REG - AstraZeneca PLC - Lynparza combo delays progression risk in prostate

AstraZenecaAnnouncement

15/02/2022 07:00

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RNS Number : 7061B  AstraZeneca PLC  15 February 2022

15 February 2022 07:00 GMT

 

Lynparza plus abiraterone reduced risk of disease progression by 34% vs.
standard-of-care in 1st-line metastatic castration-resistant prostate cancer

 

Combination was well tolerated and allowed patients to maintain their quality
of life vs. patients treated with abiraterone alone

 

PROpel Phase III trial results show clinically meaningful benefit in patients
irrespective of homologous recombination repair gene mutations

 

Positive results from the PROpel Phase III trial showed AstraZeneca and MSD's
Lynparza (olaparib) in combination with abiraterone demonstrated a
statistically significant and clinically meaningful improvement in
radiographic progression-free survival (rPFS) versus current standard-of-care
abiraterone as a 1st-line treatment for patients with metastatic
castration-resistant prostate cancer (mCRPC) with or without homologous
recombination repair (HRR) gene mutations.

 

These results will be presented on 17 February at the 2022 American Society of
Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

 

Prostate cancer is the second most common cancer in male patients, causing
approximately 375,000 deaths in 2020.(1) Patients with advanced prostate
cancer have a particularly poor prognosis and the five-year survival rate
remains low.(1,2,3) Approximately half of patients with mCRPC receive only one
line of active treatment, with diminishing benefit of subsequent
therapies.(4,5,6,7) HRR gene mutations occur in approximately 20-30% of
patients with mCRPC.(8)

 

Fred Saad, Professor and Chairman of Urology and Director of Genitourinary
Oncology at the University of Montreal Hospital Center and principal
investigator in the trial, said: "It is clear to me that the prognosis for
metastatic castration resistant prostate cancer (mCRPC) is extremely poor, and
many patients are only able to receive one line of effective therapy. The
results of the PROpel trial, which showed that olaparib in combination with
abiraterone significantly delayed disease progression versus abiraterone by
more than eight months, demonstrate the potential for this combination to
become a new standard of care option in mCRPC if approved."

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "This Lynparza combination has the potential to afford first-line
patients more time without disease progression while also maintaining their
quality of life. The PROpel results are impressive because active comparator
trials set a high bar and, in this trial, Lynparza plus abiraterone showed a
significant clinical improvement when compared to an active standard of care
in patients with metastatic castration-resistant prostate cancer, regardless
of whether they have an HRR gene mutation."

 

Roy Baynes, Senior Vice President and Head of Global Clinical Development,
Chief Medical Officer, MSD Research Laboratories, said: "Results from the
PROpel trial showed that Lynparza in combination with abiraterone plus
prednisone reduced the risk of disease progression or death by a third
compared to abiraterone plus prednisone in the first-line setting for patients
with metastatic castration-resistant prostate cancer, regardless of their
biomarker status. We look forward to discussing these important results with
global health authorities as quickly as possible. We thank the patients,
caregivers and health care providers for participating in this study."

 

In a predefined interim analysis, Lynparza in combination with abiraterone
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 rPFS was 24.8 months for Lynparza plus
abiraterone versus 16.6 for abiraterone alone.

 

Results also showed a favourable trend towards improved overall survival (OS)
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 29% data maturity). The trial will continue to assess OS
as a key secondary endpoint.

 

Additional data from efficacy endpoints such as time to first subsequent
therapy (TFST), second progression-free survival (PFS2), objective response
rate (ORR), as well as prostate-specific antigen levels and
circulating-tumour-cell counts further support the treatment benefit of
Lynparza and abiraterone compared to abiraterone alone in the overall trial
population.

 

The safety and tolerability of Lynparza in combination with abiraterone was in
line with that observed in prior clinical trials and the known profiles of the
individual medicines. There was no increase in the rate of discontinuation of
abiraterone in patients treated with Lynparza in combination with abiraterone,
and no detrimental effect on health-related quality of life versus those
treated with abiraterone alone (FACT-P (Functional Assessment of Cancer
Therapy-Prostate) questionnaire).

 

Summary of PROpel results

                                        Lynparza + abiraterone           Placebo + abiraterone

                                        (n=399)                          (n=397)
 rPFS by Investigator (1)
 Number of patients with events (%)     168 (42)                         226 (57)
 Median PFS (in months)                 24.8                             16.6
 HR (95% CI)                            0.66 (0.54, 0.81)

 p-value                                <0.0001
 rPFS by BICR(2)
 Number of patients with events (%)     157 (39)                         218 (55)
 Median PFS (in months)                 27.6                             16.4
 HR (95% CI)                            0.61 (0.49, 0.74)

 p-value(5)                             <0.0001
 OS(3)
 Number of patients with events (%)     107 (27)                         121 (30)
 Median OS (in months)                  NC(4)                            NC
 HR (95% CI)                            0.86 (0.66, 1.12)

 p-value                                0.2923
 PFS2
 Number of patients with events (%)     70 (18)                          94 (24)
 Median (in months)                     NC                               NC
 HR (95% CI)                            0.69 (0.51, 0.94)

 p-value(5)                             0.0184
 TFST
 Number of patients with events (%)     183 (46)                         221 (56)
 Median (95% CI) (in months)            25.0 (22.2, NC)                  19.9 (17.1, 22.0)
 HR (95% CI)                            0.74 (0.61, 0.90)

 p-value(5)                             0.0040
 Objective Response Rate
 Number of evaluable patients(6)        161                              160
 Number of patients with responses (%)  94 (58)                          77 (48)
 Odds ratio (95% CI)                    1.60 (1.02, 2.53)
 p-value(5)                             0.0409
 rPFS by HRR gene mutation status(7)
 HRRm
 Number of patients randomized          111                115
 Number of patients with events (%)     43 (39)            73 (63)
 Median (in months)                     NC                 13.9
 HR (95% CI)                            0.50 (0.34, 0.73)
 Non-HRRm
 Number of patients randomized          279                273
 Number of patients with events (%)     119 (43)           149 (55)
 Median (95% CI) (in months)            24.1 (19.6, 27.6)  19.0 (14.3, 21.9)
 HR (95% CI)                            0.76 (0.60, 0.97)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394
events in 796 patients)

2. Assessed by blinded independent central review (BICR)

3. OS analysis was done at 29% maturity (228 events in 796 patients) and
boundary for significance 0.001 (2-sided); statistical significance not
reached. Survival follow up continues and further analyses were planned.

4. Not calculable

5. Nominal

6. Patients with measurable disease at baseline as per RECIST 1.1 criteria,
investigator assessment.

7. Exploratory subgroup analysis by HRR status. The HRRm status of patients in
PROpel was determined retrospectively using results from tumour tissue and
plasma ctDNA HRRm tests. Patients were classified as HRRm if (one or more) HRR
gene mutation was detected by either test; patients were classified as
non-HRRm if no HRR gene mutation was detected by either test; 18 patients did
not have a valid HRR testing result from either a tumour tissue or ctDNA test
and were excluded from this subgroup analysis. The analysis was performed
using a Cox proportional hazards model including terms for treatment group,
the subgroup factor, and a treatment by subgroup interaction.

 

The most common adverse events (AEs) (greater than or equal to 20% of
patients) were anaemia (45%), nausea (28%) and fatigue (28%). Grade 3 or
higher AEs were anaemia (15%), hypertension (4%), urinary tract infection
(2%), fatigue (1%), decreased appetite (1%), vomiting (1%), asthenia (1%),
back pain (1%), diarrhoea (1%). Approximately 86% of patients treated with
Lynparza in combination with abiraterone who experienced AEs remained on
treatment at the time of data cut-off.

 

In September 2021
(https://www.astrazeneca.com/media-centre/press-releases/2021/lynparza-propel-trial-meets-primary-endpoint.html)
at a planned interim analysis, the Independent Data Monitoring Committee
concluded that the PROpel trial met the primary endpoint of rPFS.

 

Lynparza is approved in the US for patients with HRR gene-mutated mCRPC
(BRCA-mutated and other HRR gene mutations); and in the EU, Japan and China
for patients with BRCA-mutated mCRPC.

 

Notes

 

Metastatic castration-resistant prostate cancer

Metastatic prostate cancer is associated with a significant mortality rate.(3)
Development of prostate cancer is often driven by male sex hormones called
androgens, including testosterone.(9)

 

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.(10) Approximately 10-20% of patients with
advanced prostate cancer will develop castration-resistant prostate cancer
(CRPC) within five years, and at least 84% of these patients will have
metastases at the time of CRPC diagnosis.(10)

 

Of patients with no metastases at CRPC diagnosis, 33% are likely to develop
metastases within two years.(11) Despite the advances in mCRPC treatment in
the past decade with taxane and new hormonal agent (NHA) treatment, once
patients failed first line therapy, the treatment effect of second line
anti-cancer therapy diminished significantly hence there is high unmet medical
need in this population.(10,12,13,14)

 

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 1st-line setting.

 

Men in both treatment groups will also receive either prednisone or
prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints
include OS, PFS2, and TFST.

 

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 proteins 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. In the
PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which
targets the androgen receptor (AR) pathway.

 

Androgen receptor signalling engages a transcriptional programme that is
critical for tumour cell growth & survival in prostate cancer.(15,16)
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.(17,18,19)

 

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.(15,18,20) 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.(17,19,21,22)

 

Lynparza is currently approved in a number of countries across PARP-dependent
tumour types with defects and dependencies in the DDR pathway. It is approved
for the maintenance treatment of platinum-sensitive relapsed ovarian cancer as
a monotherapy and in combination with bevacizumab for the 1st-line maintenance
treatment of BRCA-mutated (BRCAm) and homologous recombination deficiency
(HRD) positive advanced ovarian cancer, respectively.

 

Lynparza is also approved for BRCAm, HER2-negative metastatic breast cancer
(in the EU this includes locally advanced breast cancer); for germline BRCAm
metastatic pancreatic cancer, and for HRR gene-mutated metastatic
castration-resistant prostate cancer (BRCAm only in the EU and Japan).

 

Lynparza, which is being jointly developed and commercialised by AstraZeneca
and MSD, 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 (olaparib), 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 in
combination with other potential new medicines and as monotherapies.
Independently, the companies will develop Lynparza and Koselugo in combination
with their respective PD-L1 and PD-1 medicines.

 

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 astrazenca.com (https://www.astrazeneca.com) and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

1. IARC. Cancer Today - Estimated number of new cases in 2020, worldwide, both
sexes, all ages. Available at https://gco.iarc.fr/today/home
(https://gco.iarc.fr/today/home) . Accessed January 2022.

2. Moreira D, et al. Predicting Time From Metastasis to Overall Survival in
Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin
Cancer. 2017;15(1):60-66.e2.

3. 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):301-15.

4. 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. 2020;
18(4):284-294.

5. de Bono JS, et al. Subsequent Chemotherapy and Treatment Patterns After
Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate
Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. 2017;71(4):656-664.

6. Ryan CJ, 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.
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7. Beer TM, et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic
Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL
Study. Eur Urol. 2017;71(2):151-154

8. Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic
prostate cancer. The New England Journal of Medicine, 373(18), pp.1697 - 1708.

9. Cancer.Net. Treatment of metastatic castration-resistant prostate cancer.
Available at

www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer
(http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer)
. Accessed January 2022.

10. Kirby, M, et al. Characterising the castration-resistant prostate cancer
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11. Smith MR, et al. Natural history of rising serum prostate-specific antigen
in men with castrate nonmetastatic prostate cancer. J Clin Oncol.
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12. 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 January 2022.

13. 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. Scientific Report. 2020;10(4240):2020.

14. UroToday. Beyond First-line Treatment of Metastatic Castrate-resistant
Prostate Cancer. Available at
https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html
(https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html)
. Accessed January 2022.

15. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth and
progression. Cancer Discov. 2012;2(12):1134-1149.

16. 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.

17. 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.

18. Polkinghorn WR, et al. Androgen receptor signaling regulates DNA repair in
prostate cancers. Cancer Discov. 2013;3(11):1245-1253.

19. Asim M, et al. Synthetic lethality between androgen receptor signalling
and the PARP pathway in prostate cancer. Nat Commun. 2017;374(8).

20. Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break required for
regulated transcription. Science. 2006;312(5781):1798-1802.

21. Goodwin JF, et al. A hormone-DNA repair circuit governs the response to
genotoxic insult. Cancer Discov. 2013;3(11):1254-1271.

22. Tarish FL, et al. Castration radiosensitizes prostate cancer tissue by
impairing DNA double-strand break repair. Sci Transl Med. 2015;
7(312):312re11.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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