REG - AstraZeneca PLC - Lynparza granted FDA priority review for PROpel

AstraZenecaAnnouncement

16/08/2022 07:00

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RNS Number : 1475W  AstraZeneca PLC  16 August 2022

 

16 August 2022 07:00 BST

 

Lynparza in combination with abiraterone granted Priority Review in

the US for patients with metastatic castration-resistant prostate cancer

 

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 of 2022.

 

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 disease."

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-combo-delays-progression-risk-in-prostate-cancer.html)
at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers
Symposium and later published in NEJM Evidence
(https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043) .

 

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.

 

Notes

 

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 testosterone.(14)

 

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

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 setting.

 

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 ClinicalTrials.gov
(https://clinicaltrials.gov/ct2/show/NCT03732820) .

 

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. 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 cancer.(18-20)

 

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 Japan).

 

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
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 (http://www.astrazeneca.com/)  and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

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
(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. 2021;5(6):pkab082.

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
(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. 2020;10(4240):2020.

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
www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer
(http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer)
. Accessed August 2022.

15.  UroToday. Beyond First-line Treatment of Metastatic Castrate-resistant
Prostate Cancer. Available at
https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html.
Accessed August 2022
(https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html.%20Accessed%20August%202022)
.

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 Med. 2014;6(4):439-441.

18.  Li L, et al. Androgen receptor inhibitor-induced "BRCAness" and PARP
inhibition are synthetically lethal for castration-resistant prostate cancer.
Sci Signal. 2017; 10(480):eaam7479.

19.  Polkinghorn WR, et al. Androgen receptor signaling regulates DNA repair
in prostate cancers. Cancer Discov. 2013;3(11):1245-1253.

20.  Asim M, et al. Synthetic lethality between androgen receptor signalling
and the PARP pathway in prostate cancer. Nat Commun. 2017;374(8).

21.  Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break required for
regulated transcription. Science. 2006;312(5781):1798-1802.

22.  Goodwin JF, et al. A hormone-DNA repair circuit governs the response to
genotoxic insult. Cancer Discov. 2013;3(11):1254-1271.

23.  Tarish FL, et al. Castration radiosensitizes prostate cancer tissue by
impairing DNA double-strand break repair. Sci Transl Med. 2015;
7(312):312re11.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

 

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