Prostate Cancer Talk Swedish Urooncological Society Oct 2014

8/10/2019 Prostate Cancer Talk Swedish Urooncological Society Oct 2014

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New Agents in mCRPC –

optimal use in an evolving

landscape?

Nicholas James

@Prof_Nick_James

#NJProstatecancer

1



Birmingham - Google Maps

Map data©2014 GeoBasis-DE/BKG (©2009), Google 50 km





Anterior Pituitary

LH

Testis

Leydig

cells

Testosterone

Prostate

Androgen pathways in human prostate

ACTH

Adrenal

cortex

DHEA

Prostate

DHT



Effect of castration on androgen levels

Labrie F. Nature Reviews Urology 2011





Hormone therapy

• Hormones are a multi-component system:

– Regulation of synthesis

– Synthesis

– Secretion

– Ligand receptor binding

– Actions of activated ligand/receptor on thetarget gene expression paterns





ADT and Cardiovascular Disease (CVD)



Risk of CV event associated with LHRH

agonist or orchidectomy

Treatment

Incident diabetes Incident CHD Myocardial infarction Sudden cardiac death

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

No treatment 1 (ref) – 1 (ref) – 1 (ref) – 1 (ref) –

LHRH agonist 1.441.34–1.55

<0.001 1.161.10–1.21

<0.001 1.111.01–1.21

0.03 1.161.05–1.27

0.004

Orchiectomy 1.341.20–1.50

<0.001 0.990.91–1.07

0.74 0.940.82–1.09

0.44 1.010.87–1.18

0.85

CHD, coronary heart disease; HR, hazard ratio

LHRH, lueteinising hormone-releasing hormone

ref, reference

Keating NL, et al. JCO 2006





Risk of CV event associated with LHRH

agonist or orchidectomy

Treatment


Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

No treatment 1 (ref) – 1 (ref) – 1 (ref) – 1 (ref) –

LHRH agonist 1.441.34–1.55

<0.001 1.161.10–1.21

<0.001 1.111.01–1.21

0.03 1.161.05–1.27

0.004

Orchiectomy 1.341.20–1.50

<0.001 0.990.91–1.07

0.74 0.940.82–1.09

0.44 1.010.87–1.18

0.85



ref, reference




CV Events over time

Duration of

treatment

(months)


Adjusted

HR

95

CI

p Adjusted HR 95 CI p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

None 1 (ref) – 1 (ref) – 1 (ref) – 1 (ref) –

1–4 1.291.12–1.49 <0.001 1.14

1.04–1.25 0.007 1.12

0.94–1.34 0.19 1.07

0.82–1.28 0.47

5–12 1.451.30–1.61

<0.001 1.191.11–1.28

<0.001 1.230.94–1.31

0.21 1.311.11–1.55

<0.001

13–24 1.541.35–1.76

<0.001 1.111.01–1.22

0.04 1.110.90–1.30

0.42 1.180.91–1.42

0.10

≥25 1.491.30–

1.71

<0.001 1.181.07–

1.30

0.001 1.080.94–

1.29

0.24 1.060.90–

1.26

0.47




ref, reference



CV Events over time

Duration of

treatment

(months)


Adjusted

HR

95

CI

p Adjusted HR 95 CI p

Adjusted

HR

95

CI

p

Adjusted

HR

95

CI

p

None 1 (ref) – 1 (ref) – 1 (ref) – 1 (ref) –

1–4 1.291.12–1.49 <0.001 1.14

1.04–1.25 0.007 1.12

0.94–1.34 0.19 1.07

0.82–1.28 0.47

5–12 1.451.30–1.61

<0.001 1.191.11–1.28

<0.001 1.230.94–1.31

0.21 1.311.11–1.55

<0.001

13–24 1.541.35–1.76

<0.001 1.111.01–1.22

0.04 1.110.90–1.30

0.42 1.180.91–1.42

0.10

≥25 1.491.30–

1.71

<0.001 1.181.07–

1.30

0.001 1.080.94–

1.29

0.24 1.060.90–

1.26

0.47




ref, reference



Discussion point

• Do we need to consider cardiovascular risk

factors when commencing ADT for prostate

cancer?



WHAT IS THE PROGNOSIS FORNEWLY DIAGNOSED HIGH RISK

PROSTATE CANCER?



STAMPEDE Trial

1. Multi-arm multi-stage trials

2. Design of STAMPEDE over time

3. Assessing new agents in hormone-naive

prostate cancer



Setting

• New treatments often not as useful as hoped

• Typical academic Phase III trial

– Years of investment from the key players

– 5 - 10 years from idea to result – Hundreds or thousands of patients

– Hundreds of research staff

– Cost millions in development

• Yet, high chance finding new treatment not better• Opportunity cost in continuing RCT which is not likely to

be “ positive”?



Need Better Strategy For

Selection• What to take into phase III trials?

• Single arm phase II trials aren’t reliable enough

• Need: Test many new promising treatments• Need: Potential to discontinue unpromising arms

• Need: Start to randomise as quickly as possible

Multi-Arm, Multi-Stage trials



ApproachMulti-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III

Multi-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III

Traditional Approach

Phase II

Phase III

T1

C T1

T2

T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2

T3

C T3

T4

C T4



Advantages of MAMS trials1. Fewer patients •Concurrent assessment of agents

•Randomise from start

•One seamless trial

•One protocol Less bureaucracy

2. Less overall time


T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III


Phase II

Phase III

T1

C T1

T2

T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2

T3

C T3

T4

C T4



Advantages of MAMS trials

3. Increased flexibility•Adapts to intermediate results

•Focus on more promising arms


T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III


Phase II

Phase III

T1

C T1

T2

T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2

T3

C T3

T4

C T4



Advantages of MAMS trials

4. Reduced costs •Limited resources for trials•Must use fairly and efficiently


T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III


Phase II

Phase III

T1

C T1

T2

T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2

T3

C T3

T4

C T4





STAMPEDE

• Recruits men from 4 groups starting long-term ADT:1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)

2. Node-positive (N+) prostate cancer

3. Newly-diagnosed metastatic (M1)

4. High risk recurrence post surgery or RT

• Tests addition of further treatments to standard care

• Radical radiotherapy in standard care:

– N+M0 patients; optional – N0M0 patients; optional Oct 2005 – Nov 2011, mandatory

from Nov-2011

27

www.stampedetrial.org



STAMPEDE outcome measures

Outcome Measure

Stage Primary Secondary

Pilot Safety Feasibility

Activity Failure-free survival Overall survival

IntermediateToxicity / safety

(phase II) Skeletal events

Efficacy Overall survival Failure-free survival

Final Toxicity / safety(Phase III) Skeletal events

Quality of life













































Accrual rates increase

Aug-2013:

5454 pts

Past 4m:

140 pts/m

End of pilot phase

Arms D &F close

Arm Gopen

Arm Hopen

Originalresearcharmsclose

Arm Gcloses

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

O c t 0 5

J a n 0 6

J u l 0 6

J a n 0 7

J u l 0 7

J a n 0 8

J u l 0 8

J a n 0 9

J u l 0 9

J a n 1 0

J u l 1 0

J a n 1 1

J u l 1 1

J a n 1 2

J u l 1 2

J a n 1 3

J u l 1 3

J a n 1 4

J u l 1 4

Date of randomisation

Cumulative randomisations overall



Accrual by comparison so far

A = ADT alone (+RT) E = A + docetaxel + zoledronic acid

B = A + zoledronic acid F = A + celecoxib + zoledronic acid

C = A + docetaxel G = A + abiraterone

D = A + celecoxib H = A + RT to the prostate (M1 pts only)



Why add arms to ongoing trial?

1. Can start recruiting quicker than a new trial – Update protocol = simple, substantial amendment

– Scientific review = amendment

2. Efficient use of volunteers

– Patients contribute to more than one comparison

– Reduce competing trials

– Seamless accrual: no gaps between “trials”

3. Efficient use of resources

– Much quicker start-up time: Start at “full speed”

– Much cheaper than separate trial

– Get answers more quickly



Quick start-up times

Ready on activation Suspended until ready

A c t i v a t

i o n d a y

0.0

0.2

0.4

0.6

0.8

1.0

104 98(6) 77(21) 58(19) 47(11) 21(26) 13(8) 13(0) 12(1) 11(1) 7(4) 7(0) 7(0) 7(0) 6(1) 3(3)approval

Sites needing

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Time (weeks) from notifying sites

Timely R&D approval for new protocol

Data from activationof “abirateronecomparison”





Why add arms to ongoing trial?

• Reasonable to update ongoing trial rather than start up anew trial if:

1. Trial going to continue recruiting for some time

2. In same population

3. With same outcome measures

4. In same sites

• Clear advantages

– Practically efficient – Financially efficient

– Avoids competition



Discussion point

• Should we set up “ programmatic” trials and

continually modify a base framework



WHAT IS THE PROGNOSISFOR NEWLY DIAGNOSED

ADVANCED PROSTATE

CANCER?







Impact of node status and radiotherapy on

failure-free survival in patients with newly-diagnosed

non-metastatic prostate cancer: v

Data from >690 patients in the control arm of the

STAMPEDE trial (MRC PR08, CRUK/06/019)

Nicholas James , MR Spears, NW Clarke, MR Sydes, CC Parker,

DP Dearnaley, JM Russell, AWS Ritchie, G Thalmann, JS De

Bono, G Attard, C Amos, MK Parmar, MD Mason and theSTAMPEDE Investigators

60



RT in high-risk M0 prostate cancer

61

• Adding RT to androgen deprivation therapy (ADT)reduces risk of death (by about 50%)

• SPCG7 - node-negative (N0) & largely at lower end of risk

spectrum (max PSA 80)

• PR07 - no mandatory nodal staging, but only for N0 if done;no PSA cap

• Uncertainty about role of RT in pts with:

• N0 PSA>80 disease

• N+ disease

• No RCT of RT in N+M0 patients



STAMPEDE

• Recruits men from 4 groups starting long-term ADT:1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)




• Tests addition of further treatments to standard care

• Radical radiotherapy in standard care:

– N+M0 patients; optional – N0M0 patients; optional Oct 2005 – Nov 2011, mandatory

from Nov-2011

62




Aims

1. Describe prognosis for men with newly-

diagnosed high-risk M0 disease

2. Describe impact of planned radical RT on time to progression

– split by nodal status

63



Primary outcome measures

• Overall survival [definitive]

– Time from randomisation to death from any cause

• Failure-free survival (FFS) [intermediate]

– Time from randomisation to evidence of at least one of:

• Biochemical failure

• Progression: local, lymph nodes, distant metastases• Death from prostate cancer

64



Methods

• Database frozen 01-May-2014

• Cox models to look at effects by node status subgroups

• Models adjusted for other prognostic factors:

– Age at randomisation (<60, 60-64, 65-69, ≥70 years)

– Log-transformed pre-ADT PSA (continuous)

– WHO performance status (0 vs 1&2)

– Initial Gleason sum score category (≤7, ≥8, unknown)

• Subgroup analyses looked at regional lymph nodes – N0 randomised <15-Nov-2011

– N+ randomised >1 year prior to data freeze

65





Newly-diagnosed M0 patients(randomised Oct-2005 to May-2014)

Number of patients 721

Median Age (years) 66 (61-77)

Median PSA pre ADT

(ng/mL)

40% (n=287/721)

Node-positive 74% (n=535/721)

Gleason summary score 8-

1015% (n=110/721)

WHO Performance Status 1-

243 (IQR 18-88)

Planned for RT 75% (n=539/721)

Median follow-up (months) 17 (IQR 6-36)

FFS events 149

Deaths 40

M0 cohort demographics

67



63.3 (IQR 26.4-NR)

0.00

0.25

0.50

0.75

1.00

721 392(7) 273(10) 173(6) 108(6) 46(9) 24(2) 8(0)Death721 345(74) 219(32) 128(18) 69(14) 35(6) 18(3) 3(2)FFS Event

N(risk)

0 12 24 36 48 60 72 84Time from randomisation (Months)

FFS Event Death

Survival & FFS outcomes – M0 cohort

68



Results – Aim 2

• Impact of planned RT on time to progression

• Split by nodal status: – N0 randomised prior to 15-Nov-2011

– N+ randomised at least 1 year prior to data freeze

69





Nodal subgroup demographics

71

Node-negative pts(rand <15-Nov-2011)

Node-positive pts(randomised >1 year)

Number of patients 180 178

Median Age (years) 66 (IQR 60-71) 65 (IQR 60-70)

Gleason summary score 8-10 75% (n=135/180) 75% (n=133/178)

WHO Performance Status 1-2 11% (n=19/180) 13% (n=24/178)

Median PSA pre-ADT (ng/mL) 26 (IQR 58-104) 35 (IQR 15-76)

Planned for RT 67% (n=121/180) 55% (n=98/178)Median follow-up (months) 46 (IQR 35-59) 27 (IQR 19-45)

FFS events 51 67

Deaths 16 22

FFS b RT t t N d ti



FFS by RT status: Node-negative

cohort

72

62% (95% CI 48-73)

87% (95% CI 79-92)

0.00

0.25

0.50

0.75

1.00

121 112(5) 101(3) 61(6) 37(5) 19(2) 8(0) 0(0)+RT59 48(11) 39(8) 29(3) 13(4) 4(3) 2(1) 2(0)-RT

N(risk)

0 12 24 36 48 60 72 84Time from randomisation (months)

-RT +RT

N0 Planned radical RT status





47% (95% CI 33-59)

71% (95% CI 58-81)

0.00

0.25

0.50

0.75

1.00

98 75(14) 42(4) 23(4) 10(2) 7(1) 4(2) 0(0)+RT80 54(18) 29(13) 15(4) 9(3) 5(0) 4(0) 1(2)-RT

N(risk)


-RT +RT

N+ Planned radical RT status

FFS by RT status: Node-positive cohort

74



47% (95% CI 33-59)

71% (95% CI 58-81)

0.00

0.25

0.50

0.75

1.00

98 75(14) 42(4) 23(4) 10(2) 7(1) 4(2) 0(0)+RT80 54(18) 29(13) 15(4) 9(3) 5(0) 4(0) 1(2)-RT

N(risk)


-RT +RT

N+ Planned radical RT status

FFS by RT status: Node-positive cohort

75

HR 0.51

(95% CI 0.31-0.84)

Note – landmark analysis of patients FFS event-free at 6m =



• Survival better than anticipated at trial inception in 2005

– In M0, control arm patients

• Effect of RT in N0M0 patients consistent with effect seen

in previous large RCTs

• Effect of RT in N+ patients similar to effect in N0 patients

• Strongly supports routine use RT in node-positive

prostate cancer – How best to administer?

ND James et al Proc ASTRO 2014.

Conclusions

76



Discussion point

• Should all cN+ patients be offered radical

RT?



STAMPEDE

• Recruits men from 4 groups starting long-term ADT:

1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)




78


Key Trial Eligibility Criteria:



Stampede

M1 controlarm

outcomes

ND James et al Eur Urol 2014, in

press

Key Trial Eligibility Criteria:

High risk newly-diagnosed non-metastatic node-negative disease

OR

Newly-diagnosed metastatic or node-positive disease

OR

Previously treated with radical surgery and/or radiotherapy, nowrelapsing

AND Fit for all protocol treatment and follow-up

Allocated to control arm

N=1,716

Allocated to research arms

N=3,556

Metastatic

N=976

Non-

metastatic

N=740

Randomised by 07-Jan-

2014

N=5,272

Newly-diagnosed

N=929

Rapidly relapsing

after previoustreatment

N=47

Diagnosed morethan

6 months prior to

randomisation

N=12

Included in

these

analysesN=917



St d M1 t l



Stampede M1 control

arm FFSTop left

• Metastatic site – bone vs

soft tissue vs both

Top Right

• Gleason score: up to 7 vs

8 or more

Bottom Left

• Performance status: 0 vs 1

or 2

Bottom Right

• Age: <60 vs 60-64 vs 65-

69 vs 70 or more



Time to subsequent therapy from



Time to subsequent therapy from

first FFS event

0.00

0.20

0.40

0.60

502 238 88 31Abiraterone502 205 83 27Bisphosphonate502 154 53 18Chemotherapy

Number at risk

0 12 24 36Time from FFS event (Months)

Chemotherapy Bisphosphonate Abiraterone

ND James et al Eur Urol 2014, in press



CASTRATE REFRACTORYPROSTATE CANCER



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)



EU/US Approvals in CRPC

US approvals

EU approvals

Enzalutamide

(post chemotherapy)2

Abiraterone*

(chemotherapy-naive-302)9

Radium-2232

Enzalutamide

(post chemotherapy)8

Docetaxel4

Abiraterone*

(chemotherapy-naive-302)3

Sipuleucel-T2

Abiraterone*

(post-chemotherapy-301)2

Cabazitaxel2 Docetaxel (1995)2

Radium-22310

20052004 2006 2007 2008 2009 2010 2011 2012 2014 20152013

Enzalutamide

(chemotherapy naive)11

Abiraterone*

(post-chemotherapy-301)7

Cabazitaxel6

Sipuleucel-T5







CRPC treatment 2010-2011

• Clinical trial

• Observation

•

2nd-line hormone Rx*

No metastases

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

Symptomatic

• Docetaxel

• Clinical trial

• Cabazitaxel

• 2nd-line hormone

Rx*

Metastases

Asymptomatic

Mottet et al. Eur Urol 2011;59:572 – 83. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v129 – 33. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical Guideline 58)

2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:1771 – 5. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011. http://www.nccn.org. Miller et al.

Aktuelle Urologie. 2006;37:201 – 4.







Abiraterone











COU 302 T i l



COU-302 Trial

98

COU-302 Progression Free and



Overall Survival

99

Progression Free Survival Overall Survival

Statistically significant survival benefit with



Statistically significant survival benefit with

abiraterone + low-dose prednisolone reached at final

analysis

• Median follow up of 49.2 months• Abiraterone treatment effect more pronounced when adjusting for 44% of placebo + low-dose

prednisolone patients who crossed over to abiraterone + low-dose prednisolone (HR=0.74)

100

80

60

40

20

0

0

O S ( % )

9 21 30 48 6039

546

542

525

509

422

401

296

261

59

42

0

0

202

148

Time to death (months)

24123 36 45 54

538

534

453

438

359

322

189

132

15

10

HR (95% CI): 0.81 (0.70 –0.93)

P value: 0.0033

Placebo + low-dose prednisolone, 30.3 months

6 15 18 27 33 42 51 57

0

1

118

84

218

176

504

493

483

466

394

363

330

292

273

227

235

201

FA

CI: confidence interval; FA: final analysis; HR: hazard ratio; OS: overall survival.



B i i



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 cancer – associated 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 marrow

microenvironment

1

RANKL

PTHrP

IL-6

PGE2

TNF

M-CSF

BMP

PDGF

FGFs

IGFs

TGF-β

Radium-223



• Alpharadin is Ra-223 salt in solution

• Acts as a calcium mimic:

– a natural bone-seeker

– targets new bone growth in and

around metastases

– incorporated into bony matrix

• Emits alpha-particles that induce primarily non-reparable, double strand DNA

breaks in adjacent tumour cells

Targets new bone in metastases Irradiates adjacent tumour cells

Bone marrowTumor

cells

Osteoclast

Osteoblast

Newlyformed

bone

Radium-223deposition

Alpha

particleradiation

Alpharadin uptake and elimination



• Cleared rapidly, directly into gut (no apparent hepatobiliary excretion)

• Spares kidney – radiation dose low

Baseline Day 2 Day 6

99m Tc - MDP 223 Ra Imaging

based on

Al t i l



Alsympca trial





Bone events



Clinical effectiveness of strontium-89 and

zoledronic acid in patients with castrate-refractory prostate cancer (CRPC) metastatic

to bone receiving docetaxel (TRAPEZE)

Nick James

On behalf of

Sarah Pirrie, Darren Barton, Janet Brown, Lucinda

Billingham, Stuart Collins, Adam Daunton, Alison Birtle,

Prabir Chakraborti, Daniel Ford, Syed Hussain, Helen Jones, Ann Pope, Emilio Porfiri, Martin Russell, Andrew Stanley,

John Staffurth, Duncan McLaren, Chris Parker, James Wylie

and the TRAPEZE trial investigators

Phase III Study treatments



Phase III Study treatments

docetaxel +

prednisolone(cycles 1-6)

Sr89 150

MBq(day 28 cycle 6)

A

B

C

D

+ 28 Days*

docetaxel + prednisolone + ZA(cycles 7-10)

+ 28 Days*

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

progression.

Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od(cycles 1-10)

docetaxel +

prednisolone +

ZA(cycles 1-6)

docetaxel +

prednisolone(cycles 7-10)

Sr89(day 28 cycle 6)

* At least 28 days

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

SRE Free Interval: ZA comparison



SRE Free Interval: ZA comparison

Presented by: Nick James



Total Skeletal Related Events bytype



type


Sr89 comparison

No Sr89 Sr89

ZA comparison

No ZA ZAN (%) N (%) N (%) N(%)

Symptomatic pathological

fractures16 18 23 11

Spinal cord or nerve root

compression39 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 pain16 12 17 11

Hypercalcaemia 0 2 2 0

Other 1 1 0 2

Total 399 349 449 299



Conclusions – TRAPEZE trial




• ZA significantly increased SRE free interval

and decreased total SRE numbers, mostly

post-progression

• ICER and net acquisition costs favourable

• No impact on overall survival

Dicussion point



p

•

What is role of bone protection agents withincreasing numbers of active anti-cancer

agents?

Presented by:

CRPC treatment early 2013



CRPC treatment early 2013

• Clinical trial

• Observation

• 2nd-line hormone Rx*

No metastases


Symptomatic

• Abiraterone

• Docetaxel

• Docetaxel

• Or

• Abiraterone

• Or

• Enzalutamide

Metastases

Asymptomatic

• Cabazitaxel

• Or

• Enzalutamide

• Or

• Abiraterone

CRPC treatment late 2013 2014



CRPC treatment late 2013-2014

• Clinical trial

• Observation


No metastases


Symptomatic

• Abiraterone

• Docetaxel

• Docetaxel

• Or

• Abiraterone

• Or

• Enzalutamide

Metastases

Asymptomatic

• Cabazitaxel

• Or

• Enzalutamide

• Or

• Abiraterone

• Radium-223

PREVAIL trial



PREVAIL trial

• Randomized, double-blind, placebo-controlled,multinational phase 3 study in chemotherapy-naive

patients with mCRPC

• randomized 1:1 to enzalutamide 160 mg/day or placebo.

• OS and rPFS co-primary endpoints

• Planned sample size 1,680 with 765 deaths toachieve 80% power to detect a target OS hazard

ratio (HR) of 0.815

118

Kaplan – Meier Estimates of Radiographic Progression-free Survival and Overall Survival.

PREVAIL trial



Beer TM et al. N Engl J Med 2014;371:424-433.

CRPC treatment late 2014



CRPC treatment late 2014

• Clinical trial

• Observation


No metastases


Symptomatic

• Abiraterone

• Docetaxel

• Enzalutamide

• Docetaxel

• Or

• Abiraterone

• Or

• Enzalutamide

Metastases

Asymptomatic

• Cabazitaxel

• Or

• Enzalutamide

• Or

• Abiraterone

• Radium-223



CAN WE PREDICT RESPONSE

TO NEW HORMONE

THERAPIES?



Resistance to Enzalutamide

Presented By Emmanuel Antonarakis at 2014 ASCO Annual Meeting



Full-Length AR (AR-FL)






Progression-Free Survival (Enzalutamide)




Prevalence of AR-V7 in CRPC (n=62)


Di i i t



Discussion point

• Do these mutations also predict response to

other therapies – how to test?



Timing of chemotherapy – ADT



g py

vs ADT + Docetaxel

• Important results presented

– CHAARTED – High risk M1

– GETUG-12 – High risk M0• Previously published

– GETUG-15 – M1- positive for PFS, negative

for OS




g py

vs ADT + Docetaxel

• Important results presented at ASCO 2014

– CHAARTED – High risk M1- Positive for OS

– GETUG-12 – High risk M0 – borderline forPFS, negative for OS

• Previously published• GETUG-15 – M1- borderline positive for PFS, negative

for OS

• Awaited - STAMPEDE



E3805 – CHAARTED Treatment

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting



Primary endpoint: Overall survival




Causes of Death




OS by extent of metastatic disease at start of ADT




Therapy beyond progression





g py

vs ADT + Docetaxel• Consensus view of STAMPEDE :

– “On review of all data, we recommended that the STAMPEDE

trial would best serve patients and the oncology community by

keeping to its original analysis plan and generating mature, robust

and reliable data.”

– On track for analysis Q2 2015

– No current case for change in M0

– GETUG 15 and CHAARTED results should be discussed with

relevant patients

Conclusions



Conclusions

• Treatment options are rapidly changing across the

whole spectrum

• Much of current sequencing driven by timing

rather than science

Prostate Cancer Talk Swedish Urooncological Society Oct 2014

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