Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University

Urology DepartmentAl-Azhar University05/04/2015

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

MJA 2008; 189: 315–318

MJA 2008; 189: 315–318

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.

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

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

No major pre-disposition genes. > 40 susceptibility loci; different

behavior. Dominant susceptibility genes

inheritance early onset of disease.

Androgenic Disease

Androgen Biosynthesis

Androgen Receptor Activity

Aggressiveness

AndrogenAndrogen Receptors

Perfect Disease Control

• Surgical Castration.• Medical Castration.

• Blocking Receptors.

HypothalamusLHRH

Pituitary

Testes Supra-renal

Testosterone

LH ACTH

Cholesterol CYP 11A1Pregnenolon

eCYP 17A1 Testosterone

ASS

NTD DBD Hinge LBD

Nuclear & Steroid

Superfamily

Androgen

Estrogen

Glucocorticoid

Mineralocorticoid

Progesterone

Constitutively Active DNA

Promoter Gene

AndrogensN/C

HSP

5@ Reductase

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.

Non Genomic Activity

Prevalent. Mortal. Aging and Black Races. PSA. Androgenic Disease. Androgen receptor is sensitive and addicted

to stimulation.

Management of Newly

Diagnosed Prostate Cancer

Risk of

Local

Recurrence

Risk of

Disseminated

Disease

PSA StagingGleason

Score

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.

A Story with Longer Cheerful Chapters.

• 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

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

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

• 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

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

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

AndrogenAndrogen Receptors

Perfect Disease Control

• Surgical Castration.• Medical Castration.

• Blocking Receptors.

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

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

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

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.

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

Surgical Castration

Serum Testosterone >

20 ng/dL

Medical Castration

Serum Testosterone >

50 ng/dL

Anti-Androgen

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.

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.

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

Prolonged ADT

CRPC

Side Effects

ADTMaximum Response

Treatment Withdrawal

ProgressionRestart ADTOutcome??

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

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).

• Loss of libido.

• Impotence.

• Hepato-splenomegaly.

• Hot flashes.

• Gynecomastia.

Obesity.

DM & CVS.

Insulin resistance.

Osteoporosis and clinical fractures.

androgen-dependent cell

CRPC

Intrinsic Resistance to ADT

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

The Hypothesis

• Docetaxel added at the time of starting ADT inhormone-sensitive metastatic prostate cancer(mHSPC) will prolong overall survival (OS)

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.

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.

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.

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.

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.

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

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

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.

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

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.

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

CholesterolCYP 11A1

Pregnenolone

CYP 17A1

Testosterone

ASS

Abiraterone Acetate

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.

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

Halabi et al. J Clin Oncol 32:671-677. © 2014

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

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*

1. ADT should be continued.2. Choose between therapies associated with

survival benefit.

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.

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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