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

Optimal glucocorticoid regimen with abiraterone acetate Gert Attard MD FRCP PhD University College London Cancer Institute Paul O’Gorman Building #AttardLab www.attardlab.com

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 Ø Reach APCCC consensus/allow informed choice on: 1. Prednisone dose and regimen 2. Indications for use of dexamethasone

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

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 LATITUDE AA + ADT 1 LATITUDE ADT 1 COU-302 2 COU-301 3 Grade 3/4 11% 1% 2% 3% hypokalemia 1 Fizazi 2017, 2 Ryan 2013, 3 de Bono 2011

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 prednisone 1 • ~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 dexamethasone 2,3 1 Venkitaraman, 2015 2 Romero-Laorden, 2018 3 Lorente, 2014

Background: CYP17A1 inhibition causes a syndrome of mineralocorticoid excess Hypokalaemia Hypertension Fluid overload Suppression of ACTH Renin Positive drive Negative feedback Deoxycorticosterone Aldosterone Pregnenolone Corticosterone CYP17: 17α Hydroxylase Cortisol 17OH- 17OH- 11-Deoxycortisol Pregnenolone Progesterone Testosterone CYP17: C17, 20-lyase Estradiol DHEA Androstenedione

Supported by Janssen

Clinical trial design Primary end-point: 164 randomly assigned % of patients with no hypertension/hypokalemia in 1 st 6 cycles Prednisone Prednisone Prednisone Dexamethasone 5mg BID 5mg QD 2.5mg BID 0.5mg QD Assigned to treatment (ITT) 41 40 42 41 Received assigned treatment 41 41 42 39 (safety analyses) Discontinued by week 24, not due 7 3 4 5 to hypertension or hypokalemia 35 37 Evaluable for primary end point* 34 38

Primary end-point: syndrome of secondary mineralocorticoid excess Prednisone Prednisone Prednisone Dexamethasone 5mg BID 5mg QD 2.5mg BID 0.5mg QD Evaluable for primary end point 38 34 35 37 24 21 14 26 Met the primary end point (70.6%) (60.0%) (36.8%) (70.3%) (no hypertension/hypokalemia) 43.6%, 53.8%, 23.4%, 54.2%, 95% Confidence Intervals 74.4% 83.2% 52.7% 82.5%

Primary end-point: syndrome of secondary mineralocorticoid excess Prednisone Prednisone Prednisone Dexamethasone 5mg BID 5mg QD 2.5mg BID 0.5mg QD Evaluable for primary end point 38 34 35 37 24 21 14 26 Met the primary end point (70.6%) (60.0%) (36.8%) (70.3%) (no hypertension/hypokalemia) 43.6%, 53.8%, 23.4%, 54.2%, 95% Confidence Intervals 74.4% 83.2% 52.7% 82.5% 5 3 1 1 Hypokalemia (13.2%) (8.1%) (2.9%) (2.9%) Grade 3 hypokalemia 0 2 0 0

Analyses of urine steroid metabolites Adrenocorticotropic hormone Deoxycorticosterone Androgen precursor metabolites metabolites ↑ P <.001 ↓ P <.05 Change from Baseline Value to Cycle 3 30 ↑ P <.001 ↑ P <.001 1000 2000 ↓ P <.001 ↓ P <.001 750 0 20 ↑ P <.001 500 ↑ P <.001 -2000 10 250 -4000 0 0 6000 -10 -250 448.1 368.3 429.4 300.6 4.3 4.2 4.2 4.7 9.6 14.8 9.7 13.1 Median Baseline Value, pmol/L Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h Prednisone 2.5mg bid Prednisone 5mg od Dexamethasone 0.5mg od Prednisone 5mg bid

Analyses of urine steroid metabolites Adrenocorticotropic hormone Deoxycorticosterone Androgen precursor metabolites metabolites ↑ P <.001 ↓ P <.05 Change from Baseline Value to Cycle 3 30 ↑ P <.001 ↑ P <.001 1000 2000 ↓ P <.001 ↓ P <.001 750 0 20 ↑ P <.001 500 ↑ P <.001 -2000 10 250 -4000 0 0 6000 -10 -250 448.1 368.3 429.4 300.6 4.3 4.2 4.2 4.7 9.6 14.8 9.7 13.1 Median Baseline Value, pmol/L Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h Prednisone 2.5mg bid Prednisone 5mg od Dexamethasone 0.5mg od Prednisone 5mg bid

Analyses of urine steroid metabolites Adrenocorticotropic hormone Deoxycorticosterone Androgen precursor metabolites metabolites ↑ P <.001 ↓ P <.05 Change from Baseline Value to Cycle 3 30 ↑ P <.001 ↑ P <.001 1000 2000 ↓ P <.001 ↓ P <.001 750 20 0 ↑ P <.001 500 ↑ P <.001 10 -2000 250 0 -4000 0 -10 -250 -6000 4.3 4.2 4.2 4.7 9.6 14.8 9.7 13.1 448.1 368.3 300.6 429.4 Median Baseline Value, pmol/L Median Baseline Value, µg/24 h Median Baseline Value, µg/24 h Prednisone 2.5mg bid Prednisone 5mg od Dexamethasone 0.5mg od Prednisone 5mg bid

Physiological considerations HOMA-IR 40 40 800 800 Serum insulin HOMA-IR ↑ P <.01 Serum insulin HOMA-IR P < .01 600 600 ↑ P <.01 20 20 400 P < .01 400 0 200 0 200 (n = 39) (n = 39) (n = 38) 0 0 (n = 38) (n = 37) (n = 37) -20 –20 (n = 39) (n = 38) -200 –200 (n = 39) (n = 38) (n = 37) -400 –400 (n = 37) -40 –40 (n = 38) (n = 38) -600 –600 (n = 38) -60 (n = 38) -800 –60 –800 Lean body mass Median baseline 20 20 Lean body mass ↓ P < .05 Body fat 150 % Change From Baseline Value to End Point ↓ P < .001 -150 Body fat ↓ P < .05 P < .05 P < .001 ↓ P < .001 10 P < .05 10 P < .001 100 100 0 0 ↑ P < .001 ↑ P < .001 P < .001 P < .001 -10 –10 50 50 (n = 28) (n = 28) -20 –20 (n = 37) (n = 30) (n = 37) (n = 30) 0 0 -30 –30 (n = 31) (n = 31) (n = 30) (n = 31) (n = 31) (n = 37) (n = 30) (n = 28) (n = 37) (n = 28) -50 -40 –50 –40 Median baseline Median baseline End of main study, up to 40 cycles

Anti-tumor activity Prednisone 5mg od Prednisone, 5 mg, bid A 25 25 Maximum PSA Change (%) From Baseline Value Maximum PSA Change (%) From Baseline Value 0 0 100 Dexamethasone 0.5mg –25 –25 80 –50% –50% % Progression-Free and Alive –50 –50 –75 –75 60 –90% –90% –100 –100 25 25 Maximum PSA Change (%) From Baseline Value Maximum PSA Change (%) From Baseline Value 40 Prednisone 5 mg BID 0 0 Prednisone 5 mg QD Prednisone 2.5 mg BID –25 –25 20 Dexamethasone 0.5 mg QD Total –50% –50% –50 –50 Censored observation 0 –75 –75 0 6 12 18 24 30 36 –90% –90% Months From Randomization –100 –100 Subjects at risk Dexamethasone 0.5mg od Prednisone 2.5mg bid *Trial not designed to compare steroid regimens

Conclusions – data-informed patient-directed treatment choice Ø Physiological long-term effects of AA + steroids had no discernible impact on quality of life Ø Prednisone 5mg bid and dexamethasone 0.5mg od minimize mineralocorticoid excess Ø Cost: increase in body fat and for dexamethasone 0.5mg od: increase in HOMA-IR and serum insulin and reduced bone mineral density Ø Prednisone 5mg daily minimizes long-term physiological side-effects with a greater risk of mineralocorticoid excess Ø Lower steroid doses require careful monitoring, ensure patients are medically optimized prior to start of AA Ø Consider dexamethasone at progression but the increased toxicity and absence of randomized data are against its use at start of AA