TIDMAZN
RNS Number : 2590B
AstraZeneca PLC
01 June 2023
1 June 2023
Lynparza plus abiraterone approved in the US for the treatment
of
BRCA-mutated metastatic castration-resistant prostate cancer
Lynparza combination reduced the risk of disease progression or
death by 76% vs. abiraterone alone
First PARP inhibitor approved in combination with a new hormonal
agent underscores clinically meaningful benefit of new treatment
approach
AstraZeneca and MSD's Lynparza (olaparib) in combination with
abiraterone and prednisone or prednisolone has been approved in the
US for the treatment of adult patients with deleterious or
suspected deleterious BRCA-mutated (BRCAm) metastatic
castration-resistant prostate cancer (mCRPC).
This approval was based on a subgroup analysis of the Phase III
PROpel trial which showed that Lynparza plus abiraterone
demonstrated highly clinically meaningful improvements in both
radiographic progression-free survival (rPFS) (HR of 0.24, 95% CI,
0.12-0.45) and overall survival (OS) (HR of 0.30, 95% CI,
0.15-0.59) versus abiraterone alone in patients with BRCA
mutations.(1) Median rPFS and median OS were not reached for
patients treated with Lynparza plus abiraterone versus a median of
8 months and 23 months, respectively, for those treated with
abiraterone alone.
Prostate cancer is the second-most common cancer in men and
despite an increase in the number of available therapies for
patients with mCRPC, five-year survival remains low.(2,3)
Approximately 10% of patients with mCRPC have BRCA mutations, which
is associated with poor prognosis and outcomes.(4,5)
Andrew Armstrong, MD, ScM, of the Duke Cancer Institute, Durham,
North Carolina, US, and an investigator in the trial, said:
"Preventing or delaying radiographic progression or death is an
important clinical endpoint in assessing cancer treatment and is
very important to patients, their caregivers and their families.
The PROpel results showed the Lynparza combination demonstrated a
notable clinically meaningful benefit that should rapidly be
considered as the standard of care treatment for patients with
BRCA-mutated metastatic castration-resistant prostate cancer."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: "There is a critical unmet need for new
first-line treatment options for patients with BRCA-mutated
metastatic castration-resistant prostate cancer and this approval
underscores the importance of BRCA testing at metastatic diagnosis.
We look forward to bringing the benefit of this Lynparza
combination to patients earlier in their treatment."
Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, MSD Research Laboratories,
said: "It is imperative that we create new ways to treat advanced
cancers and help improve patient outcomes by building on the
current standard of care. In PROpel, the Lynparza combination
improved radiographic progression-free survival and overall
survival for the subgroup of patients with BRCA-mutated metastatic
castration-resistant prostate cancer. This approval reinforces the
importance of routine testing for genetic mutations at metastatic
diagnosis to help guide clinical decisions."
The safety and tolerability profile of Lynparza plus abiraterone
in PROpel was in line with that observed in prior clinical trials
and the known profiles of the individual medicines.
Lynparza in combination with abiraterone and prednisone or
prednisolone is approved in the European Union (EU) and several
other countries for the treatment of adult patients with mCRPC
based on the PROpel trial.
Lynparza is already approved in the US based on results from the
PROfound Phase III trial as monotherapy for patients with
homologous recombination repair (HRR) gene-mutated mCRPC (BRCAm and
other HRR gene mutations) who have progressed following prior
treatment with enzalutamide or abiraterone; and in the EU, Japan,
and China for patients with BRCAm mCRPC who have progressed
following prior therapy that included a new hormonal agent.
Financial considerations
Following this approval for Lynparza in the US, AstraZeneca will
receive a regulatory milestone payment from MSD, anticipated to be
booked as Collaboration Revenue by the Company and confirmed in the
second quarter 2023 results.
Notes
Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in
men and the fifth leading cause of cancer death in men globally,
with an incidence of 1.4 million and 375,000 deaths in 2020.(2,3)
In the US, it is estimated that there will be 288,300 new cases and
34,700 deaths in 2023.(6) Overall survival for patients with mCRPC
is approximately three years in clinical trial settings, and even
shorter in the real-world.(7) Approximately half of patients with
mCRPC may receive only one line of active treatment, and those that
go on to receive further treatment often have diminishing benefit
of subsequent therapies.(8-13)
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.(14) Development of prostate cancer is often driven
by male sex hormones called androgens, including
testosterone.(15)
In patients with mCRPC, their 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.(16) Approximately
10-20% of men with advanced prostate cancer will develop
castration-resistant prostate cancer (CRPC) within five years, and
at least 84% of these men will have metastases at the time of CRPC
diagnosis.(17) Of patients with no metastases at CRPC diagnosis,
33% are likely to develop metastases within two years.(17)
Despite the advances in mCRPC treatment in the past decade with
taxane and new hormonal agent (NHA) treatment, there is high unmet
need in this population.(16-19)
PROpel
PROpel is a randomised, double-blind, multi-centre Phase III
trial testing the efficacy, safety, and tolerability of Lynparza
versus placebo when given in combination with abiraterone, as well
as prednisone or prednisolone, in men with mCRPC who had not
received prior chemotherapy or NHAs in the mCRPC setting.
The primary endpoint is rPFS and secondary endpoints include OS,
time to secondary progression or death, and time to first
subsequent therapy. In September 2021 at a planned interim
analysis, the Independent Data Monitoring Committee concluded that
the PROpel trial met the primary endpoint of rPFS.
For more information about the trial please visit
ClinicalTrials.gov .
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 HRR, such as those with
mutations in BRCA1 and/or BRCA2, or those where deficiency is
induced by other agents (such as NHAs).
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 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 homologous recombination
repair deficient (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; in combination
with abiraterone for the treatment of metastatic
castration-resistant prostate cancer in whom chemotherapy is not
clinically indicated (EU) and as monotherapy in HRR gene-mutated
metastatic castration-resistant prostate cancer in patients who
have progressed on prior NHA treatment (BRCAm only in the EU and
Japan). In China, Lynparza is approved for the treatment of
BRCA-mutated metastatic castration-resistant prostate cancer, as a
1st-line maintenance therapy in BRCA-mutated advanced ovarian
cancer as well as 1st-line maintenance treatment with bevacizumab
for HRD-positive 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 mitogen-activated protein kinase (MEK) inhibitor,
for multiple cancer types.
Working together, the companies will develop Lynparza and
Koselugo and other potential new medicines as monotherapies and as
combinations. The companies will also develop Lynparza and Koselugo
in combination with their respective PD-L1 and PD-1 medicines
independently.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
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.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialisation of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
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. Clarke N, et al. Abiraterone and Olaparib for Metastatic
Castration-Resistant Prostate Cancer. NEJM Evid. 2022;1(9).
2. Cancer.Net. Prostate Cancer: Statistics. Available at https://www.cancer.net/cancer-types/prostate-cancer/statistics . Accessed March 2023.
3. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019; 10(2):63-89.
4. de Bono, et al. Central, Prospective Detection of Homologous
Recombination Repair Gene Mutations (HRRm) in Tumour Tissue From
>4000 Men With Metastatic Castration-Resistant Prostate Cancer
(mCRPC) Screened for the PROfound Study. Presented at: ESMO
Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract
847PD
5. Na R, et al. Germline Mutations in ATM and BRCA1/2
Distinguish Risk for Lethal and Indolent Prostate Cancer and are
Associated with Early Age at Death. Eur Urol.
2017;71(5):740-747.
6. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021; 71(3):209-249.
7. Cancer.Org. Key Statistics For Prostate Cancer. Available at https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html . Accessed March 2023.
8. Ng K, et al. Metastatic Hormone-Sensitive Prostate Cancer
(mHSPC): Advances and Treatment Strategies in the First-Line
Setting. Oncol Ther. 2020;8:209-230.
9. George DJ, et al. Treatment Patterns and Outcomes in Patients
with Metastatic Castration-Resistant Prostate Cancer in a
Real-World Clinical Practice Setting in the United States. Clin
Genitourin Cancer. 2020;18:284-294.
10. de Bono J, et al. Antitumour Activity and Safety of
Enzalutamide in Patients with Metastatic Castration-Resistant
Prostate Cancer Previously Treated with Abiraterone Acetate Plus
Prednisone for >=24 weeks in Europe. Eur Urol.
2018;74(1):37-45
11. Hussein M, et al. Prostate-Specific Antigen Progression
Predicts Overall Survival in Patients with Metastatic Prostate
Cancer: Data from Southwest Oncology Group Trials 9346 (Intergroup
Study 0162) and 9916. J Clin Oncol. 2009;27(15):2450.
12. de Wit, R, et al. Real-World Evidence of Patients with
Metastatic Castration-Resistant Prostate Cancer Treated with
Cabazitaxel: Comparison with the Randomized Clinical Study CARD.
Prostate Cancer Prostatic Dis. 2022;2660.
13. Ryan C, et al. Abiraterone Acetate Plus Prednisone Versus
Placebo Plus Prednisone in Chemotherapy-Naive Men with Metastatic
Castration-Resistant Prostate Cancer (COU-AA-302): Final Overall
Survival Analysis of a Randomised, Double-Blind, Placebo-Controlled
Phase 3 Study. Lancet Oncol. 2015 Feb;16(2):152-60.
14. Miller K, et al. The Phase 3 COU-AA-302 Study of Abiraterone
Acetate Plus Prednisone in Men with Chemotherapy-Naïve Metastatic
Castration-Resistant Prostate Cancer: Stratified Analysis Based on
Pain, Prostate-Specific Antigen, and Gleason Score. Eur Urol.
2018;74(1):17-23.
15. Chowdhury S, et al. Real-World Outcomes in First-Line
Treatment of Metastatic Castration-Resistant Prostate Cancer: The
Prostate Cancer Registry. Target Oncol. 2020;15(3):301-315.
16. Cancer.Net. Treatment of Metastatic Castration-Resistant
Prostate Cancer. Available at
https://www.cancer.net/cancer-types/prostate-cancer/types-treatment
. Accessed March 2023.
17. Kirby M, et al. Characterising the Castration-Resistant
Prostate Cancer Population: Systematic Review. Int J of Clin Pract.
2021;65(11):1180-1192.
18. UroToday. What is Changing in Advanced Prostate Cancer?
Available at
https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html
. Accessed March 2023.
19. Liu J, et al. Second-Line Hormonal Therapy for the
Management of Metastatic Castration-Resistant Prostate Cancer: A
Real-World Data Study Using a Claims Database. Sci Rep.
2020;10(1):4240.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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