25 November 2024
Truqap
combination in PTEN-deficient metastatic
hormone-sensitive
prostate cancer demonstrated
statistically significant and clinically meaningful improvement in
radiographic progression-free survival
in CAPItello-281 Phase III
trial
First and only AKT inhibitor
combination to demonstrate
benefit in this specific
subtype of prostate cancer
Positive high-level results from the
CAPItello-281 Phase III trial showed that AstraZeneca's
Truqap (capivasertib)
in combination with abiraterone and androgen
deprivation therapy (ADT) demonstrated a statistically significant
and clinically meaningful improvement in the primary endpoint of
radiographic progression-free survival (rPFS) versus abiraterone
and ADT with placebo in patients with PTEN-deficient de novo metastatic hormone-sensitive
prostate cancer (mHSPC).
Overall survival (OS) data were immature at the
time of this analysis; however, the Truqap combination showed an early
trend towards an OS improvement versus abiraterone and
ADT with placebo. The trial will continue as planned
to further assess OS as a key secondary
endpoint.
Prostate cancer is the second most prevalent
cancer in men and the fifth leading cause of male cancer death
globally.1 Only one third of patients with
metastatic prostate cancer survive five years after
diagnosis.2 Newly diagnosed mHSPC is an
aggressive form of the disease associated with poor outcomes and
survival.3,4 Approximately 200,000 patients are
diagnosed with mHSPC each year, and one in four have
PTEN-deficient tumours.5 Patients with a tumour
biomarker of PTEN deficiency have a particularly poor
prognosis.6
Karim Fizazi, MD, PhD, Institut
Gustave Roussy, and University of Paris Saclay in Villejuif,
France, and principal investigator for the trial said: "Patients
with this aggressive form of prostate cancer with tumour PTEN
deficiency currently face a particularly poor prognosis, and there
is an urgent need for new treatments that improve upon current
therapies. The results seen with
capivasertib in combination with
abiraterone-prednisone and
androgen deprivation therapy in the CAPItello-281 trial represent a
step forward for these patients."
Susan Galbraith, Executive Vice President,
Oncology R&D, AstraZeneca, said: "These
results show for the first time, that adding an AKT inhibitor to a
standard-of-care therapy can provide benefit to patients with a
biomarker of PTEN-deficient metastatic hormone-sensitive prostate
cancer. By targeting a key driver of the disease, we have been able
to improve upon current therapies and demonstrate the potential
role of this combination in an area of critical unmet need. It will
be important to see greater maturity in key secondary endpoints
including overall survival."
The safety profile
of Truqap in
combination with abiraterone and ADT in CAPItello-281 was broadly
consistent with the known profile of each medicine.
Data will be presented at a
forthcoming medical meeting and shared with global regulatory
authorities.
Notes
Prostate cancer
Prostate cancer is the second most prevalent
cancer in men and the fifth leading cause of male cancer death
globally, with an incidence of more than 1.4 million and
approximately 397,000 deaths in 2022.1
Metastatic prostate cancer is associated with a
significant mortality rate, with only one third of patients
surviving five years after diagnosis.2 Development of
prostate cancer is often driven by male sex hormones called
androgens, including testosterone.7
Metastatic
hormone-sensitive prostate cancer
In patients with mHSPC, also known as
metastatic castration-sensitive prostate cancer (mCSPC), prostate
cancer cells need high levels of androgens to drive cancer
growth.4,7 Hormone therapies, such as ADT, are widely
used to block the action of male sex hormones and lower the levels
of androgens in the body.4,8 However, resistance to
these therapies is common and there is a need to extend their use
to delay disease progression and castration resistance, where the
prostate cancer grows and spreads to other parts of the body
despite the use of these therapies.3,4,8
In patients with de novo mHSPC, the cancer has spread
to distant parts of the body at the time of first
diagnosis.9
PTEN-loss or deficiency fuels the growth of
cancer cells, leading to dysregulation of the PI3K/AKT pathway, and
is associated with poor outcomes in patients with prostate
cancer.6,10
CAPItello-281
CAPItello-281 is a Phase III,
double-blind, randomised trial evaluating the efficacy and safety
of Truqap in combination
with abiraterone and ADT versus abiraterone and ADT in combination
with placebo in the treatment of patients with PTEN-deficient
de novo mHSPC.
The global trial enrolled 1,012
adult patients with histologically confirmed de novo hormone-sensitive prostate
adenocarcinoma and PTEN deficiency as confirmed by central testing.
The primary endpoint of the CAPItello-281 trial is rPFS as assessed
by investigator, with OS as a secondary endpoint.
Truqap
Truqap is a
first-in-class, potent, adenosine triphosphate (ATP)-competitive
inhibitor of all three AKT isoforms (AKT1/2/3). Truqap
400mg is administered twice daily according to an
intermittent dosing schedule of four days on and three days off.
This was chosen in early phase trials based on tolerability and the
degree of target inhibition.
Truqap is approved in the US,
EU, Japan and several other countries for the treatment of adult
patients with HR-positive (or ER-positive), HER2-negative locally
advanced or metastatic breast cancer with one or more biomarker
alterations (PIK3CA, AKT1 or PTEN) following recurrence or
progression on or after an endocrine-based regimen based on the
results from the CAPItello-291 trial. Truqap is also approved in Australia
for the treatment of adult patients with HR-positive, HER2-negative
locally advanced or metastatic breast cancer following recurrence
or progression on or after an endocrine based regimen based on
these trial results.
Truqap is currently being
evaluated in Phase III trials for the treatment of breast cancer
(CAPItello-292) and prostate cancer (CAPItello-280 and
CAPItello-281) in combination with established
treatments.
Truqap was discovered by
AstraZeneca subsequent to a collaboration with Astex Therapeutics
(and its collaboration with the Institute of Cancer Research and
Cancer Research Technology Limited).
AstraZeneca in oncology
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AstraZeneca has built one of the most diverse portfolios and
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References
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Treatment of Metastatic Castration-Resistant Prostate Cancer: The
Prostate Cancer Registry. Target
Oncol. 2020;15(3):301-315.
3. Hussain M, et al.
Metastatic Hormone-Sensitive Prostate Cancer and Combination
Treatment Outcomes A Review. JAMA
Oncol. 2024;10(6):807-820.
4. American Society of
Clinical Oncology Educational Book. Metastatic Hormone-Sensitive
Prostate Cancer: Toward an Era of Adaptive and Personalized
Treatment. Available at: https://ascopubs.org/doi/pdf/10.1200/EDBK_390166.
Accessed November 2024.
5. Cerner CancerMPact
database. Accessed November 2024.
6. Cuzick J et al. Prognostic value of PTEN loss in men with
conservatively managed localised prostate cancer. Br J Cancer.
2013;108(12):2582-2589.
7. National Cancer
Institute. Hormone Therapy for Prostate Cancer Fact Sheet.
Available at:
https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet.
Accessed November 2024.
8. Cancer Research UK. Hormone therapy for metastatic prostate
cancer. Available at:
https://www.cancerresearchuk.org/about-cancer/prostate-cancer/metastatic-cancer/treatment/hormone-therapy-for-metastatic-prostate-cancer.
Accessed November 2024.
9. McManus H et al. The Past, Present, and Future of Treatment
Intensification for Metastatic Hormone-Sensitive Prostate Cancer.
J Clin Oncol 2023;
41:3576-3579.
10. Gasmi A et al. Overview of the Development and Use of Akt
Inhibitors in Prostate Cancer. J
Clin Med. 2021;11(1):160.
Adrian Kemp
Company Secretary
AstraZeneca PLC
