Optimal glucocorticoid regimen with abiraterone acetate Gert Attard - - PowerPoint PPT Presentation

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Optimal glucocorticoid regimen with abiraterone acetate Gert Attard - - PowerPoint PPT Presentation

Jan 18, 2023 122 likes •297 views

Optimal glucocorticoid regimen with abiraterone acetate Gert Attard MD FRCP PhD University College London Cancer Institute Paul OGorman Building #AttardLab www.attardlab.com Disclosure Principal investigator for trials sponsored by

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Gert Attard MD FRCP PhD University College London Cancer Institute Paul O’Gorman Building #AttardLab www.attardlab.com

Optimal glucocorticoid regimen with abiraterone acetate

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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.

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Aims

ØReach APCCC consensus/allow informed choice on:

  • 1. Prednisone dose and regimen
  • 2. Indications for use of dexamethasone
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Clinical dilemma 1 - prednisone

Abiraterone 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

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Clinical dilemma 1 - prednisone

Abiraterone 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%

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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

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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

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Supported by Janssen

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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) Prednisone 5mg BID Prednisone 5mg QD Prednisone 2.5mg BID Dexamethasone 0.5mg QD 41 41 40 39 35 42 7 3 4 5

Clinical trial design

42 37 41 41 34 38

Primary end-point: % of patients with no hypertension/hypokalemia in 1st 6 cycles

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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

37 34 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

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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

37 34 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 2

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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

6000

  • 2000
  • 4000

13.1 9.6 14.8 9.7

448.1 368.3 429.4 300.6

Adrenocorticotropic hormone

30

Analyses of urine steroid metabolites

Change from Baseline Value to Cycle 3

  • 10

Androgen precursor metabolites Deoxycorticosterone metabolites

2000

Dexamethasone 0.5mg od Prednisone 2.5mg bid Prednisone 5mg od Prednisone 5mg bid

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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

6000

  • 2000
  • 4000

448.1 368.3 429.4 300.6

Adrenocorticotropic hormone

30

Analyses of urine steroid metabolites

Change from Baseline Value to Cycle 3

  • 10

Androgen precursor metabolites Deoxycorticosterone metabolites

2000

Dexamethasone 0.5mg od Prednisone 2.5mg bid Prednisone 5mg od Prednisone 5mg bid

13.1 9.6 14.8 9.7

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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

448.1 368.3 429.4 300.6

Adrenocorticotropic hormone

30

Analyses of urine steroid metabolites

Change from Baseline Value to Cycle 3

  • 10

Androgen precursor metabolites Deoxycorticosterone metabolites

2000

Dexamethasone 0.5mg od Prednisone 2.5mg bid Prednisone 5mg od Prednisone 5mg bid

13.1 9.6 14.8 9.7

  • 4000
  • 6000
  • 2000
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Physiological considerations

P < .01 200 400 600 800 –200 –400 (n = 38) (n = 37) (n = 38) (n = 39) –600 –800 P < .001 P < .05 P < .001 P < .05 10 20 –10 –20 (n = 31) (n = 28) (n = 30) (n = 37) –30 –40 % Change From Baseline Value to End Point Median baseline P < .01 40 HOMA-IR (n = 38) (n = 37) (n = 38) (n = 39) –60 –40 –20 20 Median baseline P < .001 P < .001 150 (n = 31) (n = 28) (n = 30) (n = 37) –50 50 100 Median baseline

Serum insulin HOMA-IR Body fat Lean body mass

  • 800
  • 600
  • 400
  • 200

200 400 600 800

  • 150

100 50

  • 50
  • 40
  • 30
  • 20
  • 10

10 20

  • 60
  • 40
  • 20

20 40

Serum insulin HOMA-IR Lean body mass Body 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

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–100 –75 –50 –25 25 Maximum PSA Change (%) From Baseline Value –50% –90% –50% –90% –50% –90% –100 –75 –50 –25 25 Maximum PSA Change (%) From Baseline Value –100 –75 –50 –25 25 Maximum PSA Change (%) From Baseline Value –100 –75 –50 –25 25 Maximum PSA Change (%) From Baseline Value –50% –90%

A

Subjects at risk 100 80 60 40 20 6 12 Months From Randomization % Progression-Free and Alive 18 24 30 36 Prednisone 5 mg BID Prednisone 5 mg QD Prednisone 2.5 mg BID Dexamethasone 0.5 mg QD Total Censored observation

Anti-tumor activity

Prednisone 5mg od Prednisone 2.5mg bid Dexamethasone 0.5mg od Prednisone, 5 mg, bid

*Trial not designed to compare steroid regimens

Dexamethasone 0.5mg

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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 excess ØCost: 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

  • f AA

ØConsider dexamethasone at progression but the increased toxicity and absence of randomized data are against its use at start of AA