RNS Number : 2233G
14 November 2022
14 November 2022 07:00 GMT
Lynparza in combination with abiraterone recommended for
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
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 which were published in NEJM
Evidence 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
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
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
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 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
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
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 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 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)
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
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
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
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
AstraZeneca in oncology
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It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
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transform the patient experience.
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eliminate cancer as a cause of death.
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development, and commercialisation of prescription medicines in
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1. Rawla, P. The Epidemiology of Prostate Cancer. World J Oncol. 2019;10(2):63-89.
2. IARC Globocan. Estimated number of incident cases and deaths
Europe, both sexes, all ages (excl. NMSC). Available at
. Accessed November 2022
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(mHSPC): Advances and Treatment Strategies in the First-Line
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8. Liu J, et al. Second-line Hormonal Therapy for the Management
of Metastatic Castration-resistant Prostate Cancer: a Real-World
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a%20set%20period%20of%20time . Accessed November 2022.
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14. Schiewer MJ & Knudsen KE. AMPed up to treat prostate
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15. Li L, et al. Androgen receptor inhibitor-induced "BRCAness"
and PARP inhibition are synthetically lethal for
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signalling and the PARP pathway in prostate cancer. Nat Commun.
18. Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break
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response to genotoxic insult. Cancer Discov.
20. Tarish FL, et al. Castration radiosensitizes prostate cancer
tissue by impairing DNA double-strand break repair. Sci Transl Med.
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November 14, 2022 02:00 ET (07:00 GMT)
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