance with Lynparza was seen
consistently across a range of clinically meaningful endpoints.
From six months onwards, more than twice as many patients receiving
Lynparza showed no disease progression vs. those receiving placebo.
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 events (AEs) >=20% were fatigue/asthenia
(60%), nausea (45%), abdominal pain (29%), diarrhoea (29%), anaemia
(28%), decreased appetite (25%) and constipation (23%). The most
common >= grade 3 AEs were anaemia (11%), fatigue/asthenia (5%),
decreased appetite (3%), abdominal pain (2%), vomiting (1%) and
arthralgia (1%). AEs led to dose reduction in 16% of patients on
Lynparza while 5% of patients discontinued treatment.
There are currently no precision medicine treatment options for
gBRCAm pancreatic cancer patients. However, 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)
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, prostate 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(R) | 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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