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Target Overview
The cell signaling network, which includes phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), is frequently dysregulated in human cancer. AKT is a central node in this network, modulating a range of substrates involved in growth, apoptosis, and metabolism. There are 3 isoforms of AKT: AKT1, 2, and 3. The most commonly mutated genes that result in activation of the PI3K/AKT/PTEN pathway are activating mutations of PIK3CA, AKT1 and loss-of-function alterations of PTEN.1,2
AKT activation has been shown to mediate resistance to inhibitors of receptor tyrosine kinases, antihormonal agents, and chemotherapy.3
Compound Overview
Capivasertib,a a pan-AKT kinase inhibitor (against isoforms AKT1, AKT2, and AKT3), inhibits AKT activity, leading to dephosphorylation of downstream targets. Given the critical position of AKT in this pathway, capivasertib’s mechanism of action serves to restrict the flow of upstream signaling, including that from activating mutations in PIK3CA and loss-of-function PTEN alterations, as well as activating mutations in AKT1 itself, before those can have further downstream effects in driving tumor growth.4-7
aFormerly known as AZD5363, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited.
Mechanism of Action
Reference: Martini M, De Santis MC, Braccini L, et al. Ann Med. 2014;46(6):372-383.
This mechanism of action is depicted for breast cancer cells and is applicable to prostate cancer, where the androgen receptor (AR) plays a role in the nucleus, analogous to the estrogen receptor (ER) in the breast cancer setting. AR pathway blockade with ARPI therapy is the standard-of-care, but inhibiting the AR pathway can result in upregulation of the AKT pathway.8-10
References
1. Altomare DA, Testa JR. Oncogene. 2005;24(50):7455-7464. 2. Liu P, Cheng H, Roberts TM, et al. Nat Rev Drug Discov. 2009;8(8):627-644. 3. Clark AS, West K, Streicher S, et al. Mol Cancer Ther. 2002;1(9):707-717. 4. Davies BR, Greenwood H, Dudley P, et al. Mol Cancer Ther. 2012;11(4):873-887. 5. Miller TW, Rexer BN, Garrett JT, et al. Breast Cancer Res. 2011;13(6):224 6. Miller C, Sommavilla R, Murphy D, et al. Br J Clin Pharmacol 2023;89(11):3330-3339 7. Miricescu D, Totan A, Stanescu-Spinu II, et al. Int J Mol Sci 2020;22(1):173 8. Gasmi A, Roubaud G, Dariane C, et al. J Clin Med. 2021;11:160. 9. Mulholland DJ, Tran LM, Li Y, et al. Cancer Cell. 2011;19:792–804. 10. Carver BS, Chapinski C, Wongvipat J, et al. Cancer Cell. 2011;19:575–586.
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Abbreviations
1L
first line
4EBP1
eukaryotic translation initiation factor 4E binding protein 1
aBC
advanced breast cancer (locally advanced [inoperable] or metastatic breast cancer)
ADT
androgen-deprivation therapy
AE
adverse event
AI
aromatase inhibitor
AKT
protein kinase B/also known as PKB
AR
androgen receptor
ARPI
androgen receptor pathway inhibitor
BC
breast cancer
BID
twice daily
BSA
body surface area
CBR
clinical benefit rate
CDK4/6
cyclin-dependent kinase 4/6
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
CRPC
castration-resistant prostate cancer
DoR
duration of response
ECOG
Eastern Cooperative Oncology Group
ERK
extracellular signal-regulated kinase
ET
endocrine therapy
FFPE
formalin-fixed paraffin-embedded
FOXO
forkhead box protein O subclass
GPCR
G-protein coupled receptor
HER2
human epidermal growth factor receptor 2
HR
hormone receptor
HRQoL
health-related quality of life
HSPC
hormone-sensitive prostate cancer
IV
intravenous
LKB1
liver kinase B1
mCRPC
metastatic castration-resistant prostate cancer
mHSPC
metastatic hormone-sensitive prostate cancer
MRI
magnetic resonance imaging
mTOR
mechanistic or mammalian target of rapamycin
mTORC
mammalian target of rapamycin complex
mTPI-2
modified toxicity probability interval
ORR
overall or objective response rate
OS
overall survival
p110
catalytic subunit of PI3K
p85
regulatory subunit of PI3K
PCWG-3
Prostate Cancer Clinical Trials Working Group 3
PDK
phosphoinositide-dependent kinase
PFS
progression-free survival
PFS2
time to second progression or death
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PIP2
phosphatidylinositol 4,5-bisphosphate
PIP3
phosphatidylinositol (3,4,5)-trisphosphate
PK
pharmacokinetics
PO
per oral
PRO
patient-reported outcomes
PS
phosphatidylserine
PTEN
phosphatase and tensin homolog
QD
once daily
R
randomization
RAS
GTPase protein family that includes KRAS, HRAS, and NRAS
RECIST
Response Evaluation Criteria in Solid Tumors
RECIST v1.1
Response Evaluation Criteria in Solid Tumors version 1.1
rPFS
radiographic progression-free survival
RTK
receptor tyrosine kinase
S6K
S6 kinase
SERD
selective estrogen receptor degrader
TNBC
triple-negative breast cancer
WHO
World Health Organization
Target Overview
The cell signaling network, which includes phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), is frequently dysregulated in human cancer. AKT is a central node in this network, modulating a range of substrates involved in growth, apoptosis, and metabolism. There are 3 isoforms of AKT: AKT1, 2, and 3. The most commonly mutated genes that result in activation of the PI3K/AKT/PTEN pathway are activating mutations of PIK3CA, AKT1 and loss-of-function alterations of PTEN.1,2
AKT activation has been shown to mediate resistance to inhibitors of receptor tyrosine kinases, antihormonal agents, and chemotherapy.3
Compound Overview
Capivasertib,a a pan-AKT kinase inhibitor (against isoforms AKT1, AKT2, and AKT3), inhibits AKT activity, leading to dephosphorylation of downstream targets. Given the critical position of AKT in this pathway, capivasertib’s mechanism of action serves to restrict the flow of upstream signaling, including that from activating mutations in PIK3CA and loss-of-function PTEN alterations, as well as activating mutations in AKT1 itself, before those can have further downstream effects in driving tumor growth.4-7
aFormerly known as AZD5363, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited.
Mechanism of Action
Reference: Martini M, De Santis MC, Braccini L, et al. Ann Med. 2014;46(6):372-383.
This mechanism of action is depicted for breast cancer cells and is applicable to prostate cancer, where the androgen receptor (AR) plays a role in the nucleus, analogous to the estrogen receptor (ER) in the breast cancer setting. AR pathway blockade with ARPI therapy is the standard-of-care, but inhibiting the AR pathway can result in upregulation of the AKT pathway.8-10
References
1. Altomare DA, Testa JR. Oncogene. 2005;24(50):7455-7464. 2. Liu P, Cheng H, Roberts TM, et al. Nat Rev Drug Discov. 2009;8(8):627-644. 3. Clark AS, West K, Streicher S, et al. Mol Cancer Ther. 2002;1(9):707-717. 4. Davies BR, Greenwood H, Dudley P, et al. Mol Cancer Ther. 2012;11(4):873-887. 5. Miller TW, Rexer BN, Garrett JT, et al. Breast Cancer Res. 2011;13(6):224 6. Miller C, Sommavilla R, Murphy D, et al. Br J Clin Pharmacol 2023;89(11):3330-3339 7. Miricescu D, Totan A, Stanescu-Spinu II, et al. Int J Mol Sci 2020;22(1):173 8. Gasmi A, Roubaud G, Dariane C, et al. J Clin Med. 2021;11:160. 9. Mulholland DJ, Tran LM, Li Y, et al. Cancer Cell. 2011;19:792–804. 10. Carver BS, Chapinski C, Wongvipat J, et al. Cancer Cell. 2011;19:575–586.
Clinical trial information
Select trial for more information
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Abbreviations
1L
first line
4EBP1
eukaryotic translation initiation factor 4E binding protein 1
aBC
advanced breast cancer (locally advanced [inoperable] or metastatic breast cancer)
ADT
androgen-deprivation therapy
AE
adverse event
AI
aromatase inhibitor
AKT
protein kinase B/also known as PKB
AR
androgen receptor
ARPI
androgen receptor pathway inhibitor
BC
breast cancer
BID
twice daily
BSA
body surface area
CBR
clinical benefit rate
CDK4/6
cyclin-dependent kinase 4/6
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
CRPC
castration-resistant prostate cancer
DoR
duration of response
ECOG
Eastern Cooperative Oncology Group
ERK
extracellular signal-regulated kinase
ET
endocrine therapy
FFPE
formalin-fixed paraffin-embedded
FOXO
forkhead box protein O subclass
GPCR
G-protein coupled receptor
HER2
human epidermal growth factor receptor 2
HR
hormone receptor
HRQoL
health-related quality of life
HSPC
hormone-sensitive prostate cancer
IV
intravenous
LKB1
liver kinase B1
mCRPC
metastatic castration-resistant prostate cancer
mHSPC
metastatic hormone-sensitive prostate cancer
MRI
magnetic resonance imaging
mTOR
mechanistic or mammalian target of rapamycin
mTORC
mammalian target of rapamycin complex
mTPI-2
modified toxicity probability interval
ORR
overall or objective response rate
OS
overall survival
p110
catalytic subunit of PI3K
p85
regulatory subunit of PI3K
PCWG-3
Prostate Cancer Clinical Trials Working Group 3
PDK
phosphoinositide-dependent kinase
PFS
progression-free survival
PFS2
time to second progression or death
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PIP2
phosphatidylinositol 4,5-bisphosphate
PIP3
phosphatidylinositol (3,4,5)-trisphosphate
PK
pharmacokinetics
PO
per oral
PRO
patient-reported outcomes
PS
phosphatidylserine
PTEN
phosphatase and tensin homolog
QD
once daily
R
randomization
RAS
GTPase protein family that includes KRAS, HRAS, and NRAS
RECIST
Response Evaluation Criteria in Solid Tumors
RECIST v1.1
Response Evaluation Criteria in Solid Tumors version 1.1
rPFS
radiographic progression-free survival
RTK
receptor tyrosine kinase
S6K
S6 kinase
SERD
selective estrogen receptor degrader
TNBC
triple-negative breast cancer
WHO
World Health Organization