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 tumors.5 Patients with a tumor
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 tumor 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.
IMPORTANT SAFETY INFORMATION ABOUT TRUQAP® (capivasertib)
tablets
TRUQAP is contraindicated in patients with severe
hypersensitivity to TRUQAP or any of its components.
Hyperglycemia
Severe hyperglycemia, associated with ketoacidosis, has occurred
in patients treated with TRUQAP. The safety of TRUQAP has not been
established in patients with Type I diabetes or diabetes requiring
insulin. Patients with insulin-dependent diabetes were excluded
from CAPItello-291.
Hyperglycemia occurred in 18% of patients treated with TRUQAP
(n=355). Grade 3 (insulin therapy initiated; hospitalization
indicated) or Grade 4 (life-threatening consequences; urgent
intervention indicated) hyperglycemia occurred in 2.8% of patients.
Diabetic ketoacidosis occurred in 0.3% of patients and diabetic
metabolic decompensation in 0.6% of patients. Dose reduction for
hyperglycemia was required in 0.6% and permanent discontinuation
was required in 0.6% of patients. The median time to first
occurrence of hyperglycemia was 15 days (range: 1 to 367).
In the 65 patients with hyperglycemia, 45% required treatment
with anti-hyperglycemic medication (insulin in 15% and metformin in
29%). Of the 29 patients who required anti-hyperglycemic medication
during treatment with TRUQAP, 66% (19/29) remained on these
medications at treatment discontinuation or last follow-up.
Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C)
and optimize blood glucose prior to treatment. Before initiating
TRUQAP, inform patients about TRUQAP’s potential to cause
hyperglycemia and to immediately contact their healthcare
professional if hyperglycemia symptoms occur (eg, excessive thirst,
urinating more often than usual or greater amount of urine than
usual, or increased appetite with weight loss). Evaluate FG at
least every two weeks during the first month and at least once a
month starting from the second month, prior to the scheduled dose
of TRUQAP. Monitor HbA1C every three months. Monitor FG more
frequently during treatment with TRUQAP in patients with a medical
history of diabetes mellitus and in patients with risk factors for
hyperglycemia such as obesity (BMI ≥ 30), elevated FG of >160
mg/dL (>8.9 mmol/L), HbA1C at or above the upper limit of
normal, use of concomitant systemic corticosteroids, or
intercurrent infections.
If a patient experiences hyperglycemia after initiating
treatment with TRUQAP, monitor FG as clinically indicated, and at
least twice weekly until FG decreases to normal levels. During
treatment with anti-hyperglycemic medication, continue monitoring
FG at least once a week for 8 weeks, followed by once every 2 weeks
and as clinically indicated. Consider consultation with a
healthcare practitioner with expertise in the treatment of
hyperglycemia and counsel patients on lifestyle changes. Withhold,
dose reduce, or permanently discontinue TRUQAP based on
severity.
Diarrhea
Severe diarrhea associated with dehydration occurred in patients
who received TRUQAP (n=355).
Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea
occurred in 9% of patients. The median time to first occurrence was
8 days (range: 1 to 519). In the 257 patients with diarrhea, 59%
required antidiarrheal medications to manage symptoms. Dose
reductions were required in 8% of patients and 2% of patients
permanently discontinued TRUQAP due to diarrhea. In patients with
Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89),
median time to improvement from the first event was 4 days (range:
1 to 154).
Monitor patients for signs and symptoms of diarrhea. Advise
patients to increase oral fluids and start antidiarrheal treatment
at the first sign of diarrhea while taking TRUQAP. Withhold, reduce
dose, or permanently discontinue TRUQAP based on severity.
Cutaneous Adverse Reactions
Cutaneous adverse reactions, which can be severe, including
erythema multiforme (EM), palmar-plantar erythrodysesthesia, and
drug reaction with eosinophilia and systemic symptoms (DRESS),
occurred in patients who received TRUQAP (n=355).
Cutaneous adverse reactions occurred in 58% of patients. Grade 3
or 4 cutaneous adverse reactions occurred in 17% of patients
receiving TRUQAP. EM occurred in 1.7% of patients and DRESS
occurred in 0.3% of patients. Dose reduction was required in 7% of
patients and 7% of patients permanently discontinued TRUQAP due to
cutaneous adverse reactions.
Monitor patients for signs and symptoms of cutaneous adverse
reactions. Early consultation with a dermatologist is recommended.
Withhold, dose reduce, or permanently discontinue TRUQAP based on
severity.
Embryo-Fetal Toxicity
Based on findings from animals and mechanism of action, TRUQAP
can cause fetal harm when administered to a pregnant woman. Advise
pregnant women and females of reproductive potential of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with TRUQAP and for
1 month after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with TRUQAP and for 4 months after the last
dose.
TRUQAP is used in combination with fulvestrant. Refer to the
full Prescribing Information of fulvestrant for pregnancy and
contraception information.
ADVERSE REACTIONS
Among the 355 patients who received TRUQAP in CAPItello-291, the
most common (≥20%) adverse reactions, including laboratory
abnormalities, were diarrhea (72%), cutaneous adverse reactions
(58%), increased random glucose (57%), decreased lymphocytes (47%),
decreased hemoglobin (45%), increased fasting glucose (37%), nausea
and fatigue (35% each), decreased leukocytes (32%), increased
triglycerides (27%), decreased neutrophils (23%), increased
creatinine (22%), vomiting (21%), and stomatitis (20%).
In the 155 patients with PIK3CA/AKT1/PTEN alterations treated
with TRUQAP + fulvestrant, dose reductions due to adverse reactions
were reported in 21% of patients. Permanent TRUQAP discontinuation
due to an adverse reaction occurred in 10% of patients. Dose
interruptions of TRUQAP occurred in 39% of patients.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid concomitant use with a
strong CYP3A inhibitor. If concomitant use cannot be avoided,
reduce the dose of TRUQAP and monitor patients for adverse
reactions.
Moderate CYP3A Inhibitors: When concomitantly used with a
moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor
patients for adverse reactions.
Strong or Moderate CYP3A Inducers: Avoid concomitant use
of TRUQAP with strong or moderate CYP3A inducers.
INDICATION AND USAGE
TRUQAP in combination with fulvestrant is indicated for the
treatment of adult patients with hormone receptor (HR)‑positive,
human epidermal growth factor receptor 2 (HER2)-negative locally
advanced or metastatic breast cancer with one or more
PIK3CA/AKT1/PTEN alteration as detected by an FDA-approved test
following progression on at least one endocrine-based regimen in
the metastatic setting or recurrence on or within 12 months of
completing adjuvant therapy.
Please see full Prescribing Information,
including Patient Information for TRUQAP.
You may report side effects related to AstraZeneca
products.
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 more than 1.4 million and over 397,000 deaths
in 2022.1
Metastatic prostate cancer is associated with a significant
mortality rate, with only a 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, randomized 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® (capivasertib)
TRUQAP® (capivasertib) is a first-in-class, potent, adenosine
triphosphate (ATP)-competitive inhibitor of all three AKT isoforms
(AKT1/2/3). TRUQAP 400 mg 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
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 catalyze 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.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization 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. For more
information, please visit www.astrazeneca-us.com and follow us on
social media @AstraZeneca.
References
- Bray F, et al. Global cancer statistics 2022: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin. 2024 Apr 4. doi:
10.3322/caac.21834.
- 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.
- Hussain M, et al. Metastatic Hormone-Sensitive Prostate Cancer
and Combination Treatment Outcomes A Review. JAMA Oncol.
2024;10(6):807-820.
- 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.
- Cerner CancerMPact database. Accessed November 2024.
- 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.
- 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.
- 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.
- 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.
- Gasmi A et al. Overview of the Development and Use of Akt
Inhibitors in Prostate Cancer. J Clin Med. 2021;11(1):160.
US-95806 Last Updated 11/24
View source
version on businesswire.com: https://www.businesswire.com/news/home/20241125437650/en/
Media Inquiries Brendan McEvoy +1 302 885 2677 Chelsea
Tressler +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Oct 2024 to Nov 2024
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Nov 2023 to Nov 2024
