# AstraZeneca Lynparza approved in the US by FDA for prostate cancer

- Link: https://www.directorstalkinterviews.com/astrazeneca-lynparza-approved-in-the-us-by-fda-for-prostate-cancer/412823568
- Published: 2020-05-20T07:24:50+01:00
- Author: Amilia Stone

**[AstraZeneca PLC](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l)**(
[LON:AZN](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l))
and MSD Inc., Kenilworth, N.J., US today announced that _Lynparza_ has been approved
in the US for patients with homologous recombination repair gene-mutated metastatic
castration-resistant prostate cancer.

The approval by the US Food and Drug Administration (FDA) was based on results from
the Phase III PROfound trial, which were published in The New England Journal of
Medicine.

Prostate cancer is the second-most common cancer in men and despite an increase 
in the number of available therapies for men with mCRPC, five-year survival remains
low. HRR gene mutations occur in approximately 20-30% of patients with mCRPC.

> **Maha Hussain, one of the principal investigators of the PROfound trial and deputy
> director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University,
> said: **“Prostate cancer has lagged behind other solid tumours in the era of precision
> medicine. I am thrilled by the approval of _Lynparza_ which now brings a molecularly
> targeted treatment to men with HRR gene-mutated metastatic castration-resistant
> prostate cancer in the US. The PROfound trial was an international effort and 
> I want to thank the patients, their families, the investigators and their teams
> involved in making it possible.”

> **Dave Fredrickson, Executive Vice President, Oncology Business Unit, said:** “
> Today marks the first approval for _Lynparza_ in prostate cancer. In the PROfound
> trial, _Lynparza_ more than doubled the median radiographic progression-free survival
> and is the only PARP inhibitor to improve overall survival, versus enzalutamide
> or abiraterone for men with BRCA or ATM mutations. These results further establish
> that genomic testing for HRR mutations should be a critical step for the diagnosis
> and determination of treatment options for men with advanced prostate cancer.”

> **Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief
> Medical Officer, MSD Research Laboratories, said, **“_Lynparza_ is the only PARP
> inhibitor approved with Phase III data for men with HRR gene-mutated metastatic
> castration-resistant prostate cancer. This approval highlights the importance 
> of genomic testing to help identify treatment options for men in this patient 
> population. We are proud to work in collaboration with AstraZeneca toward our 
> overall goal of improving outcomes for patients.”

The primary endpoint of the trial was radiographic progression-free survival (rPFS)
in men with BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.
Results showed _Lynparza_ reduced the risk of disease progression or death by 66%(
equal to a hazard ratio of 0.34; p-value <0.0001) and improved rPFS to a median 
of 7.4 months versus 3.6 months with enzalutamide or abiraterone.

_Lynparza_ also showed an rPFS benefit in the overall HRR gene-mutated trial population,
a key secondary endpoint, and reduced the risk of disease progression or death by
51% (equal to a hazard ratio of 0.49; p-value <0.0001) and improved rPFS to a median
of 5.8 months versus 3.5 months with enzalutamide or abiraterone.

Additional results from the PROfound trial announced on 24 April 2020 demonstrated
a statistically significant and clinically meaningful improvement in the key secondary
endpoint of overall survival (OS) with _Lynparza_ versus enzalutamide or abiraterone
in men with mCRPC and BRCA1/2 or ATM gene mutations. Results showed _Lynparza_ reduced
the risk of death by 31% (equal to a hazard ratio of 0.69; p-value=0.0175) and improved
OS to a median of 19.0 months versus 14.6 months with enzalutamide or abiraterone.

The full indication is for the treatment of adult patients with deleterious or suspected
deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following
prior treatment with enzalutamide or abiraterone. Patients are to be selected for
treatment based on an FDA-approved companion diagnostic test for _Lynparza_.

_Lynparza_ is currently under regulatory review in the EU and other jurisdictions
as a treatment for men with HRR gene-mutated mCRPC.

AstraZeneca and MSD are testing _Lynparza_ in additional trials in metastatic prostate
cancer including the ongoing Phase III PROpel trial as a 1st-line treatment in combination
with abiraterone acetate for patients with mCRPC versus abiraterone acetate alone.

**Financial considerations**

Following this approval for _Lynparza_ in the US, AstraZeneca will receive a regulatory
milestone payment from MSD of $35m, anticipated to be booked as Collaboration Revenue
by the Company during the second quarter of 2020.

**Metastatic castration-resistant prostate cancer**

Prostate cancer is the second-most common cancer in men, with an estimated 1.3 million
new cases diagnosed worldwide in 2018 and is associated with a significant mortality
rate.^(1 )Development of prostate cancer is often driven by male sex hormones called
androgens, including testosterone.^(2) mCRPC occurs when 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.^(2) Approximately 10-20% of men with advanced
prostate cancer will develop CRPC within five years, and at least 84% of these will
have metastases at the time of CRPC diagnosis.^(3) Of men with no metastases at 
CRPC diagnosis, 33% are likely to develop metastases within two years.^(3) Despite
an increase in the number of available therapies for men with mCRPC, five-year survival
remains low.^(3)

**HRR gene mutations**

HRR gene mutations occur in approximately 20-30% of patients with mCRPC.^(4,) HRR
genes allow for accurate repair of damaged DNA in normal cells.^(5,6) HRR deficiency(
HRD) interferes with normal cell DNA repair mechanisms and can result in normal 
cell death.^(6) This is different in cancer cells, where a mutation in HRR pathways
leads to abnormal cell growth and therefore cancer.^(6) The inability to properly
repair DNA damage leads to genomic instability and contributes to cancer aetiology.
^(6) HRD is a well-documented target for PARP inhibitors, such as _Lynparza_. PARP
inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to 
DNA single-strand breaks which leads to replication fork stalling causing their 
collapse and the generation of DNA double-strand breaks, which in turn lead to cancer
cell death.^(6)

**PROfound**

PROfound is a prospective, multicentre, randomised, open-label, Phase III trial 
testing the efficacy and safety of _Lynparza_ versus enzalutamide or abiraterone
in patients with mCRPC who have progressed on prior treatment with enzalutamide 
or abiraterone and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12
other genes involved in the HRR pathway.

The trial was designed to analyse patients with HRRm genes in two cohorts: the primary
endpoint was in those with mutations in BRCA1/2 or ATM genes and then, if _Lynparza_
showed clinical benefit, a formal analysis was performed of the overall trial population
of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; key secondary
endpoint).

In the US, patients are selected for treatment with _Lynparza_ based on the following
FDA-approved companion diagnostics_:_

·    FoundationOne CDX: to identify patients with HRR-gene alterations in prostate
tumour tissue. FoundationOne is a registered trademark of Foundation Medicine, Inc.

·    BRACAnalysis CDX: a germline test to identify patients with BRCA1 and BRCA2
gene mutations. Myriad Genetics, Inc. owns and commercialises BRACAnalysis CDX.

**Lynparza**

_Lynparza_ 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 homologous
recombination repair, such as mutations in BRCA1 and/or BRCA2. 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 being tested in a range of PARP-dependent
tumour types with defects and dependencies in the DDR pathway.

_Lynparza_ is currently approved in a number of countries, including those in the
EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer.
It is approved in the US, the EU, Japan, China, and several other countries as 1st-
line maintenance treatment of BRCA-mutated advanced ovarian cancer following response
to platinum-based chemotherapy. It is also approved in the US, Japan, and a number
of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer,
previously treated with chemotherapy; in the EU, this includes locally advanced 
breast cancer. _Lynparza_ is approved in the US and several other countries for 
the treatment of germline BRCA-mutated metastatic pancreatic cancer. Regulatory 
reviews are underway in several jurisdictions for ovarian, breast, pancreatic and
prostate cancers.

_Lynparza_, which is being jointly developed and commercialised by AstraZeneca and
MSD, has been used to treat over 30,000 patients worldwide. _Lynparza_ has the broadest
and most advanced clinical trial development programme of any PARP inhibitor, 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** **

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