TIDMAZN
RNS Number : 2779A
AstraZeneca PLC
22 September 2022
22 September 2022 07:00 BST
Lynparza approved in China as 1st-line maintenance treatment
with bevacizumab for HRD-positive advanced ovarian cancer
One in two women with advanced ovarian cancer has an
HRD-positive tumour
AstraZeneca and MSD's Lynparza (olaparib) has been approved in
China for the maintenance treatment of adult patients with advanced
epithelial ovarian, fallopian tube or primary peritoneal cancer who
are in complete or partial response to 1st-line platinum-based
chemotherapy in combination with bevacizumab, and whose cancer is
associated with homologous recombination deficiency (HRD)-positive
status .
In China, ovarian cancer is the third most common gynaecologic
cancer, with a five-year survival rate of approximately 39%,
largely because more than 70% of women are diagnosed with advanced
disease (Stage III or IV).(1,2) In 2020, there were over 55,000 new
cases of ovarian cancer in China.(3)
The approval by China's National Medical Products Administration
was based on an HRD-positive subgroup exploratory analysis of the
PAOLA-1 Phase III trial which showed Lynparza plus bevacizumab
demonstrated a substantial progression-free survival (PFS)
improvement versus bevacizumab alone for patients with HRD-positive
advanced ovarian cancer. During European Society for Medical
Oncology Congress (ESMO) 2022, the final overall survival (OS)
results were presented from the PAOLA-1 Phase III trial
demonstrating that Lynparza plus bevacizumab provided a clinically
meaningful improvement in overall survival in HRD-positive advanced
ovarian cancer.
Professor Ding Ma, Member of the Chinese Academy of Engineering,
said: "Ovarian cancer has the highest fatality rate among
gynaecologic cancers in China. The emergence of PARP inhibitors and
their application in the 1st-line treatment of ovarian cancer could
help patients delay disease progression and achieve long-term
remission. In the PAOLA-1 trial, the combination of olaparib and
bevacizumab demonstrated clinically meaningful improvements in
overall survival. This approval provides HRD-positive patients with
a new option for 1st-line maintenance therapy."
Professor Beihua Kong, Chairman of the Gynaecological Oncology
Branch of the Chinese Medical Association, said: "Ovarian cancer
has entered the era of precision medicine, and HRD detection
(including BRCA1/2 mutations) has important clinical value for
newly diagnosed patients with advanced ovarian cancer, to help
guide first-line treatment decisions. The approval of the
combination of olaparib and bevacizumab brings a clinically
meaningful survival benefit to HRD-positive patients, and further
reflects the importance of a precision approach to help guide
treatment decisions in ovarian cancer."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: "The maintenance treatment of Lynparza in
combination with bevacizumab has shown to both improve
progression-free survival and provide a clinically meaningful
improvement in overall survival in patients with HRD-positive
advanced ovarian cancer following response to platinum-based
chemotherapy. I am thrilled we can now bring this targeted
treatment option to these patients in China."
Dr Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, MSD Research Laboratories,
said: "This approval is an important milestone for patients with
newly diagnosed advanced ovarian cancer in China and underscores
the critical importance of HRD testing for all women with advanced
ovarian cancer at the point of diagnosis."
The initial results from the PAOLA-1 Phase III trial showed that
Lynparza plus bevacizumab reduced the risk of disease progression
or death by 67% in the subgroup of patients with HRD-positive
advanced ovarian cancer (based on a hazard ratio [HR] of 0.33; 95%
confidence interval [CI] 0.25-0.45 from the pre-specified
exploratory analysis). Lynparza plus bevacizumab also improved PFS
to a median of 46.8 versus 17.6 months with bevacizumab alone in
this patient population. The primary endpoint in the
intent-to-treat population was a statistically significant and
clinically meaningful improvement in PFS. The data from the PAOLA-1
trial was published in The New England Journal of Medicine in
2019.
Further results from the five-year analysis of the PAOLA-1 trial
recently presented at the ESMO 2022 showed Lynparza plus
bevacizumab increased median overall survival to 56.5 months versus
51.6 months with bevacizumab alone, in patients with newly
diagnosed advanced ovarian cancer irrespective of HRD status. This
increase was not statistically significant. In HRD-positive
patients, Lynparza plus bevacizumab provided a clinically
meaningful improvement in overall survival, reducing the risk of
death by 38% versus bevacizumab (based on a HR of 0.62; 95% CI
0.45-0.85 from the pre-specified exploratory sub-group analysis)
despite PAOLA-1 having 30% Stage IV patients. The safety and
tolerability profile of Lynparza in this trial was in line with
that observed in prior clinical trials, with no new safety
signals.
Lynparza in combination with bevacizumab is approved in the US ,
and several other countries as a 1st-line maintenance treatment for
patients with HRD-positive advanced ovarian cancer and is currently
under regulatory review in other countries around the world. In
China, Lynparza is approved for the treatment of BRCA-mutated
metastatic castration-resistant prostate cancer as well as a
1st-line maintenance therapy in BRCA-mutated advanced ovarian
cancer .
Notes
Ovarian cancer
Ovarian cancer is the eighth most common cancer in women
worldwide.(4) There were more than 313,000 new cases of ovarian
cancer in 2020, and over 207,000 deaths. The 5-year survival rate
of newly diagnosed advanced ovarian cancer patients has typically
been 30-50%.(5,6) Roughly half of women with advanced ovarian
cancer have homologous recombination deficiency (HRD)-positive
tumours including those with a BRCA mutation and up to one in five
women have a BRCA mutation.(7-9) The primary aim of 1st-line
treatment is to delay disease progression for as long as possible
with the intent to achieve long-term remission.(10-12)
PAOLA-1
PAOLA-1 is a double-blinded Phase III trial testing the efficacy
and safety of Lynparza added to standard of care bevacizumab versus
bevacizumab alone, as a 1st-line maintenance treatment for newly
diagnosed advanced FIGO Stage III-IV high-grade serous or
endometroid ovarian, fallopian tube, or peritoneal cancer patients
who had a complete or partial response to 1st-line treatment with
platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD
announced in August 2019 that the trial met its primary endpoint of
PFS in the overall trial population.
The primary analysis of the PAOLA-1 Phase III trial showed that
Lynparza, in combination with bevacizumab maintenance treatment,
reduced the risk of disease progression or death by 67% (based on a
HR of 0.33; 95% CI 0.25-0.45) in the subgroup of patients with
HRD-positive advanced ovarian cancer. The addition of Lynparza
improved PFS to a median of 46.8 months versus 17.6 with
bevacizumab alone in this patient population.
Updated results from the five-year analysis of the PAOLA-1 Phase
III trial demonstrate that in a pre-specified exploratory subgroup
analysis of HRD-positive patients, Lynparza plus bevacizumab
provided a clinically meaningful improvement in overall survival,
reducing the risk of death by 38% versus bevacizumab (based on a HR
of 0.62; 95% CI 0.45-0.85). In addition, 65.5% of patients treated
with Lynparza plus bevacizumab were still alive at five years
versus 48.4% of those treated with bevacizumab alone. Lynparza plus
bevacizumab also improved median PFS to almost four years (46.8
months) versus 17.6 months with bevacizumab plus placebo, and 46.1%
of patients treated with Lynparza plus bevacizumab remain
progression free at five years versus 19.2% of patients treated
with bevacizumab alone.
PAOLA-1 is an ENGOT (European Network of Gynaecological
Oncological Trial groups) trial, sponsored by ARCAGY Research
(Association de Recherche sur les CAncers dont GYnécologiques) on
behalf of GINECO (Groupe d'Investigateurs National des Etudes des
Cancers Ovariens et du sein), lead group for the PAOLA-1 trial.
ARCAGY-GINECO is an academic group specialising in clinical and
translational research in patients' gynaecological cancers,
labelled by the French National Cancer Institute (INCa), and a
member of the GCIG (Gynecologic Cancer InterGroup).
Homologous recombination deficiency
HRD, which defines a subgroup of ovarian cancer, encompasses a
wide range of genetic abnormalities, including BRCA mutations and
beyond. As with BRCA gene mutations, HRD interferes with normal
cell DNA repair mechanisms and confers sensitivity to PARP
inhibitors including Lynparza.(13)
Lynparza
Lynparza (olaparib) is a 1st-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 a number of countries across
multiple tumour types including maintenance treatment of
platinum-sensitive relapsed ovarian cancer and as both monotherapy
and in combination with bevacizumab for the 1st-line maintenance
treatment of BRCA-mutated (BRCAm) and HRD-positive advanced ovarian
cancer, respectively; for gBRCAm, HER2-negative metastatic breast
cancer (in the EU and Japan this includes locally advanced breast
cancer); for gBRCAm, HER2-negative high-risk early breast cancer
(in Japan this includes all BRCAm HER2-negative high-risk early
breast cancer); for gBRCAm metastatic pancreatic cancer; and HRR
gene-mutated metastatic castration-resistant prostate cancer (BRCAm
only in the EU and Japan). In China, Lynparza is approved for the
treatment of BRCA-mutated metastatic castration-resistant prostate
cancer as well as a 1(st) -line maintenance therapy in BRCA-mutated
advanced ovarian cancer .
Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, has been used to treat over 75,000 patients
worldwide. Lynparza has a broad clinical trial development
programme, 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
(selumetinib), a MEK 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
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ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
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The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyse changes in the practice of medicine and
transform the patient experience.
By harnessing the power of six scientific platforms -
Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage
Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies
- and by championing the development of personalised combinations,
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References
1. Jiang X, et al. Epidemiology of gynecologic cancers in China.
J Gynecol Oncol. 2018 Jan; 29(1): e7.
2. Bu H, et al. BRCA mutation frequency and clinical features of
ovarian cancer patients: A report from a Chinese study group. J
Obstet Gynaecol Res. 2019 Nov;45(11):2267-2274.
3. Globocan. China Globocan 2020. Available at https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf . Accessed September 2022.
4. Momenimovahed Z, et al. Ovarian Cancer in The World:
Epidemiology And Risk Factors. Int J Womens Health. 2019 Apr
30;11:287-299.
5. Torre A, et al. Ovarian Cancer Statistics. CA Cancer J Clin . 2018 Jul; 68(4):284-296.
6. National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. Available at https://seer.cancer.gov/statfacts/html/ovary.html . Accessed September 2022.
7. Pothuri B. BRCA1- and BRCA2-related mutations: therapeutic
implications in ovarian cancer. Ann of Oncol.
2018;24(8):822-827.
8. Moschetta M, et al. BRCA somatic mutations and epigenetic
BRCA modifications in serous ovarian cancer. Ann Oncol. 2016
Aug;27(8):1449-55.
9. Bonadio R, et al. Homologous recombination deficiency in
ovarian cancer: a review of its epidemiology and management.
Clinics (Sao Paulo). 2018 Aug 20;73(suppl 1):e450s.
10. Raja F, et al. Optimal first-line treatment in ovarian
cancer. Ann of Oncol. 2012;23(10):118-127.
11. NHS Choices, Ovarian Cancer Available at
https://www.nhs.uk/conditions/ovarian-cancer/treatment/ . Accessed
September 2022.
12. Ledermann J, et al. Newly diagnosed and relapsed epithelial
ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl
6:vi24-32.
13. Moore K, et al. Maintenance Olaparib in Patients with Newly
Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine.
2019;379(26), pp.2495-2505.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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