REG - AstraZeneca PLC - Lynparza combo recommended in the EU for mCRPC

AstraZenecaAnnouncement

14/11/2022 07:00

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RNS Number : 2233G  AstraZeneca PLC  14 November 2022

14 November 2022 07:00 GMT

 

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

 

First PARP inhibitor to demonstrate clinical benefit in combination with a new
hormonal agent in this setting

 

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

 

The Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency based its positive opinion 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)
which were published in NEJM Evidence
(https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043) in June 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 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
months for abiraterone alone. Results also showed that Lynparza in combination
with abiraterone extended median rPFS by almost one year, with a median rPFS
of 27.6 months versus 16.4 with abiraterone alone, as assessed by blinded
independent central review (BICR).

 

Updated results also showed a favourable trend in improved overall survival
with Lynparza plus abiraterone versus abiraterone alone, 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 real-world settings.(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, the
PROpel trial joint senior investigator, said: "Patients with metastatic
castration-resistant prostate cancer in the European Union have limited
treatment options. This form of advanced prostate cancer has a poor prognosis
and treatment decisions after initial diagnosis are critical. If approved in
the European Union for prostate cancer of this type, olaparib in combination
with abiraterone will provide a much-needed new treatment option for the many
men with this condition."

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "With the incidence and mortality of prostate cancer set to double in
the coming decades, it is more important than ever that we bring new treatment
options to suitable patients at the earliest possible moment in their care. If
approved, Lynparza in combination with abiraterone and prednisone or
prednisolone will represent the first combination of a PARP inhibitor and new
hormonal agent available to patients in the European Union."

 

Eliav Barr, Senior Vice President, Head of Global Clinical Development and
Chief Medical Officer, MSD Research Laboratories, said: "While prostate cancer
has seen many advances in care in recent decades, for those with mCRPC, new
treatment options are urgently needed. We are fully committed to bringing
Lynparza in combination with abiraterone and prednisone or prednisolone to
suitable patients in the European Union as quickly as possible."

 

Lynparza in combination with abiraterone and prednisone or prednisolone is
undergoing Priority Review in the US for the treatment of mCRPC in adult
patients based on results from the PROpel Phase III trial, with a decision
expected in Q4 2022.

 

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-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.

 

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.(5) 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.(5) Of patients with no metastases at CRPC diagnosis,
33% are likely to develop metastases within two years.(5)

 

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.(5,7,8,12)

 

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 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.

 

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 and survival in prostate cancer.(13,14) 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.(15-17)

 

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.(13,16,18) 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.(15,17,19,20)

 

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

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(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
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.

References

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Adrian Kemp

Company Secretary

AstraZeneca PLC

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