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