New$concepts$in$ADT$ Agonists$VS$Antagonists$$ … · agonist GnRH antagonist X X FSH,...

New concepts in ADT Agonists VS Antagonists

and All the Rest

Thomas E Keane MD. Professor and Chair.

Department of Urology Medical University of South Carolina.

Historical Timeline In Prostate Cancer Care

1904 First RP

1938-‐Acid Phosphatase 1940 Huggins hormone control: orchiectomy and estrogen treatment

1970s Steroidal and non-‐steroidal AAs available

1980s •  LHRH agonists •  PSA use •  TRUS biopsy •  Radical

prostatectomy 2003 First LHRH blocker (abarelix)

The Future New androgen receptor-‐targeted drugs, immunotherapy biomarkers, genomic tes8ng

1867 First perineal prostatectomy

1920s Radium treatments

1960s RT established as treatment for PCa

1960s and 70s SyntheNc estrogens (DES) Brachytherapy expands

1995 Cryosurgery accepted opNon for recurrent cancer aPer RT

2004 Docetaxel/prednisone approved

2008 Degarelix approved in US 2010 Provenge immunotherapy 2011/2012 abiraterone/enzalutamide

John Hunter 1780-‐castraNon

Original Concept Courtesy Dr. David Crawford

“Despite regressions of great magnitude, it is obvious that there

are many failures of endocrine therapy to control the disease.”

Nobel Lecture December 13, 1966

Huggins, 1966.

Charles B. Huggins Nobel Prize winner who established the fact that prostate cancer could be treated by hormonal treatment in the 1940’s He also alluded to what we now call Castration Resistant Prostate Cancer (CRPC)………

2016 CRPC Treatment Options •  Most only available since 2010 •  Androgen pathway targeting −  Abiraterone (androgen biosynthesis inhibitor) −  Enzalutamide (anti-androgen)

•  Radiopharmaceuticals − Radium 223

•  Immunotherapy −  Sipuleucel-T

•  Chemotherapy − Docetaxel (1st line) − Cabazitaxel (2nd line)

USA Today

ADT Options

•  Orchiectomy/ Estrogens: not used often – very inexpensive •  LHRH agonists

–  Block T production at the pituitary level; brief T increase; can be given depot forms 1,3,4,6 months

•  GNRH antagonists –  Block T production at the hypothalamic level but no T

increase; 28 day shots •  Anti-androgens: typically used with LHRH block- T receptor

–  Avoids brief T increase with LHRH agonists •  Secondary ADT: Ketoconazole, others •  Newer agents for mCRPC: Xtandi(enzalutamine), Zytiga

(abiraterone)

ADT: mechanism of acNon in relaNon to CV risk

LHRH agonist

GnRH antagonist

X

X

FSH, follicle-stimulating hormone LH, luteinising hormone

Inhibition of GnRH receptors

Stimulation of GnRH receptors

Prolonged suppression of FSH, LH and testosterone

FSH suppression not maintained long term

Degarelix LHRH agonists

Rapid suppression of FSH, LH and testosterone

Initial surge in FSH, LH and testosterone

No microsurges Microsurges on repeat injection

Personalized ADT for the Specific PaNent

•  Cardiac •  Obesity and testosterone •  FSH •  High volume metastaNc disease-‐ Staging •  Docetaxol before or aPer or both •  New agents and their place

Journal Article Review - Circulation –Feb 2016

Overview: Key Points

•  American Heart Association and observational studies link androgen deprivation therapy (ADT) to increased risk of cardiovascular events •  ~50% of patients with locally advanced and metastatic prostate cancer

receive ADT

•  ABCDE algorithm- awareness, aspirin, blood pressure, cholesterol, cigarette cessation, diabetes, diet, exercise- may reduce cardiovascular disease (CVD) risks

•  Study recommends initial CVD screening and quarterly monitoring appointments during the first year of therapy

•  Preliminary trials show CVD event risk with GnRH antagonist treatment (degarelix) is 50% lower than with GnRH agonist treatment (leuprolide, goserelin, triptorelin, histrelin)

Levine et al. Circulation. 2010;121. Nguyen et al. Eur Urol. 2015; 67. Conteduca et al Crit Rev Oncol Hematol. 2013; 86. Bhatia et al. Circulation. 2016; 133. Albertsen et al. Eur Urol. 2014; 65

Algorithm

ADT MedicaNons

TYPE OF DRUG COMMON BRAND NAME GENERIC NAME HOW IT IS GIVEN HOW OFTEN

LHRH AGONIST Lupron Depot leuprolide Intramuscular injecNon Every 1, 3, 4, or 6 months

LHRH AGONIST Eligard leuprolide Subcutaneous injecNon Every 1, 3, 4 or 6 months

LHRH AGONIST Zoladex goserelin Subcutaneous injecNon (absorbable implant)

Every month or every 3 months

LHRH AGONIST Telstar triptorelin Intramuscular injecNon Every 1, 3 or 6 months

LHRH AGONIST Vantas histrelin Subcutaneous implant (inner aspect upper arm)

Every 12 months

LHRH ANTAGONIST Firmagon degarelix Subcutaneous injecNon Two iniNal injecNons then monthly injecNons

ANTI-‐ANDROGEN Eulexin flutamide Oral Pill 3 Nmes daily ANTI-‐ANDROGEN Casodex bicalutamide Oral Pill Once Daily ANTI-‐ANDROGEN Nilandron nilutamide Oral Pill Once Daily ANDROGEN PATHWAY INHIBITOR FOR CRPC

Xtandi enzalutamide Oral Pills Once Daily

ANDROGEN PATHWAY INHIBITOR FOR CRPC

ZyNga abiraterone Oral Pills Daily with oral prednisone twice a day

ADT Medications

Cardiovascular risk profile and ADT

Is there a difference?

Degarelix belongs to a class of syntheNc drug, GnRH antagonist (blocker)

GnRH

D-‐Leu NEt

pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2

NH2

D-‐Ser NEt

D-‐Trp NH2

D-‐NaI D-‐Cpa D-‐PaI Aph D-Aph D-‐Ala NH2

D-‐NaI D-‐Cpa D-‐PaI D-‐Cit D-‐Ala NH2

D-‐NaI D-‐Cpa D-‐PaI N-‐Me Tyr

D-‐Asn Lys D-‐Ala NH2

D-‐NaI D-‐CPa D-‐PaI D-‐hArg D-‐hArg D-‐Ala NH2

Leuprolide

Goserelin

Triptorelin

Buserelin

Degarelix

Abarelix

Cetrorelix

Ganirelix

LHRH agonists

GnRH antagonists

D-‐Ser

Millar RP, et al. Endocr Rev 2004;25:235–75

Most acute CVD events are caused by rupture of a vulnerable atheroscleroNc plaque

The vulnerable plaque – thin cap with inflammaNon

Inflammation

Lipid core

Fibrous cap

Lumen Lumen

Fibrous cap

Lipid core

Vulnerable plaque

Plaque instability is at the heart of cardiovascular disease

Stable plaque

Libby P. CirculaNon 1995;91:2844-‐2850

Thick Cap Thin

Rich in SMC and matrix ComposiRon Rich in inflammatory cells: proteolyNc acNvity

Poor Lipid Rich

Inflammatory Inflammatory state Highly inflammatory

4.3 133.7

641.2

1152.6 1008.7

545.2

0

500

1000

1500

2000

2500

3000

3500

40-‐49 50-‐59 60-‐69 70-‐79 80-‐89 90-‐99

Prostate cancer

Incidence of both prostate cancer and CV events is highest in older men

246.9

571.1

1038.7

1719.7

2338.9

2827.1

0

500

1000

1500

2000

2500

3000

3500

40-‐49 50-‐59 60-‐69 70-‐79 80-‐89 90-‐99

All CV disease Major CV events

Driver, et al. BMJ 2008;337:a2467

CV events Prostate cancer

CV, cardiovascular Major CV events = myocardial infarcNon, stroke, or death due to CV disease All CV disease = major CV events + self-‐reported angina or revascularisaNon procedures

Age-‐specific incide

nce pe

r 100,000 person-‐years

Men with prostate cancer and pre-‐exisNng CVD have an increased risk of death

Jespersen CG, et al. BMC Cancer 2012;11:519

PopulaRon n (%)

CumulaRve survival (%) Adjusted HR (95% CI) 1-‐year 5-‐years

Overall 30,721 (100) 84.4 41.7 —

No IHD or stroke 25,114 (82) 85.4 43.5 1.0 (ref)

IHD 4,276 (14) 80.5 36.1 1.05 (1.00–1.10)

Stroke 1,331 (4) 77.6 26.5 1.20 (1.12–1.30)

CVD, cardiovascular disease IHD, ischaemic heart disease

*HR adjusted for age, stage, calendar period and comorbidity (excluding IHD and stroke)

Influence of prostate cancer therapy on mortality rates not assessed

Cardiovascular Disease is the Second Most Common Cause of Death in Men with Prostate Cancer

1. Studer, et al. J Clin Oncol 2006;24:1868-‐76 2. Calais da Silva, et al. Eur Urol 2009;55:1269–77

Cause of Death

CVD, cardiovascular disease; EORTC, European organisation for research and treatment of cancer; SEUG, South European uroncological group

Prostate cancer36%

CVD34%

Other30%

0%

EORTC 308911

Prostate cancer41%

CVD27%

Other32%

0%

SEUG 94012

This associaNon has been confirmed with other types of ADT

•  ObservaNonal study of 37,443 men with prostate cancer •  39% received some form of ADT during follow-‐up, primarily GnRH agonists (37.5%)

–  Few were treated with orchiectomy (0.8%) or oral anNandrogen monotherapy (3.3%) at any Nme or CAB (4.9%) for >6 weeks at the start of GnRH agonist therapy

ADT, androgen deprivaNon therapy CAB, combined androgen blockade CHD, coronary heart disease; ref, reference KeaNng NL, et al. J Natl Can Inst 2010;102:39–46

Treatment

Incident CHD Myocardial infarction

Sudden cardiac death Stroke

Adjusted HR (95% CI)




No ADT Ref Ref Ref Ref

GnRH agonist 1.19* (1.10–1.28)

1.28* (1.08–1.52)

1.35* (1.18–1.54)

1.21* (1.05–1.40)

Orchiectomy 1.40* (1.04–1.87)

2.11* (1.27–3.50)

1.29 (0.76–2.18)

1.49 (0.92–2.43)

CAB 1.27* (1.05–1.53)

1.03 (0.62–1.71)

1.22 (0.85–1.73)

0.93 (0.61–1.42)

Antiandrogen 1.10 (0.80–1.53)

1.05 (0.47–2.35)

1.06 (0.57–1.99)

0.86 (0.43–1.73)

*p<0.05

Swedish PCa database (n=41,362 PCa ADT+ vs 187,785 aged match PCa ADT-)

CVD-related events highest within 6 months of ADT initiation in men with pre-existing CVD

Move by FDA Based on the Agency’s Review of Seven Published Studies and an AHA/ACS/AUA Science Advisory

1.  Keating NL, et al. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-‐4456.

2.  Keating NL, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of Veterans with prostate cancer. J Natl Cancer Inst. 2010;102:39-‐46.

3.  Tsai HK, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007;99:1516-‐1524.

4.  Saigal CS, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer.Cancer. 2007;110:493-‐500.

5.  Van Hemelrijck M, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the population-‐based PCBaSe Sweden. J Clin Oncol. 2010;28:3448-‐56.

6.  Alibhai SMH, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452-‐3458.

7.  Efstathiou JA, et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-‐31. J Clin Oncol. 2008;27:92-‐99.

GnRH Agonists: Regulatory Warnings

•  October 2010: US FDA asks manufacturers of GnRH agonists to add extra safety informaNon to drug labels –  Increased risk of diabetes and certain CV diseases (heart auack,

sudden cardiac death, stroke) in men with prostate cancer •  EMA prompted a label change for GnRH agonists and GnRH

antagonists –  ‘Cardiovascular disease such as stroke and myocardial infarcNon has

been reported in the medical literature in paNents with androgen deprivaNon therapy. Therefore, all cardiovascular risk factors should be taken into account.’

Levine GN, et al. Circulation 2010;121:833–40

The risk has been shown to be increased in older men and those with comorbidiRes

•  Men aged ≥65 years receiving 6 months of ADT had shorter Nmes to fatal myocardial infarcNon compared with RT alone (p=0.017)1

•  PaNents with moderate or severe comorbidiNes* had a greater risk of a fatal myocardial infarcNon when receiving RT + ADT compared with RT alone2

1. D’Amico AV, et al. J Clin Oncol 2007;25:2420–5 2. D’Amico AV, et al. JAMA 2008;299:289–95

ADT, androgen deprivaNon therapy RT, radiotherapy *Based on Adult Comorbidity EvaluaNon 27 (ACE-‐27)

… as well as those with pre-‐exisRng cardiac disease

•  Significant increase in CV morbidity during oestrogen treatment in paNents with a history of CVD (p<0.001)

– 33% of these paNents had a CV event during PEP treatment

•  Oestrogen treatment was the greatest risk factor for CV events in a mulNvariate analysis (p=0.029)

CVD, cardiovascular disease PEP, polyestradiol phosphate Hedlund PO, et al. Scand J Urol Nephrol 2011;45:346–53

Based on the studies shown…

•  The increase in risk of CV disease in men treated with ADT (orchiectomy, oestrogen or GnRH agonist) appears to be 20–25%

•  In comparison, known major risk factors for CV disease increase lifeNme risk as follows: –  Smoking vs no smoking: 22% – Hypertension vs no hypertension: 20-‐93% –  Low vs not low HDL cholesterol: 44% – High vs low total cholesterol: 73% – Diabetes vs no diabetes: 122% – No randomized controlled trial has been performed assessing the risk of one form of ADT vs another.

Lloyd-‐Jones, et al. CirculaNon 2006;113:791-‐8

Pooled data from randomized phase III/IIIb trials of degarelix vs GnRH agonists

Study DuraRon (months) Comparator PublicaRon

CS21 Pivotal phase III, monthly dose

12 Leuprolide Klotz et al. BJU Int 2008

CS35 3-‐month depot formulaNon

12 Goserelin Shore et al. SIU 2012

CS37 Intermiuent dosing

7-‐12 Leuprolide Crawford et al. SUO 2013

CS28 LUTS relief

3 Goserelin* Anderson et al. Urol Int 2012

CS30 Neoadjuvant to radical RT

3 Goserelin* Mason et al. Clin Oncol 2013

CS31 TPV reducNon

3 Goserelin* Axcona et al. BJU Int 2012

*All patients on goserelin also received antiandrogen flare protection

LUTS, lower urinary tract symptoms RT, radiotherapy TPV, total prostate volume

Pooled analysis: Treatment groups 2328 PaNents

1491 Degarelix

837 GnRH agonist

463 (31%) CVD history

458 Goserelin

379 Leuprolide

245 (29%)

CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014:65;565-‐73

Selected baseline demographics relaNng to CV risk

Variable Degarelix n=1491

GnRH agonist n=837

Age (yrs) 71.7 71.6

Body mass index >30, n (%)

27.2 334 (22)

27.5 200 (24)

History of CVD, n (%) 463 (31) 245 (29)

History of smoking, n (%) 707 (47) 432 (52)

History of alcohol use, n (%) 889 (60) 475 (57)

History of hypertension, n (%) 1117 (75) 615 (74)

Serum cholesterol >6.2 mmol/L, n (%) 399 (27) 247 (30)

StaNn medicaNon use, n (%) 400 (27) 234 (28)

History of diabetes, n (%) 221 (15) 128 (15)


Results: Overall incidence of CV events*

•  A serious CV event was an event considered life-threatening or that required hospitalization

Degarelix, n (%) n=1491

GnRH agonist, n (%) n=837

Any CV event 37 (2.5) 40 (4.7)

Serious CV event 25 (1.7) 24 (2.9)

Albertsen PC, et al. Eur Urol 2014:65;565-‐73 Tombal B, et al. EAU 2013;Poster 677 *Data classified according to the MedDRA system

Overall survival

Miller K, et al. EAU 2013; Poster 678

HR=0.47 (95% CI 0.25–0.90) p=0.022

CVD, cardiovascular disease

Prostate cancer was not the cause of death in the majority of these paNents.

Lower risk of CV event or death with degarelix (all paNents)

HR adjusted for common CV risk factors including age, staNn use, hypertension and serum cholesterol by Cox regression

Albertsen PC, et al. Eur Urol 2014:65;565-‐73 Tombal B, et al. EAU 2013;Poster 677

HR=0.60 (95% CI 0.41-‐0.87) p=0.008

Lower risk of CV event or death with degarelix in men with baseline CVD

HR adjusted for common CV risk factors including age, staNn use, hypertension and serum cholesterol by Cox regression CVD, cardiovascular disease

HR=0.44 (95% CI 0.26–0.74) p=0.002

Albertsen PC, et al. Eur Urol 2014:65;565-‐73 Tombal B, et al. EAU 2013;Poster 677

Effect of degarelix remains when adjusted for common CVD variables

Covariate HR esRmate 95% CI p-‐value

Degarelix treatment 0.44 0.26–0.74 0.002

StaNn medicaNon use 0.54 0.28–1.03 0.061

Alcohol consumpNon 0.43 0.24–0.77 0.005

Hypertension* 2.09 1.08–4.06 0.030

Cigareue smoking 1.26 0.72–2.19 0.417

Serum cholesterol >6.2 mmol/L 1.14 0.62–2.08 0.681

Treated type 2 diabetes 0.83 0.34–2.00 0.669

Treated hypertension 0.63 0.32–1.24 0.182

Age at baseline 1.03 0.99–1.07 0.152

Baseline testosterone 0.79 0.66–0.94 0.009

Baseline body mass index 0.97 0.91–1.04 0.357

Albertsen PC, et al. Eur Urol 2014:65;565-‐73 *Diastolic >90 or systolic >140 mmHg CVD, cardiovascular disease

Pooled analysis: Summary

•  When treated with degarelix compared with a GnRH agonist, paNents with pre-‐exisNng CVD: – Had significantly fewer CV events during the first year of treatment

– Had a relaNve risk reducNon of >50% (absolute risk reducNon 8.2%)


GnRH receptors are expressed by smooth muscle cells in atheroscleroNc plaques

Hultgårdh, Nilsson et al, unpublished

Leuprolide induces necrosis in stable oscillatory shear stress-‐induced plaques

Hultgårdh, Nilsson et al, unpublished

16 weeks 18 weeks 26 weeks 30 weeks Cholesterol -rich diet

Shear stress- modifier

Degarelix Leuprolide Untreated

End point

Untreated Degarelix Leuprolide

Untreated Degarelix Enanton0.02.55.07.5

10.012.515.017.520.022.5

__________________*

% n

ecro

sis

Untreated Degarelix Leuprolide

PotenNal mechanisms for differences in CV risk with different forms of ADT

Differences in CV risk could be due to differences in the effect of different ADTs on: 1. Metabolic changes

2.  GnRH receptor acNvaNon 3.  FSH levels

T cells express GnRH receptors: Agonists and antagonists have different effects

T cells

GnRH-R

GnRH or GnRH agonist

Increased proliferation and activity

Fibrotic cap disruption and plaque instability

T cells

GnRH-R

GnRH antagonist

Complete blockade of receptors with no signal transduction

Inhibition of stimulated responses

Chen HF, et al. J Clin Endocrinol Metab 1999;84:743-‐50 Tanriverdi F, et al. Clin Exp Immunol 2005;142:103-‐10

Grasso G, et al. Life Sci 1998;62:2005-‐14; Jacobson JD, et al. Endocrinol 1994;134:2516-‐23 IFN, interferon

T Ly

DisrupNon of the fibroNc cap

Increased risk of thrombo-‐embolic complicaNons and

cardiovascular disease

Plaque instability

T lymphocytes are key drivers of collagen metabolism in atheroscleroNc plaques

Libby P J. Lipid Res 2009;50:S352-‐S357

T lymphocytes may be key drivers of collagen metabolism in atheroscleroNc plaques

T Lyphocyte

FibroNc cap disrupNon and plaque instability

Increased risk of thrombo-‐embolic complicaNons

T lymphocyte

IFN-‐γ secreNon

InhibiNon of collagen synthesis

CD40L

UpregulaNon of collagenases

Libby P. J Lipid Res 2009;50:S352–7 Andersson J, et al. Clin Immunol 2010;134:33–46

Does the disNnct mechanism of acNon of GnRH antagonists alter the risk of a CV event?

CV, cardiovascular; FSH, follicle-‐sNmulaNng hormone; GnRH, gonadotropin-‐releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone-‐releasing hormone

InhibiNon of GnRH receptors SNmulaNon of GnRH receptors

PotenRal for agonists to have a plaque destabilising effect due to inducRon of necrosis and T cell and macrophage

sRmulaRon

Prolonged suppression of FSH, LH and testosterone

FSH suppression not maintained long term

Increased potenRal for metabolic syndrome and atherogenesis with agonist therapy

GnRH Antagonist GnRH/LHRH agonists

Rapid suppression of FSH, LH and testosterone

IniNal surge in FSH, LH and testosterone

No microsurges Microsurges on repeat injecNon

Unlikely that long-‐term castraRon effect can explain differences in risk

LHRH agonist

GnRH antagonist

X

X


•  Cardiac

• Obesity and testosterone •  FSH •  High volume metastaNc disease •  Docetaxol •  Significant LUTS

ADT has been associated with metabolic changes

•  Metabolic syndrome is a disorder of energy uNlisaNon and storage, diagnosed by co-‐occurrence of any 3 of: –  Abdominal (central) obesity –  Elevated blood pressure –  Elevated fasNng plasma glucose –  High serum triglycerides –  Low high-‐density (HDL) cholesterol levels

•  Metabolic syndrome increases the risk of developing CVD

•  ADT leads to: –  Insulin resistance –  AccumulaNon of subcutaneous fat and decreased lean body mass –  Increased glucose levels –  AbnormaliNes in lipid levels Kelly DM, Jones TH. J Endocrinol 2013;217:R25-‐45

Metabolic syndrome and metabolic changes induced by ADT are different

Metabolic syndrome Metabolic changes with ADT

Increased triglycerides Increased triglycerides

Increased visceral fat Increased subcutaneous fat

Reduced HDL Increased HDL

Hypertension Hypertension

Increased fasNng glucose Increased fasNng glucose

Decreased adiponecNn Increased adiponecNn

Increased C-‐reacNve protein Normal C-‐reacNve protein

Saylor PJ, Smith MR. J Urol 2009;181:1998–2008


•  Cardiac •  Obesity and testosterone •  FSH •  High volume metastaNc disease •  Docetaxol •  Significant LUTS

FSH and adipogenesis

•  SNmulaNon of FSH receptors possibly alters endothelial cell funcNon, lipid metabolism and fat accumulaNon

•  Preclinical studies have shown:1 – Mice treated with degarelix have lower FSH levels than those treated with LHRH agonist or orchiectomy

– Degarelix-‐treated mice gain less weight and visceral fat than mice treated with LHRH agonists

1. Hopmans SN, et al. Urol Oncol 2014; In press

Overall survival

Miller K, et al. EAU 2013; Poster 678

HR=0.47 (95% CI 0.25–0.90) p=0.022

CVD, cardiovascular disease

Prostate cancer was not the cause of death in the majority of these paNents.

n  Time to PSA failure* or death – all patients

3.2 years

All patients

(ITT)

Hazard rates CS21 >1 year

(leuprolide ! degarelix)

P value

Degarelix 240/80 mg 0.11 0.14 0.464

Leuprolide 7.5 mg 0.20 0.08 0.003

CS21A (extension)

⇦ Maintained ⇦ Improved

PSA Progression-Free Survival Beyond 1 Year

49

Reproduced from The Journal of Urology, Vol 186, No 3, Crawford E, Tombal B, Miller K, et al. A phase III extension trial with a 1-‐arm crossover from leuprolide to degarelix: comparison of gonadotropin-‐releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186(3):889-‐897, Copyright 2011, with permission from Elsevier.

*PSA increase ≥50% from nadir and ≥5 ng/mL on 2 consecutive occasions ≥2 weeks apart.

a

CS21: degarelix or leuprolide CS21A: all degarelix

Further FSH suppression after crossover from leuprolide to degarelix

aMedian (quarNles) percentage change from baseline FSH, follicle-‐sNmulaNng hormone Crawford ED, et al. J Urol 2011;186:889–97

Median ConcentraNon of FSH aPer Abarelix and aPer GnRH-‐agonist with AnNandrogen

GnRH agonist ± antiandrogen Abarelix

0 5 10 15 20 25 30 35 40 45 50 55 65 60 70 75 80 85 0

10

20

30

40

Time (Days)

Med

ian

FSH

con

cent

ratio

n M

edia

n FS

H L

evel

(IU

/L)

Garnick MB et al. Mol Urol. 2000;4:275-277.

FSH receptor is strongly expressed by human prostate tumor blood vessels

FSH, follicle-stimulating hormone; PCa, prostate cancer

A higher density of blood vessels is present in the tumor compared to normal tissue

100

75

50

25

0 ‒6 ‒4 ‒2 0 2 4 6 8 10

0

10

20

30

40

50

Vessels E

xpressing FSH Re

ceptor, %

No. of V

essels pe

r mm

2

Tumor Normal Tissue

FSH-‐expressing vessels No. of vessels

Distance From Tumor Border, mm

More FSH-R expressing vessels are present at or near the tumor border Yellow = ColocalizaNon

of markers

Red = FSH-‐R immunostaining

Human prostate tumor secNon labeled for FSH receptor and vascular endothelial cell marker

Green = Vascular endothelial cell marker

Analysis of samples from 773 patients with PCa; all samples expressed FSH receptor, whereas normal tissue had no receptor expression

Radu A. New Engl J Med. 2010;363:1621–30

Conclusion

•  Data indicate clinical benefits with degarelix including a significant improvement in

•  PSA progression free survival •  Overall Survival •  Reduced incidence of joint, and musculoskeletal events compared with LHRH agonists.


•  Cardiac •  Obesity and testosterone •  Fsh • High volume metastaRc disease •  Docetaxol •  Significant LUTS

High Volume MetastaNc Disease

•  Rapidity of CastraNon and PSA suppression •  Lack of flare and miniflare •  Beuer FSH suppression •  Beuer suppression of S-‐ALP •  Less SRE •  Longer duraNon of HSPCa state •  Differences were more apparent in pts with higher PSAs and more advanced disease .

Sources of Androgen Production

LHRH Agents Anti-Androgens

Androgen pathway blockers help block here

•  Androgens are produced at 3 sites: -  Testes -  Adrenal gland -  Prostate tumor cells

(NEW DISCOVERY!)

Abiraterone •  Androgen synthesis inhibitor (CYP17 inhibitor)

−  Approved by the FDA: April 2011 post chemo, December 2012 pre chemo −  Interferes with steroidal hormone biosynthesis pathway

•  IndicaNons −  CombinaNon with prednisone for the treatment of mCRPC who have

received prior chemotherapy w/docetaxel −  CombinaNon with prednisone for the treatment of mCRPC who had

not received prior cytotoxic chemotherapy

Gaya, JM et al. Expert Review Anticancer Therapy. 2013:13: 819-827. Abiraterone acetate [prescribing information]. 2013.

17α-‐OH-‐ Pregnenolone

17α-‐OH-‐ Progesterone

DHEA Androstenedione

Testosterone DHT Cholesterol Pregnenolone

Progesterone

CYP17: 17α-hydroxylase

CYP17: C17,20-lyase

Abiraterone

ACTH

Androgen Receptor

Abiraterone Phase 3 Trial: COU-AA-301

•  Initiated in April 2008

•  Post-docetaxel mCRPC •  Up to 2 prior therapies •  ECOG PS 0-1 •  Medical or surgical

castration, testosterone < 50 ng/dL

•  n = 1158

R 2:1

Primary endpoint: Overall survival

Secondary endpoints: Progression-free survival (PFS), Proportion achieving 50% PSA reduction, time to PSA

progression, QOL

Abiraterone acetate 1000 mg/day (4 x 250 mg tablets)

PO; 5 mg prednisone/prednisolone BID

Placebo plus 5 mg prednisone/prednisolone BID

de Bono JS, et al. N Engl J Med. 2011;364:1995-2005.

Abiraterone Phase 3 Trial COU-AA-302

•  Initiated in April 2009 •  Asymptomatic or

mildly symptomatic mCRPC

•  Progression after previous anti-androgen withdrawal

•  ECOG PS 0-1 •  Medical or surgical

castration, testosterone < 50 ng/dL

•  n = 1000

R 1:1

Abiraterone acetate 1000 mg/day (4 x 250 mg tablets)

PO; 5 mg prednisone/prednisolone BID

Placebo plus 5 mg prednisone/prednisolone

BID

Primary endpoints: OS and PFS

Secondary endpoints: Time to opiate use, time to chemo, time to first ECOG PS deterioration, time to PSA progression

Ryan et al. N Engl J Med. 2013 ;368:138-148.

Enzalutamide

•  Androgen receptor blocker −  FDA Approved: Post August 2012;Pre September

2014 •  Indications

− mCRPC with recurrence or metastasis − mCRPC in patients who had received prior docetaxel − May be used in men who are not candidates for

chemotherapy •  Trials:

− AFFIRM (post-docetaxel) Post approval study −  PREVAIL (pre-docetaxel) Pre approval study −  STRIVE (vs. bicalutamide with CRPC) completed

Hoffman-Censits, J. Can J Urol April 2014 (Volume 21, Supplement 1), 64 – 69 Beers T NEJM 2014; 371:424-433July 31, 2014

Prevail – extended analysis •  Reduced risk of radiographic progression by 68% or death by 23%

•  rPFS was 20 months vs 5.4 for placebo •  Median OS -‐35.3 vs 31.3 for placebo.

•  Evaluated longer term efficacy/safety up to the prespecified number of deaths in the final analysis. 20 m for rPFS, 9 m for OS, 4 m for safety

•  A/E back pain, consNpaNon, faNgue and arthralgia

STRIVE •  Enzalutamide vs Bicalutamide in men with Pca progressing on ADT. 198pts in each arm.

•  PFS-‐Overall-‐ (PSA, Radiographic or death) •  19.4 vs 5.7m p<0.0001

•  Time to PSA progression – NA vs 8.3 m p<0.0001 •  % -‐PSA response> 50% 81.3 vs 31.35 •  DuraNon of RPFS-‐ Na vs 8.3m •  Best overall soP Nssue response % 60 vs 14 AEs and QOL no difference

NA – median Nme and 95% confidence interval not available due to insufficient number of events

1984-‐1989

1.  The Leuprolide Study Group. NEJM 1984;311:1281-‐1286. 2. Crawford ED, et al. NEJM. 1989;321:419-‐424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-‐1764. 4. Saad F, et al. JNCI 2002;94:1458-‐1468. 5. Petrylak DP, et al. NEJM. 2004;351:1513-‐1520. 6. Tannock IF, et al. NEJM. 2004;351:1502-‐1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-‐1154. 8. Kantoff PW, et al. NEJM. 2010;363:411-‐422. 9. Fizazi K, et al. Lancet. 2011;377:813-‐822. 10. de Bono JS, et al. NEJM. 2011;364:1995-‐2005. 11. Scher HI, et al. NEJM. 2012 Sep 27;367(13):1187-‐97. 12. Parker et al. NEJM. 2013;369:213-‐223.13. Beer T et al. 2014 ASCO GU San Francisco, CA 14. Beer T NEJM 2014; 371:424-‐433

1996 2002 2004 .... 2010 2011 2012

Mitoxantrone[3] Docetaxel[5,6]

Sipuleucel-‐T[8]

LHRH agonists[1,2] Abiraterone Post[10]

Reversible AR blockers[1,2]

Denosumab[9] Zoledronic Acid[4]

2014

Enzalutamide Post[11]

Cabazitaxel [7]

Abiraterone Pre[13]

Enzalutamide Pre [14]

Radium-‐223[12]

Before 2010, the last agent approved for the treatment of CRPC was docetaxel

New concept

•  Should these advances be applied to Hormone SensiNve Prostate Cancer and if so:

•  Which agents and when

Discussion Topics

•  E3805 (CHAARTED) data review •  Comparison with GETUG-‐AFU 15 •  Who really should receive docetaxel? The high vs. low volume/risk disease debate

•  Safety and toxicity consideraNons

E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen AblaNon for MetastaNc Prostate Cancer

STRATIFICATION Extent of Mets - High vs Low Age ≥70 vs < 70yo ECOG PS - 0-1 vs 2 CAB> 30 days -Yes vs No SRE Prevention -Yes vs No Prior Adjuvant ADT ≤12 vs > 12 months

RANDOMIZE

ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles

ARM B: ADT (androgen deprivaRon therapy alone)

Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks

Evaluate every 12 weeks

Follow for Rme to progression and overall survival Chemotherapy at invesRgator’s discreRon at progression

Sweeney C et al. ASCO 2014; Abstract LBA2.

•  ADT allowed up to 120 days prior to randomizaNon •  Intermiuent ADT dosing was not allowed •  Standard dexamethasone premedicaNon but NO DAILY PREDNISONE

•  Original design n=568 for high volume disease •  Adjustments for allowance of low volume

disease and projected OS based on S9346 data n=780



•  N=790 men accrued 07/28/06 -‐ 11/21/12

•  Planned interim analysis at 53% informaNon met 10/13

•  01/16/14 median followup 29 months

•  136 (110 high volume) deaths ADT alone vs. 101 (82 high volume) deaths ADT+D

•  83.6% vs. 83.2% of deaths from prostate cancer

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTALA 397 101 296 57.6B 393 136 257 44.0

Pro

ba

bili

ty

HR=0.61 (0.47-‐0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months

Primary endpoint – Overall survival



0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTALA 263 82 181 49.2B 251 110 141 32.2

Pro

babili

ty

p=0.0006 HR=0.60 (0.45-‐0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months

>4 bone lesions and >1 lesion in any bony structure beyond the spine/pelvis OR visceral disease

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTALA 134 19 115 .B 142 26 116 .

Pro

babili

ty p=0.1398 HR=0.63 (0.34-‐1.17) Median OS: ADT + D: Not reached ADT alone: Not reached

High volume Low volume

OS by extent of metastaRc disease at start of ADT

Gravis et al. Lancet Oncol. 2013; 14:149-‐58.

Overall Survival Biochemical PFS



Key Differences between GETUG-‐AFU 15 and CHAARTED

GETUG-‐15 CHAARTED

N 385 790

Docetaxel cycles Up to 9 (median 8) 6

Gleason 8-‐10 56.1% 68.6%

PSA median (ng/mL) ADT 25.8; ADT+D 26.7 ADT 50.5; ADT+D 56.0

High volume/risk 21.6%1 65.1%2,3

DisconNnuaNons early for toxicity 20.3% 12.5%

Treatment related deaths 4 (2.1%) 1 (0.3%) but 8 (2%) unknown

Median followup 50 months (data cutoff July 31, 2011) 29 months

Subsequent docetaxel with CRPC (%) ADT (62); ADT+D (28) ADT 129/174 (74.1) ; ADT+D 49/145 (33.8)

Subsequent potent AR therapy with CRPC (%) ADT (<15); ADT+D (<16) ADT 79/174 (45.5); ADT+D 92/145 (62.8)

1. Glass TR et al. J Urol 2003; 169:164-‐9; 2. Eisenberger M et al. N Engl J Med 1998; 339:1036-‐42; 3. Millikan RE et al. J Clin Oncol 2008; 26: 5936-‐42.

Summary of Factors that may have Contributed to Different Results between

GETUG-‐AFU 15 and CHAARTED •  Study size/staNsNcal power •  Prognosis and staging definiNons and disease risk/volume were different

•  ? Toxicity e.g. deaths and early disconNnuaNons and the use of other subsequent therapies were different

Grade 3-‐5 Hematologic Toxicity from TAX327 in mCRPC vs. GETUG-‐AFU 15 vs. CHAARTED

Toxicity TAX327 (%) GETUG-‐AFU 15 (%) CHAARTED (%)

Neutropenia 32 32* 12

Febrile neutropenia 3 7* 6

Death 0.3 2.1 0.3^

*APer 56% accrual and 4 treatment-‐related deaths, DSMC recommended GCSF days 5-‐10 with Grade ¾ neutropenia rate decline from 41% to 15%, febrile neutropenia decline from 8% to 6% and no more deaths. ^2% of deaths were unknown

Tannock IF et al. N Engl J Med 2004; 351:1502-‐12.

Key Conclusion: Tough to interpret toxicity data with incomplete informaNon on growth factors and prophylacNc anNbioNcs, but, is there some a sense that docetaxel may surprisingly be more toxic in mHSPC?

Docetaxel PK varies with CastraNon State •  10 non-‐castrate and 20 castrate

men with similar demographics •  Clearance of docetaxel in castrate

men was 100% increased with 2 fold reducNon in AUC

•  Erythromycin breath test indicated hepaNc CYP3A4 acNvity, for docetaxel metabolism, was not different

•  Castrate rats have higher AUC of docetaxel in liver compared to intact animals

Franke RM et al. J Clin Oncol 2010; 28:4562-‐67; *Bruno R et al. J Clin Oncol 1998; 16:187-‐96.

50% decrease in docetaxel clearance associated with >430% increase in odds of grade ¾ neutropenia*

What are the ImplicaNons of these PK Differences?

Between Different Trials •  May explain some of the greater

hematologic toxicity but also survival benefit observed in castraNon-‐sensiNve compared to castraNon-‐resistant trials

•  Why was there greater hematologic toxicity in GETUG-‐AFU 15 compared to CHAARTED?

–  How many paNents were non-‐castrate vs. castrate in each trial?

•  GETUG-‐AFU 15: 47% iniNated ADT within 15 days of enrollment

•  CHAARTED: iniNated ADT median 1.1 months to enrollment

–  How much GCSF was used in each trial?

For the PracRcing Clinician •  Consider waiNng unNl aPer 1-‐2

months of ADT or castrate testosterone levels have been reached before starNng docetaxel?

•  Use GCSF, at least for the first couple cycles, unNl castrate

STAMPEDE: Docetaxel and/or Zoledronic Acid in Hormone-‐Naive MetastaRc PCa

* Pairwise comparisons to control SOC study arm were calculated for each research arm.

•  Docetaxel, and not ZDA, improves overall survival compared to SoC •  Docetaxel + ZDA improves survival but offers no obvious benefit over

docetaxel alone James ND et al. Proc ASCO 2015;Abstract 5001.

SoC Doc + SoC ZDA + SoC Doc + ZDA + SoC

77 mo 80 mo 72 mo 0.76 (0.003) 0.93 (0.44) 0.81 (0.02)

37 mo 21 mo 37 mo

Median overall survival 67 mo

Hazard raRo (p-‐value) Ref*

Median failure-‐free survival

21 mo

Hazard raRo (p-‐value) Ref* 0.62 (<0.1 x 10-‐10) 0.62 (<0.1 x 10-‐10) 0.93 (0.26)

First overall survival analysis of paRents enrolled in the following 4 study arms:

•  Standard of care (SOC; n = 1,184) •  Docetaxel (Doc) + SOC (n = 592)

•  Zoledronic acid (ZDA) + SOC (n = 593) •  Doc + ZDA + SOC (n = 593)

QuesNon ?

•  If toxicity is greater with the use of Docetaxol in the pre-‐ castrate state might not efficacy also be ?

•  We need a trial.

A PHASE II STUDY OF DOCETAXEL BEFORE MEDICAL CASTRATION WITH DEGARELIX IN PATIENTS WITH NEWLY DIAGNOSED METASTATIC PROSTATIC

ADENOCARCINOMA.

N = 50 paNents Enrolling men with newly diagnosed treatment naïve metastaNc prostate cancer of all volume statuses.

S

8

CT

>>>

Primary Endpoint – ProporNon of men who maintain a PSA < 0.2 ng/ml at 40 weeks on study(7 months ADT) AddiNonal Endpoints – Toxicity, PSA response to Docetaxel alone, Nme to development of castraNon resistance, overall survival, correlaNng genomics with response.

Clinical consideraNons for the use of ADT: A hormonal therapy algorithm

History of CVD? •  Coronary artery disease •  Myocardial ischaemia and infarcNon •  Cerebrovascular accident •  Angina pectoris •  Coronary artery bypass

Degarelix •  >50% lower CVD risk

over one year1

PSA >20 ng/mL or metastases?

PaNents with Met-‐ HSPCA for Chemo/ADT

Degarelix •  Longer PSA PFS2 •  No clinical flare3 •  Beuer S-‐ALP control4 •  Beuer bone pain control5

Degarelix-‐ Maybe Castrate in 48 hrs

YES

YES

YES

NO

No

NO

Either if none of above

1. Albertsen PC, et al. Eur Urol 2014;65:565–73; 2. Boccon-‐Gibod L, et al. Therap Adv Urol 2011;3:127–40; 3. Klotz L, et al. BJU Int 2008; 102:1531–8; 4. Schroder FH, et al. BJU Int 2010;106:182–7; 5. Shore N, et al. Presented at SUO 2012;Poster 84;

6. Anderson J, et al. Urol Int 2013;90:321–8; 7. Mason M, et al. Clin Oncol 2013;25:190–6; 8. Axcona K, et al. BJU Int 2012;110:1721–8

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