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TRANSCRIPT
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)
Adjusted HR (95% CI)
Adjusted HR (95% CI)
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)
CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014:65;565-‐73
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%)
CVD, cardiovascular disease Albertsen PC, et al. Eur Urol 2014:65;565-‐73
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
Personalized ADT for the Specific PaNent
• 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
Personalized ADT for the Specific PaNent
• 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.
Personalized ADT for the Specific PaNent
• 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
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen AblaNon for MetastaNc Prostate Cancer
Sweeney C et al. ASCO 2014; Abstract LBA2.
• 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
Sweeney C et al. ASCO 2014; Abstract LBA2.
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen AblaNon for MetastaNc 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 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
HR=1.01 (0.75-‐1.36) p=0.955 Median OS: ADT + D: 58.9 months ADT alone: 54.2 months
HR=0.72 (0.57-‐0.91) p=0.005 Median OS: ADT + D: 22.9 months ADT alone: 12.9 months
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