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Prostate cancer: “Keep Tackling The Androgenic Nature”
Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University
SUN Annual Urology MeetingASTRA Zeneca Symposium
Hilton Borg Al-Arab12/11/2015
Speaker DisclosuresMember of Advisory Board, Consultant, and Speaker for:● Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:
Basic Facts:
● 2nd most cancer in men (27%).● 1/6 men prostate cancer.● 2nd leading cause of cancer related death in
men (10%).● World Wide: > 1000000 new case annually.● > 300000 death/year.● Closely related to age & Androgens● Wide geographic and ethnic variations.● Pre- and post-PSA era.
MJA 2008; 189: 315–318
Prostate Cancer: The Story:
Dr. Huggins(1941): Orchiectomy and DES Effective Disease Control Noble Price 1966.
Dr. Shcally et al: (1977): LHRH Analogue Effective disease Noble Price
Prostate Cancer: Best Identity:
Natural History
Androgen Biosynthesis
Androgen Receptor Activity
Aggressiveness
AndrogenicDisease
HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease:
LHRH Analogue
Bilateral Orchiectomy
Steroidogenesis & Prostate Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
Prostate = Androgen Self Sufficient Organ
NTD DBD Hinge LBD
Nuclear & Steroid
Superfamily
Androgen
EstrogenGlucocorticoidMineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
AndrogenN/C
HSP
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure”
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Testosterone DHT5@ Reductase
DHT+AR+HSP Active AR
Active AR Active AR Active AR
Proliferation
Angiogenesis
Metastases
AREAR
Degraded
Genomic ActivityPSA, IGF, …
Testosterone 5 α Reductase DHT + AR (LBD)
PI3KCaveolae
RTKGPCR
AR Activation & Dimerization
HSP
AKTSrc
MAPKERK1/2
Nuclear Transcription
Factors
• Proliferation, Angiogenesis, …• No AR Degradation.
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Non Genomic Activity
Androgen Receptor in Prostate Cancer:
Prostate Cancer: A Panoramic View:
Pre-Receptor
Level
Receptor Level
ANDROGEN
DISEASE PROGRESSION
Anti-Androgen
Synthesis:Abiraterone
Receptor:Enzalutamide
Cytotoxic Therapy
Androgen Deprivation Therapy (ADT)
Heemers HV> Int. J. Biol. Sci. 2014, Vol. 10
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Long Term ADT > Short Term ADT
Biochemical Failure Free Survival
OAS
Metastasis Free Survival
Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Practice Changing Guidelines:
Primary Hormonal Manipulation:1. Surgical Castration:
Bilateral Sub-
Capsular Orchiectomy
1 2 3 4 50
100
200
300
Serum Testosterone Following Bilateral
Orchiectomy
Days following Bilateral orchiectomySe
rum
Tes
tost
eron
e (n
g/m
l)
Primary Hormonal Manipulation:2. Medical Castration:
PituitaryLHRH Agonist LHRH Antagonist
+ LH & FSH
+ Testes
+ Testosterone
Neg
ativ
e Fe
ed B
ack
Mec
hani
sm
+ Symptoms FLARE
3 –
4 W
eeks
Castrate Level
Castrate Level
72 –
96
Hou
rs
Disease Control
Primary Hormonal Manipulation:
Medical Castration Surgical Castration Items
GnRH Agonists Bilateral Sub-Capsular Orchiectomy
Procedure
Reversible Irreversible Castration
3-4 weeks Rapidly Achieved Castrate Level of Testosterone
Elective Emergency Application
Yes no Flare
May be Required Not Required Prior Anti-Androgens
More Less Cost
More Preferred Less Preferred Psychological Element
Discussion
GnRH Antagonist versus Agonist:
Agonist Antagonist Item
3-4 weeks 96 Hours Castrate Level
Yes No Flare
14.1% 8.9% PSA Failure
1% 40% Local Injection Reaction
Similar Cardiovascular Complications
Every 3 Months Monthly AdministrationSchroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106:182.Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010; 57:836. Smith MR, Klotz L, Persson BE, et al. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol 2010; 184:2313.
Surgical versus Medical Castration?
Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.
Meta-AnalysisOf 1908 Patients
Surgical Castration
Medical Castration
EquivalentOASPFSTTF
Maintaining testosterone <32 ng/dL was associated with significantly longer mean survival free of CRPC compared with levels >32 ng/dL
Survival free of CRPC in 73 patients with non-metastatic prostate cancer receiving ADT.*Patients with three serum testosterone determinations <32 ng/dL; †Patients with breakthrough increases >32 ng/dL.Serum testosterone was measured every 6 months. ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer.Figure adapted from Morote J, et al. J Urol 2007;178:1290–5.
100
80
60
40
20
0Cum
ulat
e su
rviv
al fr
ee o
f CR
PC (%
)
0 50 100 150 200 250
Follow up (months)
>32 ng/dL†
<32 ng/dL*
p=0.0258
Testosterone ≤30 ng/dL has been associated with longer overall survival versus >30 ng/dL
VariableTestosteroneContinuous
variable*
Testosterone<50 ng/dL
(n=94)
Testosterone≤30 ng/dL
(n=56)
Testosterone<20 ng/dL
(n=25)
Time to progressionHR (95% CI)p value
1.76 (0.62–5.01)0.29
0.84 (0.52–1.37)0.51
0.76 (0.46–1.26)0.30
0.58 (0.30–1.15)0.12
Overall survivalHR (95% CI)p value
2.47 (0.70–8.75)0.16
0.74 (0.42–1.33)0.32
0.45 (0.22–0.94)0.034
0.19 (0.04–0.76)0.020
*Testosterone was considered a continuous (values were measured on a continuous scale) not categorical variable in this analysis. CI=confidence interval; HR=hazard ratio.Bertaglia V, et al. Clin Genitourin Cancer 2013;11:325–30.
Maintaining testosterone levels at <20 ng/dL correlated with improved duration of response to ADT*
*Investigators defined CRPC as rising PSA >4 ng/mL with testosterone <3.0 nmol/L. Retrospective analysis of patients with biochemical failure after radiation or surgery plus radiation; n=626 patients with ≥3 testosterone levels in first year. Secondary analysis of PR-7 intermittent vs. continuous ADT trial. Conversion of testosterone values: 0.7 nmol/L=20 ng/dL; 1.7 nmol/L=50 ng/dL.ADT=androgen-deprivation therapy; CI=confidence interval; CRPC=castration-resistant prostate cancer; HR=hazard ratio.Figure adapted from Klotz L, et al. Nadir testosterone on ADT predicts for time to castrate resistant progression: A secondary analysis of the PR-7 intermittent vs continuous ADT trial. Poster. Presented at: 29th Annual Congress of the European Association of Urology, 11–15 April 2014, Stockholm, Sweden.
100
80
60
40
20
0
Perc
ent
0 2 4 6 8 12Time (years)
10
Log rank p=0.0092HR (95% CI): 0.7<testosterone<1.7/testosterone ≤0.7: 1.41 (1.07–1.84)Testosterone ≥1.7/testosterone ≤0.7: 1.91 (1.11–3.29)
Median testosterone ≤0.7 nmol/L0.7 nmol/L <median testosterone <1.7 nmol/LMedian testosterone ≥1.7 nmol/L
ADT: Key points from EAU guidelines 2014
ADT=androgen-deprivation therapy; EAU=European Association of Urologists; mCRPC=metastatic castration-resistant prostate cancer.Mottet N, et al. EAU Guidelines on Prostate Cancer 2014. Available at: http://www.uroweb.org. Last accessed January 2015.
Optimal castration testosterone level is defined as <20 ng/dL
In high-risk localised and locally advanced prostate cancer, the combination of radiotherapy and ADT is recommended because it
improves survival
First-line ADT is the standard of care for metastatic prostate cancer
Testosterone suppression should be continued indefinitely even when the disease becomes castration resistant
Second-line therapies for mCRPC should not be started unless patient testosterone levels are <50 ng/dL
Monitoring testosterone levels should be considered as partof routine clinical practice
NCCN GUIDELINES:
Management of CRPC:
1. ADT should be continued.2. Inhibition of bone resorption3. Risk Stratification.4. Choose between therapies associated with survival
benefit.
NCCN GUIDELINES:
NCCN GUIDELINES:
Take Home Message:
● Prostate cancer is a prevalent and lethal disease.● Prostate cancer is an ANDROGENIC disease.● Androgen receptors are ACTIVE & ADDICTED TO STIMULATION ADT is an
INTEGRAL part of therapy across disease spectrum after active surveillance.● Long term ADT (2-3 years) plus radiation therapy is mandatory for high risk and
very high risk patients.● Castrate level should be ensured for patients with CRPC.● Keep an eye on ADT related adverse events. ● Post-Receptor directed therapies would be of interest in the nearby future.
Localized Metastatic HRPC
Loco-Regional Treatment ADT ADT
ADT – Short Term +/- Anti-Androgen Biosynthesis Abiraterone Acetate
ADT – Long Term +/- Chemotherapy AR – Signaling Enzalutamide
Anti-Androgen (Flare) +/- Radiation Therapy Cytotoxic Docetaxel
Cabazitaxel Anti-Androgen + RTH Bone Targeted Agents Immunotherapy
Sipuleucel TBone Targeted
Radium 223
Take Home Message:
Thank You