REG - AstraZeneca PLC - ODAC vote on Lynparza combo in prostate cancer

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02/05/2023 07:00

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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
(https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043) . 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 believe 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
(https://www.astrazeneca.com/media-centre/press-releases/2023/overall-survival-analysis-of-the-lynparza-propel-phase-iii-trial-in-metastatic-castration-resistant-prostate-cancer.html)
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
(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; 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  (https://www.astrazeneca.com/) and follow the
Company on Twitter @AstraZeneca (https://mobile.twitter.com/AstraZeneca) .

 

Contacts

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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
(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.

5.   Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer
J Clin. 2021; 71(3):209-249.

6.   Cancer.Org. Key Statistics For Prostate Cancer. Available
at https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html
(https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html) .
Accessed March 2023.

7.   Ng K, et al. Metastatic Hormone-Sensitive Prostate Cancer (mHSPC):
Advances and Treatment Strategies in the First-Line Setting. Oncol Ther.
2020;8:209-230.

8.   George DJ, et al. Treatment Patterns and Outcomes in Patients with
Metastatic Castration-Resistant Prostate Cancer in a Real-World Clinical
Practice Setting in the United States. Clin Genitourin Cancer.
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9.   de Bono J, et al. Antitumour Activity and Safety of Enzalutamide in
Patients with Metastatic Castration-Resistant Prostate Cancer Previously
Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in
Europe. Eur Urol. 2018;74(1):37-45

10.  Hussein M, et al. Prostate-Specific Antigen Progression Predicts
Overall Survival in Patients with Metastatic Prostate Cancer: Data from
Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. J Clin
Oncol. 2009;27(15):2450.

11.  de Wit, R, et al. Real-World Evidence of Patients with Metastatic
Castration-Resistant Prostate Cancer Treated with Cabazitaxel: Comparison with
the Randomized Clinical Study CARD. Prostate Cancer Prostatic Dis. 2022;2660.

12.  Ryan C, et al. Abiraterone Acetate Plus Prednisone Versus Placebo Plus
Prednisone in Chemotherapy-Naive Men with Metastatic Castration-Resistant
Prostate Cancer (COU-AA-302): Final Overall Survival Analysis of a Randomised,
Double-Blind, Placebo-Controlled Phase 3 Study. Lancet Oncol. 2015
Feb;16(2):152-60.

13.  Miller K, et al. The Phase 3 COU-AA-302 Study of Abiraterone Acetate
Plus Prednisone in Men with Chemotherapy-Naïve Metastatic
Castration-Resistant Prostate Cancer: Stratified Analysis Based on Pain,
Prostate-Specific Antigen, and Gleason Score. Eur Urol. 2018;74(1):17-23.

14.  Chowdhury S, et al. Real-World Outcomes in First-Line Treatment of
Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer
Registry. Target Oncol. 2020;15(3):301-315.

15.  Cancer.Net. Treatment of Metastatic Castration-Resistant Prostate
Cancer. Available
at https://www.cancer.net/cancer-types/prostate-cancer/types-treatment
(https://www.cancer.net/cancer-types/prostate-cancer/types-treatment) .
Accessed March 2023.

16.  Kirby M, et al. Characterising the Castration-Resistant Prostate
Cancer Population: Systematic Review. Int J of Clin Pract.
2021;65(11):1180-1192.

17.  UroToday. What is Changing in Advanced Prostate Cancer? Available at
https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html
(https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html)
. Accessed March 2023.

18.  Liu J, et al. Second-Line Hormonal Therapy for the Management of
Metastatic Castration-Resistant Prostate Cancer: A Real-World Data Study Using
a Claims Database. Sci Rep. 2020;10(1):4240.

19.  UroToday. Beyond First-line Treatment of Metastatic Castrate-Resistant
Prostate Cancer. Available at
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(https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistan%20t-prostate-cancer.html)
. Accessed March 2023.

20.  Schiewer MJ, et al. Dual roles of PARP-1 Promote Cancer Growth and
Progression. Cancer Discov. 2012;2(12):1134-1149.

21.  Asim M, et al. Synthetic Lethality Between Androgen Receptor Signalling
and the PARP Pathway in Prostate Cancer. Nature. 2017;8:374.

22.  Li L, et al. Androgen Receptor Inhibitor-Induced "BRCAness" and PARP
Inhibition are Synthetically Lethal for Castration-Resistant Prostate Cancer.
Sci Signal. 2017; 10(480):eaam7479.

23.  Polkinghorn WR, et. Androgen Receptor Signalling Regulates DNA Repair in
Prostate Cancers. Cancer Discov. 2013; 3(11):1245-1253.

24.  Clarke N, et al. Olaparib Combined with Abiraterone in Patients with
Metastatic Castration-Resistant Prostate Cancer: A Randomised, Double-Blind,
Placebo-Controlled, Phase 2 Trial. Lancet Oncol. 2018;19(7):975-986.

25.  Pommier Y, et al. Laying a Trap to Kill Cancer Cells: PARP Inhibitors
and Their Mechanisms of Action. Sci Transl Med. 2016;8(362):362ps17.

26.  Schiewer MJ & Knudsen KE. AMPed Up To Treat Prostate Cancer: Novel
AMPK Activators Emerge for Cancer Therapy. EMBO Mol Med. 2014;6(4):439-441.

27.  Gui B, et al. Selective Targeting of PARP-2 Inhibits Androgen Receptor
Signaling and Prostate Cancer Growth Through Disruption of FOXA1
Function. Proc Natl Acad Sci U S A. 2019 Jul 16; 116(29): 14573-14582.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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