# AstraZeneca granted PDUFA extension to allow further time for a full review on Lynparza

- Link: https://www.directorstalkinterviews.com/astrazeneca-granted-pdufa-extension-to-allow-further-time-for-a-full-review-on-lynparza/4121094551
- Published: 2022-12-15T07:28:43+00:00
- 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 today announced that the US Food and Drug Administration (FDA) has informed
AstraZeneca that it will extend the Prescription Drug User Fee Act (PDUFA) date 
by three months to provide further time for a full review of the supplementary new
drug application (sNDA) for _Lynparza_ (olaparib) in combination with abiraterone
and prednisone or prednisolone for the treatment of metastatic castration-resistant
prostate cancer (mCRPC). The companies will continue to work with the FDA to facilitate
the completion of the agency’s review.

The sNDA is based on results from the pivotal PROpel Phase III trial, which were
published in June 2022 in NEJM Evidence. In August 2022, the sNDA was granted Priority
Review and AstraZeneca and MSD are committed to working with the FDA to bring this
treatment option to patients with mCRPC.

In November, the European Medicines Agency’s Committee for Medicinal Products for
Human Use adopted a positive opinion recommending approval of _Lynparza_ in combination
with abiraterone and prednisone or prednisolone in the EU for the treatment of adult
patients with mCRPC for whom chemotherapy is not clinically indicated. This combination
is also undergoing regulatory reviews in other countries.

_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 hormonal agent.

**Notes**

**Metastatic castration-resistant prostate cancer**

Metastatic prostate cancer is associated with a significant mortality rate.^(11)
Development of prostate cancer is often driven by male sex hormones called androgens,
including testosterone.^(12)

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.^(6) 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.^(6)
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.^(6,8,9,13)

**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 received either prednisone or prednisolone twice
daily. The primary endpoint is investigator-assessed rPFS, with sensitivity analyses
by BICR, and secondary endpoints include overall survival, time to secondary progression
or death, time to first subsequent therapy, and quality of life measures.

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.^(14,15) 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.^(16-18)

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.^(
14,17,19) 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.^(16,18,20,21)

For more information about the trial please visit ClinicalTrials.gov.

**_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.

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