Prostate Cancer UK MAsterclass Coventry July 2013

7/28/2019 Prostate Cancer UK MAsterclass Coventry July 2013

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Prostate cancer and management

Nicholas JamesSchool of Cancer Sciences

University of Birmingham


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Prostate cancer

Most common cancer in men Occurs in later life

Occult disease common

80% of 80 year olds have prostate cancer at post mortem,

30% of 50 year olds

Clinical prevalence in 60 year old men around 4% Aetiological factors unknown


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New cases prostate cancer by age


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Screening & diagnosis

4


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Diagnostic triad for early detectionof prostate cancer


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PSA testing

PSA is a protein produced in the epithelial cells of the prostate1

Blood levels of PSA can be used for screening or monitoring of patient

with diagnosed prostate cancer1

Consistent elevated PSA level should be further investigated,e.g. with prostate biopsy2

PSA >4 ng/mL does not necessarily indicate prostate cancer as PSA level

is a continuous parameter2

The higher the value the more likely the existence of prostate cancer

BPH=benign prostatic hyperplasia; PSA=prostate-specific antigen; WHO=World Health Organization.1. NCI. PSA Test Fact Sheet. Available from: http://www.cancer.gov/cancertopics/factsheet/Detection/PSA. Last accessed January 2013.

2. Heidenreich A, et al. Eur Urol2011;59:6171.6


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Characterising the tumour

7


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Gleason grading system

The Gleason grading system is based on glandular architecture, dividedinto five patterns of growth with different levels of differentiation

The Gleason score is the sum of the two most common patterns e.g. 4 (most prevalent pattern) + 3 (secondary pattern) = 7

SEER training modules: Morphology & grade. Available at:

http://training.seer.cancer.gov/prostate/abstract-code-stage/morphology.html. Last accessed January 2013.

Histological appearance and Gleason pattern Gleason score

2,3,4

5,6

7,8,9,10

8


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Imaging techniques

Transrectal ultrasound Scintigram

Computed tomography

MRI

Radionuclide bone scan

9


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Primary tumour (T)

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

T1 Clinically unapparent tumour neither palpable nor visible

by imagingT1a: Tumour incidental histological finding in 5% of tissue resected

T1b: Tumour incidental histological finding in >5% of tissue resectedT1c: Tumour identified by needle biopsy (e.g. because of elevated

PSA)

T2 Tumour confined within prostate*T2a: Tumour involves 50% of one lobe

T2b: Tumour involves >50% of one lobe but not both lobes

T2c: Tumour involves both lobes

T3 Tumour extends through the prostate capsule

T3a: Extracapsular extension (unilateral or bilateral)

T3b: Tumour involves seminal vesicle(s)

T4 Tumour is fixed or invades adjacent structures other than

seminal vesicles, such as external sphincter, rectum,

bladder, levator muscles, and/or pelvic wall

Regional Nodes (N)

NX Regional lymph nodes were

not assessed

N0 No regional lymph node

metastases

N1 Metastasis in regional lymph

node(s)

Distant Metastases (M)

M0 No distant metastases

M1 Distant metastases

M1a: Non-regional lymph node(s)M1b: Bone(s)

M1c: Other site(s) with or without

bone disease

*Tumour found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging is classif ied as T1c.Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classif ied not as T3 but as T2.

AJCC: Prostate. In: Edge SB, eds.AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p45768.

Classification and staging: TNM system

10


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Clinical practice:Staging and risk assessment

Category of localised

prostate cancer1Risk assessment criteria Recommended follow-up

Low risk All of T12a

Gleason


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Initial treatment ofprostate cancer


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Prostate cancer treatment paradigms

ClinicallyLocalized

Hormone/CastrateRefractory

Local treatmentChemotherapy,

new hormone therapies,

Radium-223, etc

Hormonal

Relapsedand

Newly diagnosed M+

T1/2 T3/4 N+ M+ HRPC

Low risk High risk


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Options for initial treatment

Active monitoring Watch and wait

Treatments of curative intent

Surgery

Radiotherapy

External beam

Brachytherapy

New modalities

Cryotherapy

High-intensity focused ultrasound (HIFU)


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Treatment of localised prostate cancerIncreasing risk

Active monitoring

Surgery

Radiotherapy

+ short course ADT

Radiotherapy

+ long course ADT

Hormone therapy alone

Brachytherapy/

HIFU/Cryo


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Active monitoring vs. watch and wait

AM No immediate treatment

Low risk cases only

Early intervention for

progression

W&W Any category patient

No intervention for PSA

progression

TURP for obstructive

symptoms

Hormones for distant spread


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Brachytherapy:Insertion of needles


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10-15


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Brachytherapy: Side effects

Symptoms (% G3/4) 3 months 6 months 12 months

Frequency 36/2 12/0 0/0

Dysuria 18/4 5/0 0/0

Nocturia 28/10 3/0 6/0

Urgency 10/2 6/6 0/0

Incontinence 3/0 0/0 0/0

Proctitis 6/0 4/0 2/0

Perineal pain 2/0 0/0 0/0

AL Booz et al BJU International 82 53-56


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External beam radiotherapy (EBRT)


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Neoadjuvant hormone therapyRTOG 8610 disease-specific survival

ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy.

Roach M, III et al. J Clin Oncol 2008;26:58591.

Disease-specific mortality. Failure is defined as death resulting from prostate

cancer. Time to a disease-specific mortality is measured from the date of random

assignment to the date of death or to the date of the most recent follow-up.


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Neoadjuvant hormone therapyRTOG 8610 overall survival

Overall survival. Failure is defined as death resulting from any cause. Survival

time is measured from the date of random assignment to the date of death or last

follow-up.

ADT, androgen deprivation therapy; MST, median survival time; EBRT, external-beam radiotherapy.Roach M, III et al. J Clin Oncol 2008;26:58591.


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T1T4, N0, M0(n=415)

RT alone(n=198)

Hormonal therapyat progression

EORTC 22863 trial: study design

Bolla M et al. N Engl J Med1997;337:295300; Bolla M et al. Eur J Cancer1999;35(Suppl 4):S82 (Abstr 266).

Randomized

RT + goserelin3.6 mg (n=205)


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Disease-free survival

Percentage

ofpatients 100

90

80

70

60

50

40

30

20

10

0

RT(n=198)

RT+LHRH(n=203)

p


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EORTC 22863

Overall survival

0 1 2 3 4 5 6 7 8 9 10Percentage

ofpatients 100

90

80

70

60

50

40

30

2010

0

p


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Hormone therapy pus radiotherapy

Hormone therapy pre-RT improves overall survival Hormone therapy post-RT improves overall survival

Benefit probably biggest in highest-risk cases

Do we need the RT at all?


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SPCG-7

Locally advancedCaP

PSA up to 70(n=880)

Randomised

Initial androgen ablationRT 70Gy to Prostate + pelvisAdjuvant oral anti-androgen

Initial androgen ablationSwitch to

Adjuvant oral anti-androgen

Initial results with 10 year follow up

reported ASTRO 2008


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SPCG-7 results

Widmark et al The Lancet 2009 373, 301-308


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Intergroup Randomized Phase III Studyof Androgen Deprivation Therapy +Radiation Therapy in Locally Advanced

Prostate Cancer

NCIC CTG PR.3/ MRC PR07/ SWOG JPR3

(NCT00002633, ISRCTN24991896)

M. D. Mason, P.R. Warde, M. R. Sydes, M. K.

Gospodarowicz, G. P. Swanson, P. Kirkbride, E.

Kostashuk, J. Hetherington,K. Ding, W. R. Parulekar

On behalf of all trial collaborators


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PR07 PR3 disease specific survival

HR=0.57 (95% C.I. 0.37-0.78) p=0.001

140 Deaths from Prostate Cancer89 ADT alone, 51 RT+ADT

# at Risk

ADT

ADT+RT

ADT

ADT+RT

Percentage

0

20

40

60

80

100

0 3 6 9

602

603

509

512

Time (Years)213

232

51

60

7 yr DSS 90%

7 yr DSS 79%


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Surgery

Open Laparoscopic

Robotic

No trials of surgery vs. radiotherapy


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Surgery vs WW for low risk disease

Bill-Axelson et al NEJM 352 1977-84 2005.


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PIVOT trial

Radical prostatectomy versus observation for localizedprostate cancer

N Engl J Med 2012; 367:203-213


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Pre-op PSA velocity and risk ofprostate cancer death

DAmico et al NEJM 351 125-35 2004.


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Da Vinci Robots


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Early disease

Huge overtreatment

Many options

Low risk of death

Little data on relative outcomes

Significant morbidity


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Hormone therapy

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Hormone therapy strategies

Block synthesis

At level of regulation

At level of synthetic pathways

Block binding to receptor

Block post-receptor effects

Add alternative hormones to alter environment


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Hormone therapy strategies

Block synthesis

At level of regulationLHRH analogues

At level of synthetic pathwaysCYP17 inhibitors

Block binding to receptorbicalutamide, enzalutamide

Block post-receptor effectsenzalutamide

Add alternative hormones to alter environmentdiethylstilboestrol,

dexamethasone


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Anterior Pituitary

LH

Testis

Leydig

cells

Testosterone

Prostate

Androgen pathways in human prostate

LHRH

Agonists

Antiandrogens

ACTH

Adrenal

cortex

DHEA

Prostate

DHT


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Effect of castration on androgen levels

Labrie F. Nature Reviews Urology 2011


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Androgen deprivation therapy (ADT)

ADT is the standard of care for advanced prostate cancer1,2

Current approaches to ADT focus on inhibiting testicular production

of androgens via surgical or medical castration3

Surgical castration (orchidectomy)

Chemical castration

LHRH analogues (agonists and antagonists)

Anti-androgens

Combined androgen blockade

Oestrogens

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ADT=androgen deprivation therapy; LHRH=luteinising hormone-releasing hormone.

1. Heidenreich A, et al. Guidelines on Prostate Cancer. Available from:

http://www.uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th%202012.pdf. Last accessed February 2013.

2. Horwich A, et al. Ann Oncol2010;21:v12933.

3. Hou X, Flaig TW.Adv Urol2012 doi:10.1155/2012/978531.

4. Ryan CJ, Tindall DJ. J Clin Oncol2011;29:365158.


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Side effects: ADT

Endocrine

Hot flushes, gynaecomastia, mastalgia, testicular atrophy, impotence,

and/or libido decrease

Haematological: anaemia

Central nervous system

Insomnia, dizziness, headache General

Fatigue, hypertriglyceridemia

Weight gain, loss of muscle bulk, gain in body fat

Osteoporosis


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Anti-androgens

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Anti-androgens bind toandrogen receptors in

the target cell

Compete with

exogenous or

endogenous androgens


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Older anti-androgen drugs

Steroidal

Cyproterone

Non-steroidal

Bicalutamide

Flutamide Nilutamide


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Limitations of anti-androgens

Low binding affinity to androgen receptor

Bicalutamide has an approximately 30-fold lower affinity to the AR

than DHT

Relatively high doses are required to suppress AR signalling in the

presence of androgens

May act as a partial agonist which often manifests when AR

signalling is already aberrant;

AR overexpression

AR mutations

A clinically significant consequence of the partial agonist activity

is the anti-androgen withdrawal syndrome

46


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Stilboestrol

Very first drug licenced for cancer therapy

Still used as palliative therapy after failure of first line therapy

Often used with dexamethasone and aspirin or warfarin

(risk of DVT)


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Disease course

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N t l hi t f l ll d d


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Natural history for locally advancedpatients

PSA

Initial Diagnosis& Therapy ADT

Death

~2 yr

Bone Mets

~1.5 yr

CRPC(PSA relaps e under ADT)

SRE

Course of Disease

?


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Natural history for metastatic patients

PSA

Initial diagnosis& ADT

Death

~2 yr ~1.5 yr

SRE

?

Second line

hormone therapy

Chemotherapy

CRPC(PSA relapse un der ADT)


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Development of CRPC

Intraprostatic androgen synthesis

Increased expression of enzymes converting DHEA to testosterone and

DHT in tumour tissue

Increased androgen synthesis

Androgen receptor (AR) abnormalities

Increased AR expression

Mutation of AR ligand binding domain

Constitutively active AR mutants (truncated AR)


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Abiraterone


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AFFIRM phase 3 trial of Enzalutamide


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AFFIRM phase 3 trial of Enzalutamide(MDV3100) post-chemotherapy

N = 1199

mCRPC12 prior

chemothera

py

regimens*

R

2:1

MDV3100 160 mg qd

Placebo qd

Phase 3 randomized, double-blind, placebo-controlled trial

http://clinicaltrials.gov/ct2/show/NCT00974311http://www.astellas.com/en/corporate/news/pdf/111104_Eg.p

Primary endpoint: Overall survival

Secondary endpoints: radiographic PFS, time to first SRE,

time to PSA progression

* 1 docetaxel


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AFFIRM trial: Summary of adverse events

*Includes terms hyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased

The adverse event reporting period was on average more than twice as long for MDV3100 compared with placebo

Data are percent of patients

Total events Grade 3 events

MDV3100(n = 800)

Placebo(n = 399)

MDV3100(n = 800)

Placebo(n = 399)

Adverse events 98.1% 97.7% 45.3% 53.1%

Serious adverse events 33.5% 38.6% 28.4% 33.6%

Discontinuations due toadverse events 7.6% 9.8% 4.6% 7.0%

Adverse events leading todeath

2.9% 3.5% 2.9% 3.5%

Adverse events of interest

Cardiac disorders 6.1% 7.5% 0.9% 2.0%

Myocardial infarction 0.3% 0.5% 0.3% 0.5%

LFT abnormalities* 1.0% 1.5% 0.4% 0.8%

Seizure 0.6% 0.0% 0.6% 0.0%

Scher HI et al. J Clin Oncol 2012;30 (suppl 5; abstr LBA1).


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MDV3100 trial results

37% improvement in survival times More side effects reported in placebo arm

Minimal drug related side effects

Control arm patients had longer survival times than

in the abiraterone trial due to exposure abiraterone

and cabazitaxel

Suggests different drugs can be added to each other for

further benefit


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Clinical presentation of CRPC

In CRPC, prostate cancer progresses despite castrate serum levels

of testosterone (4 ng/mL is ~68 months in patients with mCRPC, this may

be evidenced by:2

Appearance of local disease-related symptoms, e.g. obstructive voidingsymptoms, or

Documented metastatic disease progression, e.g. from bone scan

or CT/MRI, and bone pain

Huge variation with case-mix

mCRPC=metastatic castration-resistant prostate cancer; EAU=European Association of Urology; CT=computed tomography;

MRI-magnetic resonance imaging; PSA=prostate-specific antigen.

1. Ryan CJ, Tindall DJ. J Clin Oncol2011;29:36518.

2. Chodak GW. Prostate Cancer Treatment and Management 2013 Available at:

http://emedicine.medscape.com/article/1967731-treatment. Last accessed February 2013.57


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Metastatic disease

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CRPC: Sites of metastases

Prostate cancer more commonly metastasises to the bone but other

sites include distant organs such as the liver, lungs and brain1

90% of men develop bone metastases2

10% of men develop lung metastases3

3% of men develop liver metastases3

~40% of men develop a combination of both osseous and

soft tissue lesions3

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CPRC=castration-resistant prostate cancer.

1. Jin JK, et al. Int J Cancer2011;128:254561; 2. Beltran H, et al. Eur Urol2011;60:27990;3. Heidenreich A, et al. Urol Int2010;85:110.


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Steps in metastasis

Primary malignant neoplasm New vessel formation Invasion Embolism

Bone

metastases

Extravasation Adherence

Endothelial

cell

Arrest in distant

capillary bed in bone

Multi cell aggregates

(Lymphocytes, platelets)

Tumor cell

Proliferation

Response to

Microenvironment


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Bone metastasis in prostate cancer

Bone: most frequent site of prostate cancer metastasis

Favorable microenvironment for prostate tumor cells

Lesions first appear in axial skeleton, then appendicular skeleton

Main source of prostate cancerassociated morbidity

1. Roodman GD, et al. N Engl J Med. 2004;15:1655-1664.

The vicious cycle

of bone metastases

and tumor cell growth

in the bone marrowmicroenvironment1

RANKL

PTHrP

IL-6

PGE2TNF

M-CSF

BMP

PDGF

FGFs

IGFs

TGF-


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Chemotherapy

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Docetaxel:


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0%

20%

40%

60%

80%

100%

0 12 24 36 48Months

D+E

M+P

# at

Risk338

336

# of

Deaths217

235

Median

in Months18

16

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

Docetaxel:Overall survival SWOG 9916

Docetaxel:


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Docetaxel:TAX 327 overall survival

Median

survival Hazard

(mos) ratio P-value

Combined: 18.2 0.83 0.03

D 3 wkly: 18.9 0.76 0.009

D wkly: 17.3 0.91 0.3

Mitoxantrone 16.4

Months

Probability

of

Surviving

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone


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Cabazitaxel:TROPIC overall survival (ITT analysis)

MP 377 300 188 67 11 1

CBZP 378 321 231 90 28 4

Numberat risk

ProportionofOS(%)

80

60

40

20

0

100

0 months 6 months 12 months 18 months 24 months 30 months

15.112.7Median OS(months)

0.590.8395% CI


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Bone targeted therapies


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Bone metastases

Orthopaedic

SurgeryRadiation

to BonePathologic

FractureSpinal Cord

compression

SREs are clinically important endpoints

The burden of bone metastases

Pain

Disability

Hospitalizations Cost

Denosumab versus zoledronic acid in


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Perc

entofSubjectsWithFirstSRE

Radiation

to BoneFracture

Surgery

to Bone

Spinal Cord

Compression

20.0

14.7

3.3

0.3

All subjects

0

5

10

15

20

25

30

Denosumab versus zoledronic acid inCRPC type of SREs

Denosumab Versus Zoledronic Acid in


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CRPC Time to First On-Study SRE

Zoledronic Acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Subjects at risk:

0

1.00

ProportionofSubjectsWithoutSRE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Months

Denosumab

Zoledronic acid

20.7

17.1

HR 0.82 (95% CI: 0.71, 0.95)P= 0.0002 (Non-inferiority)

P= 0.008 (Superiority)

Study Month

Denosumab versus zoledronic acid in


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Denosumab versus zoledronic acid inCRPC cumulative number of SREs

*Events occurring at least 21 days apart

Rate Ratio = 0.82 (95% CI: 0.71, 0.94)

Study Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

CumulativeMeanNumberofSREs

perPatient

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

DenosumabZoledronic acid 584

494

Events

P= 0.008

SRE frequency in trial of Ra223 vs


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SRE frequency in trial of Ra223 vsplacebo

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Radium-223 chloride (Alpharadin) impact on overall survival and skeletal-related events in patients with castration-

resistant prostate cancer with bone metastases: A phase III randomized trial (ALSYMPCA). Sartor et al AUA 2012

0

5

10

15

20

25

30

Pathologic Bone Fracture Spinal Cord Compression External beam RT Surgical intervention

Ra-223

Placebo


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Phase III Study treatments

Presented by: Nick James

ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease

progression.

ADocetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od

(cycles 1-10)

docetaxel +

prednisolone(cycles 1-6)

Sr89 150

MBq(day 28 cycle 6)

C + 28 Days*

docetaxel +

prednisolone(cycles 7-10)

* At least 28 days

Bdocetaxel + prednisolone + ZA 4mg iv(cycles 1-10)

D

docetaxel +

prednisolone + ZA(cycles 7-10)

+ 28 Days*

docetaxel +

prednisolone +

ZA(cycles 1-6)

Sr89(day 28 cycle 6)


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SRE Free Interval: ZA comparison



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Total Skeletal Related Events by type


Sr89 comparison

No Sr89 Sr89

ZA comparison

No ZAZA

N (%) N (%) N (%) N(%)

Symptomatic pathological

fractures16 18 23 11

Spinal cord or nerve rootcompression 39 45 52 32

Cancer related surgery to

bone10 13 18 5

Radiation therapy to bone 317 258 337 238

Change in antineoplastic

therapy to treat bone pain 16 12 17 11Hypercalcaemia 0 2 2 0

Other 1 1 0 2

Total 399 349 449 299


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Skeletal Related Events per patient


Sr89 comparisonNo Sr89 Sr89

ZA comparisonNo ZA

ZA

N(%) N(%) N(%) N(%)

0 196 (52) 201 (53) 185 (49) 213 (56)

1 92 (25) 96 (25) 91 (24) 97 (26)

2 32 (8) 38 (10) 33 (9) 37 (10)

3 28 (7) 20 (5) 38 (10) 10 (3)

4 11 (3) 11 (3) 13 (3) 9 (2)

5 or more 19 (5) 12 (4) 21 (5) 10 (3)

Number of patients with

at least one SRE

182 (48) 177 (47) 196 (51) 163 (44)


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Radio-isotopes


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Alpharadin

Radium 223 calcium mimetic agent

High uptake in bone metastases

Alpha-particle emitter

Phase III licencing trial completed


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Alsympca overall survival

Parker et al ESMO 2011.


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Current EU CRPC treatment

Clinical trial

Observation

2nd-line hormone Rx*

No metastases


Abiraterone

Clinical trial

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole

Symptomatic

Docetaxel

Mitoxantrone

Clinical trial

Cabazitaxel

Docetaxel

rechallenge

Abiraterone

Mitoxantrone

2nd-line hormoneRx*

Metastases

Asymptomatic

Mottet et al. Eur Urol 2011;59:57283. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v12933. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical

Guideline 58) 2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:17715. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011.

http://www.nccn.org. Miller et al. Aktuelle Urologie. 2006;37:2014.

Note: Added abiraterone here


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Future CRPC treatment

Clinical trial

Observation


No metastases

Abiraterone

Docetaxel

Symptomatic

Docetaxel

Radium 223

Cabazitaxel

Docetaxel

Abiraterone

Enzalutamide

Metastases

Asymptomatic


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Conclusions

Prostate cancer is a spectrum from trivial to veryserious disease

Treatment options are rapidly changing across

the whole spectrum

Many new drugs being licenced for advanceddisease

Management of bone metastases a substantial

burden and some treatments controversial

Prostate Cancer UK MAsterclass Coventry July 2013

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