RNS Number : 1475W
16 August 2022
16 August 2022 07:00 BST
Lynparza in combination with abiraterone granted Priority Review
the US for patients with metastatic castration-resistant
First PARP inhibitor to demonstrate clinical benefit in
combination with a new hormonal agent irrespective of homologous
recombination repair (HRR) gene mutations
AstraZeneca's supplemental New Drug Application (sNDA) for
Lynparza (olaparib) in combination with abiraterone and prednisone
or prednisolone has been accepted and granted Priority Review in
the US for the treatment of adult patients with metastatic
castration-resistant prostate cancer (mCRPC).
Lynparza is being jointly developed and commercialised by
AstraZeneca and MSD.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that offer significant advantages over
available options by demonstrating safety or efficacy improvements,
preventing serious conditions, or enhancing patient compliance. (1)
The Prescription Drug User Fee Act date, the FDA action date for
their regulatory decision, is anticipated during the fourth quarter
In the US, prostate cancer is the second most common cancer in
male patients and is projected to cause approximately 35,000 deaths
in 2022.(2) Overall survival for patients with mCRPC is
approximately three years in clinical trial settings, and even
shorter in the real world.(3-6) Approximately half of patients with
mCRPC may receive only one line of active treatment, with
diminishing benefit of subsequent therapies.(6-11)
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: "There remains a critical unmet need among
patients diagnosed with metastatic castration-resistant prostate
cancer, where the prognosis remains poor and treatment options are
limited. Today's news is another step towards bringing forward a
new, much-needed treatment option in this setting. If approved,
Lynparza with abiraterone will become the first combination of a
PARP inhibitor and a new hormonal agent for patients with this
Dr. Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, MSD Research Laboratories,
said: "MSD is committed to developing new treatment options for
patients with metastatic castration-resistant prostate cancer , a
complex disease that urgently needs more therapies. We look forward
to working with the FDA towards the goal of bringing a new option
to patients with mCRPC with or without HRR gene mutations. "
The sNDA was based on results from the PROpel Phase III trial
presented at the 2022 American Society of Clinical Oncology (ASCO)
Genitourinary Cancers Symposium and later published in NEJM
These results showed Lynparza in combination with abiraterone
reduced the risk of disease progression or death by 34% versus
abiraterone alone (based on a hazard ratio [HR] of 0.66; 95%
confidence interval [CI] 0.54-0.81; p<0.0001). Median
radiographic progression-free survival (rPFS) was 24.8 months for
Lynparza plus abiraterone versus 16.6 for abiraterone alone. The
safety and tolerability of Lynparza in combination with abiraterone
was in line with that observed in prior clinical trials and the
known profiles of the individual medicines.(12)
Lynparza is approved in the US for patients with HRR
gene-mutated mCRPC (BRCA-mutated 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
BRCA-mutated mCRPC who have progressed following prior therapy that
included a new hormonal agent (NHA). These approvals were based on
the data from the PROfound Phase III trial.
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.(13) Development of prostate cancer is often driven
by male sex hormones called androgens, including
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.(7) 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.(7) Of patients with no metastases at CRPC diagnosis, 33%
are likely to develop metastases within two years.(6)
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.(7,9,10,15)
PROpel is a randomised, double-blind, multi-centre Phase III
trial testing the efficacy, safety, and tolerability of Lynparza
versus placebo when given in addition to abiraterone in men with
mCRPC who had not received prior chemotherapy or NHAs in the mCRPC
Men in both treatment groups will also receive either prednisone
or prednisolone twice daily. The primary endpoint is rPFS and
secondary endpoints include overall survival, time to secondary
progression or death, and time to first subsequent therapy.
For more information about the trial please visit
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. In the PROpel Phase III trial, Lynparza is
combined with abiraterone, an NHA which targets the androgen
receptor (AR) pathway.
Androgen receptor signalling engages a transcriptional programme
that is critical for tumour cell growth & survival in prostate
cancer.(16,17) Preclinical models have identified interactions
between PARP signalling and the AR pathway which support the
observation of a combined anti-tumour effect of Lynparza and NHAs,
like abiraterone, in both HRR deficient and HRR proficient prostate
The PARP1 protein has been reported to be required for the
transcriptional activity of androgen receptors; therefore
inhibiting PARP with Lynparza may impair the expression of androgen
receptor target genes and enhance the activity of NHAs.(16,19,21)
Additionally, it is thought that abiraterone may alter/inhibit the
transcription of some HRR genes which may induce HRR deficiency and
increase sensitivity to PARP inhibition.(18,20,22,23)
Lynparza is currently approved in a number of countries across
PARP-dependent tumour types with defects and dependencies in the
DDR pathway 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 germline
BRCAm (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; for gBRCAm
metastatic pancreatic cancer; and HRR gene-mutated metastatic
castration-resistant prostate cancer (BRCAm only in the EU and
Lynparza , which is being jointly developed and commercialised
by AstraZeneca and MSD, is the foundation of AstraZeneca's
industry-leading portfolio of potential new medicines.
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. 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 (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 .
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1. US Food and Drug Administration. Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review . Accessed August 2022.
2. Cancer.org. Key Statistics for Prostate Cancer. Available at https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. Accessed August 2022.
3. 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.
4. Shore N, et al. Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors. Adv Ther. 2021;38:4520-4540.
5. Wallis C, et al. Real-World Use of Androgen-Deprivation
Therapy: Intensification Among Older Canadian Men With de Novo
Metastatic Prostate Cancer. JNCI Cancer Spectrum.
6. George D, 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. Clinical
Genitourinary Cancer. 2020 Aug;18(4):284-294.
7. Kirby, M, et al. Characterising the castration-resistant
prostate cancer population: a systematic review. International
Journal of Clinical Practice, 2021;65(11):1180-1192.
8. Smith MR, et al. Natural history of rising serum
prostate-specific antigen in men with castrate nonmetastatic
prostate cancer. J Clin Oncol. 2005;23(13):2918-25.
9. 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 August 2022.
10. 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. Scientific Report.
11. Mateo J, et al. DNA-Repair Defects and Olaparib in
Metastatic Prostate Cancer. N Engl J Med. 2015; 373:1697-1708.
12. Clarke N, et al. Abiraterone and Olaparib for Metastatic
Castration-Resistant Prostate Cancer. NEJM. 2022;1(7)
13. 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):301-15.
14. Cancer.Net. Treatment of metastatic castration-resistant
prostate cancer. Available at
. Accessed August 2022.
15. UroToday. Beyond First-line Treatment of Metastatic
Castrate-resistant Prostate Cancer. Available at
Accessed August 2022 .
16. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer
growth and progression. Cancer Discov. 2012;2(12):1134-1149.
17. Schiewer MJ & Knudsen KE. AMPed up to treat prostate
cancer: novel AMPK activators emerge for cancer therapy. EMBO Mol
18. Li L, et al. Androgen receptor inhibitor-induced "BRCAness"
and PARP inhibition are synthetically lethal for
castration-resistant prostate cancer. Sci Signal. 2017;
19. Polkinghorn WR, et al. Androgen receptor signaling regulates
DNA repair in prostate cancers. Cancer Discov.
20. Asim M, et al. Synthetic lethality between androgen receptor
signalling and the PARP pathway in prostate cancer. Nat Commun.
21. Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break
required for regulated transcription. Science.
22. Goodwin JF, et al. A hormone-DNA repair circuit governs the
response to genotoxic insult. Cancer Discov.
23. Tarish FL, et al. Castration radiosensitizes prostate cancer
tissue by impairing DNA double-strand break repair. Sci Transl Med.
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(END) Dow Jones Newswires
August 16, 2022 02:00 ET (06:00 GMT)
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