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Gert Attard MD FRCP PhDUniversity College London Cancer InstitutePaul O’Gorman Building#AttardLabwww.attardlab.com
Optimal glucocorticoid regimen with abiraterone acetate
Disclosure
• Principal investigator for trials sponsored by Janssen, Pfizer/Astellas and Arno
• Received:-
• Consulting fees and travel support from Janssen, Astellas,
Medivation/Pfizer, Sanofi-Aventis, Ferring, Veridex, Roche/Ventana, Essa.
• Speaker’s fees from Janssen, Astellas, Ferring, Ipsen, and Sanofi-Aventis.
• Grant support from Janssen, AstraZeneca, Arno.
• On the Institute of Cancer Research (ICR) rewards to inventors list of
abiraterone.
Aims
ØReach APCCC consensus/allow informed choice on:
1. Prednisone dose and regimen
2. Indications for use of dexamethasone
Clinical dilemma 1 - prednisoneAbiraterone acetate label:• For newly diagnosed high-risk metastatic hormone sensitive prostate
cancer, with prednisone 5mg daily• For metastatic castration-resistant prostate cancer, with prednisone
10mg daily
Clinical dilemma 1 - prednisoneAbiraterone acetate label:• For newly diagnosed high-risk metastatic hormone sensitive prostate
cancer, with prednisone 5mg daily• For metastatic castration-resistant prostate cancer, with prednisone 10mg
daily
• Half-life of prednisone is < 16 hours
1Fizazi 2017, 2Ryan 2013, 3de Bono 2011
LATITUDE AA + ADT1 LATITUDE ADT1 COU-3022 COU-3013
Grade 3/4 hypokalemia
11% 1% 2% 3%
Clinical dilemma 2 - dexamethasone
• Longer half-life
• Higher ratio of glucocorticoid to mineralocorticoid activity than
prednisone
• Greater activity as a single-agent in mCRPC compared to
prednisone1
• ~25% of patients progressing on AA with prednisone have a
decline in PSA (with confirmed radiological responses in a
proportion) after a steroid switch to dexamethasone2,3
1Venkitaraman, 2015 2Romero-Laorden, 2018
3Lorente, 2014
Background: CYP17A1 inhibition causes a syndrome of mineralocorticoid excess
Hypokalaemia
Hypertension
Fluid overload
Suppression of
Renin
Aldosterone
Negative feedback
ACTH
Pregnenolone Deoxycorticosterone Corticosterone
CYP17:
17α Hydroxylase
17OH-
Pregnenolone
17OH-
Progesterone
11-Deoxycortisol Cortisol
CYP17:
C17, 20-lyase
DHEA Androstenedione
Testosterone
Estradiol
Positive drive
Supported by Janssen
164 randomly assigned
Received assigned treatment(safety analyses)
Discontinued by week 24, not due to hypertension or hypokalemia
Evaluable for primary end point*
Assigned to treatment (ITT)
Prednisone5mg BID
Prednisone5mg QD
Prednisone2.5mg BID
Dexamethasone0.5mg QD
41 41 40
39
35
42
7 3 4 5
Clinical trial design
42
37
4141
34 38
Primary end-point:% of patients with no hypertension/hypokalemia in 1st 6 cycles
Met the primary end point(no hypertension/hypokalemia)
Prednisone
5mg BID
Prednisone
5mg QD
Prednisone
2.5mg BID
Dexamethasone
0.5mg QD
35
Primary end-point: syndrome of secondary
mineralocorticoid excess
3734 38
24
(70.6%)
14
(36.8%)
21
(60.0%)
26
(70.3%)
54.2%,
82.5%
43.6%,
74.4%
23.4%,
52.7%
53.8%,
83.2%
Evaluable for primary end point
95% Confidence Intervals
Met the primary end point(no hypertension/hypokalemia)
Prednisone
5mg BID
Prednisone
5mg QD
Prednisone
2.5mg BID
Dexamethasone
0.5mg QD
35
Primary end-point: syndrome of secondary
mineralocorticoid excess
3734 38
24
(70.6%)
14
(36.8%)
21
(60.0%)
26
(70.3%)
54.2%,
82.5%
43.6%,
74.4%
23.4%,
52.7%
53.8%,
83.2%
Evaluable for primary end point
95% Confidence Intervals
1
(2.9%)
5
(13.2%)
1
(2.9%)
3
(8.1%)
Hypokalemia
Grade 3 hypokalemia 0 2 0 0
0
10
20
4.3 4.2 4.2 4.7
Median Baseline Value, pmol/L
↑P<.001↑P<.001
↑ P<.001
↑ P<.001
↑ P<.001
↓P<.05
↓ P<.001 ↓ P<.001
Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h
250
500
750
1000
-250
0
6000
0
-2000
-4000
13.1 9.6 14.8 9.7448.1 368.3 429.4 300.6
Adrenocorticotropic hormone
30
Analyses of urine steroid metabolites
Cha
nge
from
Bas
elin
e Va
lue
to C
ycle
3
-10
Androgen precursor metabolites
Deoxycorticosterone metabolites
2000
Dexamethasone 0.5mg odPrednisone 2.5mg bidPrednisone 5mg odPrednisone 5mg bid
0
10
20
4.3 4.2 4.2 4.7
Median Baseline Value, pmol/L
↑P<.001↑P<.001
↑ P<.001
↑ P<.001
↑ P<.001
↓P<.05
↓ P<.001 ↓ P<.001
Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h
250
500
750
1000
-250
0
6000
0
-2000
-4000
448.1 368.3 429.4 300.6
Adrenocorticotropic hormone
30
Analyses of urine steroid metabolites
Cha
nge
from
Bas
elin
e Va
lue
to C
ycle
3
-10
Androgen precursor metabolites
Deoxycorticosterone metabolites
2000
Dexamethasone 0.5mg odPrednisone 2.5mg bidPrednisone 5mg odPrednisone 5mg bid
13.1 9.6 14.8 9.7
0
10
20
4.3 4.2 4.2 4.7
Median Baseline Value, pmol/L
↑P<.001↑P<.001
↑ P<.001
↑ P<.001
↑ P<.001
↓P<.05
↓ P<.001 ↓ P<.001
Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h
250
500
750
1000
-250
0
0
448.1 368.3 429.4 300.6
Adrenocorticotropic hormone
30
Analyses of urine steroid metabolites
Cha
nge
from
Bas
elin
e Va
lue
to C
ycle
3
-10
Androgen precursor metabolites
Deoxycorticosterone metabolites
2000
Dexamethasone 0.5mg odPrednisone 2.5mg bidPrednisone 5mg odPrednisone 5mg bid
13.1 9.6 14.8 9.7
-4000
-6000
-2000
Physiological considerations
Abiraterone plus prednisone 5 mg BID Abiraterone plus prednisone 5 mg QD Abiraterone plus prednisone 2.5 mg BID Abiraterone plus dexamethasone 0.5 mg BID
P < .01
P < .001P < .05
P < .001
P < .05
P < .001
200
400
600
800
A Serum insulin
0
–200
–400
(n = 38)
(n = 37)
(n = 38) (n = 39)
–600
–800
Seru
m Ins
ulin (
pmol/
L)Ch
ange
From
Bas
eline
Valu
e to E
nd P
oint
P < .01
40
B HOMA-IR
(n = 38)
(n = 37)(n = 38)
(n = 39)
–60
–40
–20
0
20
HOMA
-IRCh
ange
From
Bas
eline
Valu
e to E
nd P
oint
0
10
20
C Lean body mass
–10
–20
(n = 31)
(n = 28)
(n = 30) (n = 37)
–30
–40
Lean
Mas
s Tot
al Bo
dy%
Cha
nge F
rom
Base
line V
alue t
o End
Poin
t
P < .001
150
D Body fat
(n = 31)(n = 28)
(n = 30) (n = 37)
–50
0
50
100
Total
Bod
y Fat
% C
hang
e Fro
m Ba
selin
e Valu
e to E
nd P
oint
Median baselinevalue (pmol/L): 94.1 55.6 72.9 68.8
Median baselinevalue: 3.62 1.90 2.54 2.31
Median baselinevalue (kg): 55.4 52.3 53.7 50.9
Median baselinevalue (kg): 30.4 23.4 29.3 27.3Abiraterone plus prednisone 5 mg BID Abiraterone plus prednisone 5 mg QD Abiraterone plus prednisone 2.5 mg BID Abiraterone plus dexamethasone 0.5 mg BID
P < .01
P < .001P < .05
P < .001
P < .05
P < .001
200
400
600
800
A Serum insulin
0
–200
–400
(n = 38)
(n = 37)
(n = 38) (n = 39)
–600
–800
Seru
m In
sulin
(pm
ol/L
)Ch
ange
Fro
m B
asel
ine
Valu
e to
End
Poi
nt
P < .01
40
B HOMA-IR
(n = 38)
(n = 37)(n = 38)
(n = 39)
–60
–40
–20
0
20
HOM
A-IR
Chan
ge F
rom
Bas
elin
e Va
lue
to E
nd P
oint
0
10
20
C Lean body mass
–10
–20
(n = 31)
(n = 28)
(n = 30) (n = 37)
–30
–40
Lean
Mas
s To
tal B
ody
% C
hang
e Fr
om B
asel
ine
Valu
e to
End
Poi
nt
P < .001
150
D Body fat
(n = 31)(n = 28)
(n = 30) (n = 37)
–50
0
50
100
Tota
l Bod
y Fa
t%
Cha
nge
From
Bas
elin
e Va
lue
to E
nd P
oint
Median baselinevalue (pmol/L): 94.1 55.6 72.9 68.8
Median baselinevalue: 3.62 1.90 2.54 2.31
Median baselinevalue (kg): 55.4 52.3 53.7 50.9
Median baselinevalue (kg): 30.4 23.4 29.3 27.3
Abiraterone plus prednisone 5 mg BID Abiraterone plus prednisone 5 mg QD Abiraterone plus prednisone 2.5 mg BID Abiraterone plus dexamethasone 0.5 mg BID
P < .01
P < .001P < .05
P < .001
P < .05
P < .001
200
400
600
800
A Serum insulin
0
–200
–400
(n = 38)
(n = 37)
(n = 38) (n = 39)
–600
–800
Seru
m Ins
ulin (
pmol/
L)Ch
ange
From
Bas
eline
Valu
e to E
nd P
oint
P < .01
40
B HOMA-IR
(n = 38)
(n = 37)(n = 38)
(n = 39)
–60
–40
–20
0
20
HOMA
-IRCh
ange
From
Bas
eline
Valu
e to E
nd P
oint
0
10
20
C Lean body mass
–10
–20
(n = 31)
(n = 28)
(n = 30) (n = 37)
–30
–40
Lean
Mas
s Tot
al Bo
dy%
Cha
nge F
rom
Base
line V
alue t
o End
Poin
t
P < .001
150
D Body fat
(n = 31)(n = 28)
(n = 30) (n = 37)
–50
0
50
100
Total
Bod
y Fat
% C
hang
e Fro
m Ba
selin
e Valu
e to E
nd P
oint
Median baselinevalue (pmol/L): 94.1 55.6 72.9 68.8
Median baselinevalue: 3.62 1.90 2.54 2.31
Median baselinevalue (kg): 55.4 52.3 53.7 50.9
Median baselinevalue (kg): 30.4 23.4 29.3 27.3
Abiraterone plus prednisone 5 mg BID Abiraterone plus prednisone 5 mg QD Abiraterone plus prednisone 2.5 mg BID Abiraterone plus dexamethasone 0.5 mg BID
P < .01
P < .001P < .05
P < .001
P < .05
P < .001
200
400
600
800
A Serum insulin
0
–200
–400
(n = 38)
(n = 37)
(n = 38) (n = 39)
–600
–800
Seru
m In
sulin
(pm
ol/L)
Chan
ge F
rom
Bas
eline
Valu
e to
End
Poin
t
P < .01
40
B HOMA-IR
(n = 38)
(n = 37)(n = 38)
(n = 39)
–60
–40
–20
0
20
HOM
A-IR
Chan
ge F
rom
Bas
eline
Valu
e to
End
Poin
t0
10
20
C Lean body mass
–10
–20
(n = 31)
(n = 28)
(n = 30) (n = 37)
–30
–40
Lean
Mas
s Tot
al Bo
dy%
Cha
nge
From
Bas
eline
Valu
e to
End
Poin
t
P < .001
150
D Body fat
(n = 31)(n = 28)
(n = 30) (n = 37)
–50
0
50
100
Tota
l Bod
y Fat
% C
hang
e Fr
om B
aseli
ne V
alue
to E
nd P
oint
Median baselinevalue (pmol/L): 94.1 55.6 72.9 68.8
Median baselinevalue: 3.62 1.90 2.54 2.31
Median baselinevalue (kg): 55.4 52.3 53.7 50.9
Median baselinevalue (kg): 30.4 23.4 29.3 27.3
Serum insulin HOMA-IR
Body fatLean body mass
-800
-600
-400
-200
0
200
400
600
800
-150
100
50
-50
0
-40
-30
-20
-10
0
10
20
-60
-40
-20
0
20
40
Serum insulin HOMA-IR
Lean body massBody fat
↑ P < .001 ↑ P < .001
↓ P < .001↓ P < .001
↑ P <.01↑ P <.01
↓ P < .05 ↓ P < .05
(n = 38)
(n = 38)
(n = 38)
(n = 38)
(n = 37)
(n = 37)
(n = 37)
(n = 37)
(n = 39)
(n = 39)
(n = 31) (n = 31)
(n = 28)
(n = 28)
(n = 30)
(n = 30)
End of main study, up to 40 cycles
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–50%
–90%
–50%
–90%
–50%
–90%
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–50%
–90%
A
B
Subjects at riskPred 5 mg BIDPred 5 mg QD
Pred 2.5 mg BIDDex 0.5 mg QD
Total
100
80
60
40
20
00 6 12
Months From Randomization
% P
rogr
essi
on-F
ree
and
Aliv
e
18 24 30 36
41 29 20 15 10 2 041 29 17 11 4 1 040 26 17 10 4 3 042 31 25 21 10 2 0
164 115 79 57 28 8 0
Prednisone 5 mg BIDPrednisone 5 mg QDPrednisone 2.5 mg BIDDexamethasone 0.5 mg QDTotalCensored observation
Prednisone 5 mg BID Prednisone 5 mg QD Prednisone 2.5 mg BID Dexamethasone 0.5 mg QD
C
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18Cycle
EQ-5D-5L visual analog scale
0
12
24
36
48
60
72
84
96
108
120
132
144
156
0 6 12 18Cycle
FACT-P global score
Mea
n Va
lue
by V
isit,
Plo
tted
on
Sca
le R
ange
No. of patients withobserved data, by cycle
Pred 5 mg BID 35 28 16 38 34 16Pred 5 mg QD 38 30 13 37 31 12Pred 2.5 mg BID 36 29 10 37 32 11Dex 0.5 mg QD 34 30 18 37 34 20
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–50%
–90%
–50%
–90%
–50%
–90%
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–100
–75
–50
–25
0
25
Max
imum
PS
A C
hang
e (%
) Fro
m B
asel
ine
Valu
e
–50%
–90%
A
B
Subjects at riskPred 5 mg BIDPred 5 mg QD
Pred 2.5 mg BIDDex 0.5 mg QD
Total
100
80
60
40
20
00 6 12
Months From Randomization
% P
rogr
essi
on-F
ree
and
Aliv
e
18 24 30 36
41 29 20 15 10 2 041 29 17 11 4 1 040 26 17 10 4 3 042 31 25 21 10 2 0164 115 79 57 28 8 0
Prednisone 5 mg BIDPrednisone 5 mg QDPrednisone 2.5 mg BIDDexamethasone 0.5 mg QDTotalCensored observation
Prednisone 5 mg BID Prednisone 5 mg QD Prednisone 2.5 mg BID Dexamethasone 0.5 mg QD
C
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18Cycle
EQ-5D-5L visual analog scale
0
12
24
36
48
60
72
84
96
108
120
132
144
156
0 6 12 18Cycle
FACT-P global score
Mea
n Va
lue
by V
isit,
Plo
tted
on
Sca
le R
ange
No. of patients withobserved data, by cycle
Pred 5 mg BID 35 28 16 38 34 16Pred 5 mg QD 38 30 13 37 31 12Pred 2.5 mg BID 36 29 10 37 32 11Dex 0.5 mg QD 34 30 18 37 34 20
Anti-tumor activityPrednisone 5mg od
Prednisone 2.5mg bid Dexamethasone 0.5mg od
Prednisone, 5 mg, bid
*Trial not designed to compare steroid regimens
Dexamethasone 0.5mg
Conclusions – data-informed patient-directed treatment choice
ØPhysiological long-term effects of AA + steroids had no discernible impact on quality of life
ØPrednisone 5mg bid and dexamethasone 0.5mg od minimize mineralocorticoid excessØCost: increase in body fat and for dexamethasone 0.5mg od: increase in HOMA-IR and serum insulin
and reduced bone mineral density
ØPrednisone 5mg daily minimizes long-term physiological side-effects with a greater risk of mineralocorticoid excess
ØLower steroid doses require careful monitoring, ensure patients are medically optimized prior to start of AA
ØConsider dexamethasone at progression but the increased toxicity and absence of randomized data are against its use at start of AA