TIDMAZN
RNS Number : 9780X
AstraZeneca PLC
02 May 2023
2 May 2023
Update on FDA Advisory Committee vote on Lynparza plus
abiraterone for metastatic castration-resistant prostate
cancer
The Food and Drug Administration's (FDA) Oncologic Drugs
Advisory Committee (ODAC) has recognised a favourable benefit risk
profile for AstraZeneca and MSD's Lynparza (olaparib) plus
abiraterone and prednisone or prednisolone for the treatment of
adult patients with BRCA-mutated (BRCAm) metastatic
castration-resistant prostate cancer (mCRPC) based on the PROpel
Phase III trial. The Committee voted 11 to 1, with 1 abstaining,
that the indication should be limited to patients whose tumours
have a BRCA mutation.
In August 2022, the FDA accepted the supplemental New Drug
Application (sNDA) for Lynparza based on positive results from the
pivotal PROpel trial, also published in NEJM Evidence . The ODAC
provides the FDA with independent, expert advice and
recommendations on marketed and investigational medicines for use
in the treatment of cancer. The FDA is not bound by the Committee's
guidance but takes its advice into consideration. AstraZeneca and
MSD will continue to work with the FDA as it completes its review
of the application.
Neal Shore, Chief Medical Officer of Urology and Surgical
Oncology for Genesis Care, US and PROpel trial investigator , said:
"Today's recommendation by the ODAC is disappointing news for
clinicians and prostate cancer patients alike. Preventing or
delaying radiographic progression is an important clinical endpoint
in assessing oncologic treatment and is very relevant to patients,
their caregivers and their families. It is essential that
physicians and patients have an opportunity to choose treatment
with the goal of optimising cancer care outcomes."
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca said: "Novel treatment options are urgently needed for
patients with metastatic castration-resistant prostate cancer.
While we are pleased with the recognition of the benefit of
Lynparza plus abiraterone for patients with BRCA-mutated metastatic
castration-resistant prostate cancer, we are disappointed with the
outcome of today's ODAC meeting. We strongly beli eve in the
results of the PROpel trial, which demonstrated the clinically
meaningful benefit for this combination in a broad population of
patients regardless of biomarker status ."
Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, MSD Research Laboratories,
said "With the incidence and mortality of prostate cancer set to
double in the coming decades, it is critical that we bring new
treatment options with the potential to reduce the risk of disease
progression or death to patients at the earliest possible moment in
their care. While we are pleased that the ODAC recommended Lynparza
for patients with metastatic castration-resistant prostate cancer
who have BRCA mutations, we believe in the potential of Lynparza
plus abiraterone for a broad range of patients with metastatic
castration-resistant prostate cancer, based on the results of
PROpel. We look forward to the outcome of the FDA's review of the
application."
Results from the PROpel trial showed a statistically significant
and clinically meaningful 34% reduction in the risk of radiographic
disease progression or death with Lynparza plus abiraterone with
prednisone or prednisolone, versus abiraterone alone in patients
with mCRPC (hazard ratio [HR] 0.66; 95% confidence interval [CI]
0.54-0.81; p<0.001). Median radiographic progression-free
survival (rPFS) was 24.8 months and 16.6 months,
respectively.(1)
Further results from the final prespecified overall survival
(OS) analysis presented at ASCO Genitourinary Cancers Symposium
2023 showed Lynparza plus abiraterone and prednisone or
prednisolone demonstrated median OS of 42.1 months versus 34.7
months for abiraterone plus placebo. This result represents a
7.4-month absolute difference in median OS versus a standard of
care (47.9% maturity, HR of 0.81, 95% CI 0.67-1.00; p=0.0544).
While this numerical increase in median OS did not achieve
statistical significance, it builds on the meaningful survival
gains achieved for patients in this setting treated with
abiraterone alone, a current standard of care.
In exploratory analyses of the BRCAm subgroup, Lynparza plus
abiraterone demonstrated improvements in both rPFS (HR of 0.23, 95%
CI, 0.12-0.43) and OS (HR of 0.29, 95% CI, 0.14-0.56). In the
non-BRCAm subgroup, Lynparza plus abiraterone also showed
improvements in rPFS (HR of 0.76, 95% CI, 0.61-0.94), and a modest
trend for OS (HR of 0.91, 95% CI, 0.73-1.13).
The safety and tolerability of Lynparza plus abiraterone in
PROpel was in line with that observed in prior clinical trials and
the known profiles of the individual medicines.
Lynparza in combination with abiraterone and prednisone or
prednisolone is approved in the EU and several other countries for
the treatment of adult patients with mCRPC based on the PROpel
trial.
Notes
Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in
men and the fifth leading cause of cancer death in men globally,
with an incidence of 1.4 million and 375,000 deaths in 2020.(2-4)
In the United States, it is estimated that there will be 288,300
new cases and 34,700 deaths in 2023.(5) Overall survival for
patients with mCRPC is approximately three years in clinical trial
settings, and even shorter in the real-world.(6) Approximately half
of patients with mCRPC may receive only one line of active
treatment, and those that go on to receive further treatment often
have diminishing benefit of subsequent therapies.(7-12)
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.(13) Development of prostate cancer is often driven
by male sex hormones called androgens, including
testosterone.(14)
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.(15) 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.(16) Of patients with no metastases at CRPC diagnosis,
33% are likely to develop metastases within two years.(16)
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.(15-18)
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 combination with 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 OS,
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.(18,19) In addition, the AR also plays a role in repairing
DNA damage in prostate cancer cells, including damage not normally
repaired by homologous recombination repair (HRR). Preclinical
models have suggested a number of potential mechanisms that could
account for increased combination efficacy in both HRR deficient
and HRR proficient prostate cancer.(1,19-25) Recent data provide
evidence that PARP facilitates AR-DNA binding in the presence of
DNA damage (AZ internal data on file) and that combined inhibition
of PARP with Lynparza and AR activity with an NHA results in
enhanced DNA damage and anti-tumour activity in non-HRRm prostate
cancer models.(1,21,24,26,27)
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; in combination
with abiraterone for the treatment of metastatic
castration-resistant prostate cancer in whom chemotherapy is not
clinically indicated (EU) and as monotherapy in HRR gene-mutated
metastatic castration-resistant prostate cancer in patients who
have progressed on prior NHA treatment (BRCAm only in the EU and
Japan). In China, Lynparza is approved for the treatment of
BRCA-mutated metastatic castration-resistant prostate cancer, as a
1st-line maintenance therapy in BRCA-mutated advanced ovarian
cancer as well as 1st-line maintenance treatment with bevacizumab
for HRD-positive 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 and follow the
Company on Twitter @ AstraZeneca .
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References
1. Clarke N, et al. Abiraterone and Olaparib for Metastatic
Castration-Resistant Prostate Cancer. NEJM Evid. 2022;1(9).
2. Clarke N, et al. Final Overall Survival (OS) in PROpel:
Abiraterone (abi) and Olaparib (ola) Versus Abiraterone and Placebo
(pbo) as First-Line (1L) Therapy For Metastatic
Castration-Resistant Prostate Cancer (mCRPC). Presented at ASCO
Genitourinary Cancers Symposium. California, USA. 16 January
2023.
3. Cancer.Net. Prostate Cancer: Statistics. Available at https://www.cancer.net/cancer-types/prostate-cancer/statistics . Accessed March 2023.
4. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019; 10(2):63-89.
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Prostate Cancer. Available at
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. Accessed March 2023.
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2021;65(11):1180-1192.
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. Accessed March 2023.
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Adrian Kemp
Company Secretary
AstraZeneca PLC
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