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REG - AstraZeneca PLC - Lynparza approved in EU for prostate cancer

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RNS Number : 3942K  AstraZeneca PLC  21 December 2022

21 December 2022 07:05 GMT

 

Lynparza in combination with abiraterone approved in the EU as 1st-line
treatment for patients with metastatic castration-resistant prostate cancer

 

First approved PARP inhibitor to demonstrate clinically meaningful benefits in
combination with a new hormonal agent

 

Lynparza in combination with abiraterone extended median radiographic
progression-free survival benefit beyond two years in this setting

 

AstraZeneca and MSD's Lynparza (olaparib) in combination with abiraterone and
prednisone or prednisolone has been approved in the European Union for the
treatment of metastatic castration-resistant prostate cancer (mCRPC) in adult
men for whom chemotherapy is not clinically indicated.

 

This approval by the European Commission was based on results from the PROpel
Phase III trial
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-combo-delays-progression-risk-in-prostate-cancer.html)
and follows the positive recommendation
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-in-combination-with-abiraterone-recommended-for-approval-in-the-eu-by-chmp-as-1st-line-treatment-for-patients-with-metastatic-castration-resistant-prostate-cancer.html)
in the EU by the Committee for Medicinal Products for Human Use in November
2022.

 

In the trial, Lynparza in combination with abiraterone and prednisone or
prednisolone, reduced the risk of disease progression or death by 34% versus
abiraterone and prednisone or prednisolone (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 months for abiraterone alone. Furthermore, a
planned rPFS analysis by blinded independent central review (BICR) showed
Lynparza plus abiraterone had a median rPFS of 27.6 months compared to 16.4
months with abiraterone alone, extending median rPFS by almost one year.

 

Updated results from a second planned analysis presented at ESMO 2022 showed a
favourable trend towards improved overall survival with Lynparza plus
abiraterone versus abiraterone alone (based on HR of 0.83; 95% CI 0.66-1.03;
p=0.11), however, the difference did not reach statistical significance at the
time of this data cut-off (analysis at 40% data maturity).

 

Prostate cancer is the most common cancer in men in Europe, with an estimated
473,000 patients diagnosed and 108,000 deaths in 2020.(1,2) Overall survival
for patients with mCRPC is approximately three years in clinical trial
settings, and even shorter in the real-world.(3) Approximately half of
patients with mCRPC may receive only one line of active treatment, with
diminishing benefit of subsequent therapies.(4-9)

 

Noel Clarke, Urological Surgeon and Professor of Urological Oncology at
Manchester's Christie/Salford Royal Hospitals and Manchester University, a
senior investigator of the PROpel trial, said: "The results of the PROpel
Phase III trial of olaparib in combination with abiraterone as a first-line
treatment show that this therapeutic combination can provide significant
clinical benefit to patients with metastatic castration-resistant prostate
cancer. Patients with this condition in the EU will now, for the first time,
have the opportunity to benefit from this new treatment combination."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "Many patients with metastatic castration-resistant
prostate cancer are only able to receive one line of active therapy, as the
disease can progress quickly. Lynparza in combination with abiraterone has
been shown to reduce the risk of disease progression by 34% versus the
standard of care treatment in the PROpel trial. Moreover, the combination of
Lynparza with abiraterone as a first-line treatment expands the use of
Lynparza to a broader group of metastatic castration-resistant prostate cancer
patients than those treated with Lynparza alone in the second-line setting in
the PROfound trial. Today's approval marks a significant advance toward
addressing the unmet need of patients with metastatic castration-resistant
prostate cancer in the EU."

 

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. This approval by the European Commission marks another step
towards delivering on that commitment and we look forward to extending the
benefits of Lynparza to more patients with metastatic castration-resistant
prostate cancer in the EU."

 

The safety and tolerability of Lynparza in combination with abiraterone in
PROpel was in line with that observed in prior clinical trials and the known
profiles of the individual medicines. There was no increase in the rate of
discontinuation of abiraterone in patients treated with Lynparza in
combination with abiraterone and no detrimental effect on health-related
quality of life versus those treated with abiraterone alone (Functional
Assessment of Cancer Therapy-Prostate questionnaire).

 

In August
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-granted-fda-priority-review-for-propel.html)
, supplemental New Drug Application (sNDA) for Lynparza in combination with
abiraterone and prednisone or prednisolone was accepted and granted Priority
Review in the US for the treatment of adult patients with mCRPC. The
Prescription Drug User Fee Act (PDUFA) date is anticipated
(https://www.astrazeneca.com/media-centre/press-releases/2022/update-on-us-review-of-lynparza-propel-snda.html)
during the first quarter of 2023.

 

Lynparza is approved in the US based on results from the PROfound Phase III
trial
(https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-more-than-doubled-the-time-without-disease-progression-in-patients-with-brca1-2-atm-mutated-metastatic-castration-resistant-prostate-cancer-30092019.html)
as monotherapy for patients with homologous recombination repair (HRR)
gene-mutated mCRPC (BRCA 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.

 

Financial considerations

Following this approval for Lynparza in the EU, AstraZeneca will receive a
regulatory milestone payment from MSD of $105m, anticipated to be booked as
Collaboration Revenue by the Company during the fourth quarter of 2022.

 

Notes

 

Metastatic castration-resistant prostate cancer

Metastatic prostate cancer is associated with a significant mortality
rate.(10) Development of prostate cancer is often driven by male sex hormones
called androgens, including testosterone.(11)

 

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.(12) 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.(12) Of patients with no metastases at CRPC diagnosis,
33% are likely to develop metastases within two years.(12)

 

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.(12,13,14,15)

 

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, 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 overall survival,
time to secondary progression or death, and time to first subsequent therapy.

 

In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA
which targets the androgen receptor (AR) pathway. AR 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
deficient phenotype, which may increase sensitivity to PARP
inhibition.(18,20,22,23)

 

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.

 

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; 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 1st-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 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 (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.   Rawla, P. The Epidemiology of Prostate Cancer. World J Oncol.
2019;10(2):63-89.

2.    IARC GloboCan. Prostate Cancer Factsheet. 2020. Available at
https://gco.iarc.fr/today/data/factsheets/cancers/27-Prostate-fact-sheet.pdf
(https://gco.iarc.fr/today/data/factsheets/cancers/27-Prostate-fact-sheet.pdf)
. Accessed December 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.    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.

5.    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

6.    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.

7.    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.

8.    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
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9.    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.

10.   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.

11.   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.%20)
Accessed: December 2022.

12.   Kirby M, et al. Characterising the Castration-Resistant Prostate Cancer
Population: Systematic Review. Int J of Clin Pract. 2021;65(11):1180-1192.

13.   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 December 2022.

14.   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.

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
(https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html%20)
. Accessed December 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 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;8(1):374.

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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