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Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University
Urology DepartmentAl-Azhar University05/04/2015
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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
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MJA 2008; 189: 315–318
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MJA 2008; 189: 315–318
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Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part I: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61-71.
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Genetic Factors: Definitely is playing a role; more in prognosis.
BRACA1 & BRACA2 mutations Earlier screening. Other Factors: Diet and Obesity.
Alcohol.
Smoking.
Anabolic.
Physical Activity.
Ejaculatory Frequency.
Better Life
Style
www.uptodate.com Accessed Dec. 2014
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Disease Evolution & Molecular Events:
Normal
prostate
Histologic prostate
cancer
Localized prostate
cancer
Metastatic
prostate cancer
Androgen-independent
prostate cancer
p53 gene inactivation
Retinoblastoma gene loss
Decreased adhesion
molecule expression
bcl-2 oncogene
overexpression
H-ras enegocno
noisserpxerevo
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No major pre-disposition genes. > 40 susceptibility loci; different
behavior. Dominant susceptibility genes
inheritance early onset of disease.
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Androgenic Disease
Androgen Biosynthesis
Androgen Receptor Activity
Aggressiveness
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AndrogenAndrogen Receptors
Perfect Disease Control
• Surgical Castration.• Medical Castration.
• Blocking Receptors.
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HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
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Cholesterol CYP 11A1Pregnenolon
eCYP 17A1 Testosterone
ASS
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NTD DBD Hinge LBD
Nuclear & Steroid
Superfamily
Androgen
Estrogen
Glucocorticoid
Mineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
AndrogensN/C
HSP
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5@ Reductase
Genomic ActivityPSA, IGF, …
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Testosterone 5 α Reductase DHT + AR (LBD)
PI3KCaveolae
RTKGPCR
AR Activation & Dimerization
HSP
AKTSrc
MAPKERK1/2
Nuclear Transcription Factors
• Proliferation, Angiogenesis, …• No AR Degradation.
Non Genomic Activity
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Prevalent. Mortal. Aging and Black Races. PSA. Androgenic Disease. Androgen receptor is sensitive and addicted
to stimulation.
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Management of Newly
Diagnosed Prostate Cancer
Risk of
Local
Recurrence
Risk of
Disseminated
Disease
PSA StagingGleason
Score
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1. Estimated outcome with every treatment modality.
2. Complications with treatment procedures.3. Comorbidity.4. % of positive biopsies.5. Cancer volume.6. Peri-neural invasion.7. Disseminated cancer cells.
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A Story with Longer Cheerful Chapters.
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• Very Low - Risk: “All Should be Present”1. Disease is detected only on biopsy (No Clinical or
radiologic suspicion).
2. PSA < 10 ng/ml.
3. Gleason Score < 6
4. < 3 positive biopsy cores.
5. < 50% positivity within any core.
6. PSA density less than 0.15 ng/mL/gram
Uptodate.com 2015
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1. Active Surveillance.1. Very – Low Risk.
2. Life Expectancy < 20 years.
2. Radiation Therapy (External or Brachytherapy).
3. Radical Prostatectomy, (LNs. Dissection is an Optional Procedure).
1. No Randomized head to head comparison.2. Local Ablative Procedures may be advocated; no long term data.3. Postoperative histopathology might change the strategy
Uptodate.com 2015
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1. Radiation Therapy (External or Brachytherapy).
2. Addition of ADT is advisable.
3. Radical Prostatectomy with LNs Dissection. Postoperative histo-pathology might indicate the need for adjuvant therapy.
4. Active Surveillance???
Uptodate.com 2015
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• 2028 Patients.• Localized Disease.
• PSA < 20 ng/ml
ADT2 months
ADT + RTh2 months
ADT2 months
Rth Only
OAS10 Years
62%
57%
Jones CU. Data Presented at: 51st ASTRO Meeting: Nov. 1-5, 2009; Chicago, Illinois
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1. External Beam Radiation Therapy with Long Term (2 – 3 Years) ADT.
2. Radical Prostatectomy with Lymph Node Dissection. Postoperative Irradiation +/- ADT are to be considered.
Uptodate.com 2015
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1. External Beam Radiation Therapy + Long Term ADT.
2. Radical Prostatectomy and Lymph Node Dissection might be a less appealing option.
3. Nodal Affection: Radiation Therapy with ADT.
Uptodate.com 2015
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AndrogenAndrogen Receptors
Perfect Disease Control
• Surgical Castration.• Medical Castration.
• Blocking Receptors.
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Bilateral Sub-Capsular
Orchiectomy
0
100
200
300
1 2 3 4 5
Se
rum
Te
sto
ste
ron
e (
ng
/ml)
Days following Bilateral orchiectomy
Serum Testosterone Following Bilateral
Orchiectomy
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PituitaryLHRH Agonist LHRH Antagonist
+ LH & FSH
+ Testes
+ Testosterone
Ne
ga
tive
Fe
ed
Ba
ck M
ech
an
ism
+ Symptoms FLARE
3 –
4 W
ee
ks
Castrate Level
Castrate Level
72 –
96
Ho
urs
Disease Control
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Medical CastrationSurgical CastrationItems
GnRH AgonistsBilateral Sub-Capsular Orchiectomy
Procedure
ReversibleIrreversibleCastration
3-4 weeksRapidly AchievedCastrate Level of Testosterone
ElectiveEmergencyApplication
YesnoFlare
May be RequiredNot RequiredPrior Anti-Androgens
MoreLessCost
More PreferredLess PreferredPsychological Element
Discussion
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AgonistAntagonistItem
3-4 weeks96 HoursCastrate Level
YesNoFlare
14.1%8.9%PSA Failure
1%40%Local Injection Reaction
SimilarCardiovascular Complications
Every 3 MonthsMonthlyAdministration
Schroder 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.
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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
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Surgical Castration
Serum Testosterone >
20 ng/dL
Medical Castration
Serum Testosterone >
50 ng/dL
Anti-Androgen
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Competitive inhibition of peripheral androgen receptors.
No action on hypothalamic receptors. Inferior to ADT in phase III trials. Not suitable in hormone naive patients as a
mono-therapy. Used in combined androgen blockade & to
prevent flare & manage non-satisfactory results after ADT only.
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Equivalent to Castration at a dose of 150 mg in advanced M0 Prostate Cancer in terms of OAS with significant lower incidence of hot flashes.
Significant differences in quality of life favoring Bicalutamide.
Bicalutamide (50 mg) + LHRH is superior to Flutamide + LHRH in terms of OAS.
Quite beneficial (150 mg) in early prostate cancer.
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NCCN: CAB is APPROPRIATE but NO SPECIFIC RECOMMENDATION.
INT 0063 (Leuprolide +/- Flutamide):
Significant OAS & PFS difference.
INT 0105 (Orchiectomy +/- Flutamide):
Numerically better but not significant.
Cost & Complications
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Prolonged ADT
CRPC
Side Effects
ADTMaximum Response
Treatment Withdrawal
ProgressionRestart ADTOutcome??
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IDTADTItem
5.1 y5.8 yMedian OAS
38%42%7 –Year OAS
1.09HR
INT 0162 – Non-Inferiority Trial 3040 Patients - ASCO 2012
ADT IDT
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A 2007 meta-analysis combined the resultsfrom 3065 patients in four randomized trials.
Early ADT was associated with a statisticallysignificant decrease in prostate cancer-related deaths (relative risk [RR] 0.84; 95% CI0.77-0.92.
Although there was no significant benefit inoverall survival (RR 0.98; 95% CI 0.95-1.01).
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• Loss of libido.
• Impotence.
• Hepato-splenomegaly.
• Hot flashes.
• Gynecomastia.
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Obesity.
DM & CVS.
Insulin resistance.
Osteoporosis and clinical fractures.
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androgen-dependent cell
CRPC
Intrinsic Resistance to ADT
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At Risk
0%
20%
40%
80%
60%
100%
0 24 48 72Months After End of Induction
96 120
At Risk Deaths in MonthsMedian
Intrinsic Resistance to ADT-Overall Survival in mHSPC Patients by Nadir PSA
Hussain M, et al. J Clin Oncol. 2006;24(24):3984-3990.
PSA≤ 0.2
0.2 < PSA≤ 4.0
PSA > 4.0
Undetected 453 206 60
Normalized 213 72 19
Neither 91 17 7
≤ 0.2 602 199 75
>0.2 - ≤4 360 166 44> 4 383 322 13
P < .0001
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The Hypothesis
• Docetaxel added at the time of starting ADT inhormone-sensitive metastatic prostate cancer(mHSPC) will prolong overall survival (OS)
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n = 385 pts
2 ADT:- LHRH agonist- or maximum androgen blockade- or orchiectomy
3 75 mg/m2 q3 up to 9 cycles
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
1 GlassTR, et al. J Urol.2003;169(1):164-169.
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Median PFS:ADT + D: 23 mo [19.6-28.4]ADT: 13 mo [11.9-17.7]HR [95%CI]: 0.72 [0.57-0.91] P = .0052
ADT+ docetaxelADT
ADTADT+ docetaxel
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
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Median cPFS:ADT + D: 23 mo [20.5-32]ADT: 15 mo [12.5-20]HR [95%CI]: 0.75 [0.59-0.94] P = .0147
ADT+ docetaxelADT
ADT
ADT+ docetaxel
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
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Median OS:ADT + D: 59 mo [51-69]ADT: 54 mo [42-NR]HR [95%CI]: 1.01 [0.75-1.36] P = .95
ADT + docetaxelADT
ADT
ADT + docetaxel
Median follow-up: 50 months [49 - 54]Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
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E3805 – CHAARTED
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
R
A
N
D
O
M
I
Z
E
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for maximum
6 cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate
every 3 weeks
while
receiving
docetaxel and
at week 24
then every 12
weeks
Evaluate
every 12
weeks
Follow for time
to progression
and overall
survival
Chemotherapy
at investigator’s
discretion at
progression
Presented by: Christopher J. Sweeney, MBBS ASCO Plenary 2014
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.
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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
36 48
OS(Months)
0 12 24 60 72 84
Pro
babili
ty
Sweeney C, et al. J Clin Oncol. 2014;3A2(Suppl): Abstract7A2.
HR = 0.61 (0.47-0.80) P = .0006
Median OS:
ADT + D: 57.6 months
ADT: 44.0 months
ADT + D
ADT
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Causes of Death
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.
ADT + D
(N=397)
N
ADT
(N=393)
N
Due to prostate
cancer
83 112
Due to protocol
treatment
1 0
Other cause 8 11
Unknown 8 9
Missing 1 4
Total 101 136
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 48
OS(Months)
0 12 24 60 72 84
Arm ALIV
E
115116
DEA
D 1926
MEDIAN
.
.
TOTAL
A 134
High-voB lume dise25a1 se:11017 m141onth32.2improvement inBmedian OS142
Pro
babili
ty
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 48
OS(Months)
0 12 24 60 72 84
Pro
bab
ility
49.2 versus 32.2 months
OS by Extent of Metastatic Disease atStart of ADT
High Volume Low Volume
p=0.0006
HR=0.60 (0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT : 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT : Not reached
ADT + D
ADT
ADT + D
ADT
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.
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Combined ADT + D prolongs OS in men withhormone-sensitive metastatic prostate cancer
who are suitable for docetaxel therapy
the certainty of the data is strong for patients with high-volume metastatic disease, and clearly justifies its usebased on prognosis
longer follow-up is required to determine if there is benefit in patients with low-volume metastatic disease
- HR is 0.63 but NS
- Median OS of patients on GETUG 12 study more similar tothose in CHAARTED with low-volume metastatic disease
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Denosumab to Prevent Skeletal-Related Events: Phase III Study
Primary endpoint: time to first on-study skeletal-related event
Denosumab 120 mg SC
+
Placebo IV q4w
N = 950
Zoledronic Acid 4 mg IV
+
Placebo SC q4w
N = 951
Patients with CRPC
and bone metastases1901 Patients
Fizazi K, et al. ASCO 2010ABL tcartsbA .4507.
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Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39
Pts at Risk, N
0
1.00
Pro
port
ion o
f S
ubje
cts
Without S
RE
0 3 6 9 12 15 18 21 24 27
0.25
0.50
0.75
KM Estimate ofMedian Mos
Denosumab
Zoledronic acid
20.7
17.1
HR: 0.82(95% CI: 0.71-0.95;
P . =0002 noninferiority;
P . =008 superiority)
Study Mo
18%Risk
reduction
Time to First On-Study Skeletal-Related Event
Fizazi K, et al. Lancet. 2011;377:813-822.
Reprinted from The Lancet with permission from Elsevier. www.sciencedirect.com/science/journal/01406736
Denosumab vs Zoledronic Acid
Time to First Skeletal-Related Event
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CholesterolCYP 11A1
Pregnenolone
CYP 17A1
Testosterone
ASS
Abiraterone Acetate
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1. Competitively
inhibits androgen
binding to AR
2. Impairs AR
nuclear
translocation
3. Inhibits AR
interaction with DNA
A
AR
Cell nucleus AR
Cell cytoplasm
Tran C, et al. Science. 2009;324(5928):787-790.
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1. Site of Metastases: 5 RCTs:
0 5 10 15 20 25 30
Liver
Lungs
Bone
LNs
Months
OAS
Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 32, No 15_suppl (May 20 Supplement), 2014: 5002
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Halabi et al. J Clin Oncol 32:671-677. © 2014
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2. Circulating Tumor Cells: < 5/7.5 mL: med. OAS 22.1 months.
> 5/7.5 mL: med. OAS 10.9 months.3. Markers of Bone Metabolism:
2 markers of bone resorption (N-Telopeptide & Pyridinoline) and 2 markers of bone formation (C-Terminal Collagen Peptide & Bone Alkaline Phosphatase).
Higher levels are correlated with poor med. OAS 5 versus 13 months.
4. Gene Expression Profiles: 6 &9 Gene Assays.Scher et al. J Clin Oncol. 2011;29:293s.
Lara et al. J Natl Cancer Inst. 2014.Olmos et al. Lancet Oncol. 2012;13(11):1114
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1984-1989
...but this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy
Mitoxantrone3 Docetaxel5,6*
Sipuleucel-T8*
LHRH agonists1*
1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et
al. J Clin Oncol. 1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med.
2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8.
Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol. 2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med.
2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
1996 2002 2004 .... 2010
Abiraterone10*
Reversible AR
blockers2
Cabazitaxel7*
2011
Denosumab9
Radium 223?
Zoledronic Acid4
2012
Enzalutamide11*
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1. ADT should be continued.2. Choose between therapies associated with
survival benefit.
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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.
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ADT is the preferred initial therapy for Metastatic PC.
Surgical castration is preferred if rapid lowering of serum androgens is required.
Anti-androgens should be used prior to GnRH to prevent flare phenomenon.
CAB is associated with modest survival benefit but with higher toxicity.
Continuous and early treatment rather than intermittent and late.
The use of bone modifying agents should be adopted as early as possible.
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THANK YOU