presentación de powerpoint€¦ · hussain m et al. oral presentation, asco, chicago, 3 june 2012...

Prostate Cancer Standard of Practice in 2018

and future directions

Eleni Efstathiou MD PhD

Disclosures – Eleni Efstathiou

Research Support/P.I.Janssen-Cilag, Sanofi-Aventis,

Astellas/Medivation

Employee NA

ConsultantJanssen-Cilag, Sanofi-Aventis,

Astellas/Medivation. Oric

Major Stockholder NA

Speakers Bureau NA

Honoraria Janssen-Cilag, Sanofi-Aventis

Scientific Advisory BoardJanssen-Cilag, Sanofi-Aventis, MSD, Viamet,

Takeda, Tokai, Bayer

Presentation includes discussion of the off-label use of a drug or drugs(depending on country of origin)

‘Discovery is our Business’

Charles Huggins (1902-1997)

Nobel Prize in Medicine 1966

1.Local disease treatment

2.Biochemical Recurrence

3. Metastatic Diseasehormone naive (HNPC)

castrate resistant (CRPC)

A Medical Oncologist should be the “coordinator”

We care for the Man not the cancer :

keeping him healthy against the odds of ADT and other treatmentsProviding coaching for diet exercise well being Information Clarity are paramount .

M F. Berger et al. Nature 470, 214-220 (2011) doi:10.1038/nature09744

Graphical representation of seven prostate cancer genomes

Prostate Cancer Heterogeneityhas not been addressed

Pathology dictated by Morphology

Gleason Grade and Score

(STILL!!)

Tips to remember: Gleason Scoring differs Between biopsy and Prostatectomy specimen Gleason Scoring does notapply when Androgen

Deprivation is used Cribriform / intraductal spreadAssociated with more aggressive Disease

Hormone Naïve Prostate Cancer

Chemotherapy

Tum

or

volu

me

& a

ctiv

ity

1.De Novo Metastatic2. Biochemical Recurrence

3. Recurrent Metastatic Hormone Sensitive

Intermittent ADT (IAD) is non inferior to Continuous (CAD) in Biochemical Recurrence

Crook et al NEJM 2012

Causes of Death

Crook et al NEJM 2012More PCa related deaths in IAD arm

Hussain M et al. Oral presentation, ASCO, Chicago, 3 June 2012

Overall conclusion: in mHNPCIAD is NOT non inferior compared to CAD

Hussain et al NEJM 2014

Progress Report 2014-2017Three practice changing years in Hormone Naive Prostate Cancer

To date the biggest impact in survival

exhibited

1. The reemergence of Chemotherapy (2 positive / 1 negative trial)

2. Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum (2 positive trials)

GETUG 15ADT-docetaxel: 60.9 m ADT alone: 46.5 m p = 0.44

Gravis, et al. Lancet Oncology 2015 12

Upfront Use of Chemo in Hormone Sensitive Metastatic Disease

Failed Attempt 1 : GETUG 15

GETUG15 The first trial in HSPC testing Docetaxel A negative Trial

Successful Attempt 2 :CHAARTED

Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2)Sweeney C J et al. N Engl J Med. 2015;373(8):737–46.

Patient Characteristics

• Diagnosis of prostate cancer with metastatic disease

• ECOG PS 0-2• Prior adjuvant ADT was allowed

if the duration o ≤24 months and progression >12 months after completion

• Patients receiving ADT for metastatic disease were eligible if no evidence of progression and treatment commenced ≤120 days before randomization

Stratification• Extent of metastasis: high volume vs low volume*• Age: ≥70 vs <70 years• ECOG: 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

D

1

:

1

ARM AADT + Docetaxel 75 mg/m2

21 days for maximum 6 cycles

ARM BADT (androgen deprivationtherapy alone)

Evaluate every 3 weeks whilereceivingdocetaxel and atweek 24 thenevery 12 weeks

Evaluate every 12 weeks

Follow up for time to progression andoverall survival

Chemotherapy atinvestigator’sdiscretion atprogression

Phase 3, multicenter, open label study

(N = 790)

• ADT allowed up to 120 days prior to randomization• Intermittent ADT dosing was not allowed• Standard dexamethasone premedication but no daily prednisone

*At study start only pts with high volume disease were to be enrolled. Study was amended to also include patients with low-volume disease.

CHAARTED Overall Survival

High Volume:

>=4 bone mets at least 1

Outside axial skeleton

Or /and visceral mets

All Patients

p=0.0006HR=0.60 (0.45-0.81)Median OS: ADT + D: 49.2 monthsADT alone: 32.2 months

Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2)Sweeney C J et al. N Engl J Med. 2015;373(8):737–46.

Hazard Ratios for Death in Subgroups.

Sweeney CJ et al. N Engl J Med 2015;373:737-746

Sweeney CJ et al. N Engl J Med 2015;373:737-746

CHAARTED: Overall QoL on FACT-P

Patrick-Miller al. J Clin Oncol 2016;34(suppl): abstract 5005

Of interest the final improvement of qol for ADT +Docetaxel: dual interpretation …

E-3805 CHAARTED UPDATEDSURVIVAL POINTS TO HETEROGENEITY

First data (NEJM 2015) Updated data (ESMO 2016)

HR=0.60 (95%CI 0.32-1.13)HR=1.04 (95%CI 0.70-1.55)

Hig

h v

olu

me d

isease

Low

volu

me d

isease

HR=0.60 (95%CI 0.45-0.81) HR=0.63 (95%CI 0.50-0.79)

Sweeney et al #720

Updated Survival Analysis :

Low Volume mHNPC

Does not derive benefit from

Addition of Docetaxel

Attempt 3 : STAMPEDE

Nicholas JamesUniversity of Warwick and Queen Elizabeth Hospital Birmingham on behalf of

Matthew Sydes, Malcolm Mason, Noel Clarke, David Dearnaley, Melissa Spears, Robin Millman, Chris Parker, Alastair Ritchie, J. Martin Russell, John Staffurth, Robert Jones, Shaun Tolan, John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison Birtle, Joe O'Sullivan, Richard Cathomas, Mahesh Parmar and the STAMPEDE Investigators

Lancet dec 21 2015

Docetaxel & ZA comparisons: patients

Docetaxel: SurvivalSOC 405 deathsSOC+Doc 165 deaths

HR (95%CI) 0.76 (0.63, 0.91)P-value 0.003

Non-PH p-value 0.51

Median OS (95% CI)SOC 67m (60, 91m)SOC+Doc 77m (70, NR)

Restricted mean OS timeSOC 58.8m SOC+Doc 63.4mDiff (95%CI) 4.6m (1.8, 7.3m)

21

2015 Standard of care for men with mHNPCADT + Docetaxel

21

1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746; Sweeney C, et al. Ann Oncol. 2016;27(Suppl 6):243-265. 3. James N, et al. Lancet. 2016;387:1163-1177. and Vale C, et al. Lancet Oncol2016;17:243-256.

62.1 48.60.88 (0.68-

1.14)0.3

57.6 47.20.73 (0.59-

0.89)0.0018

60 450.76 (0.62-

0.92)0.005

ADT + DOC

ADT

Median

(mos)

Median (mos)

HR (95% CI) P Value

GETUG-151

CHAARTED2

STAMPEDE3

Overall

Survival

Docetaxel in mHNPC

Conclusions & Questions

Conclusions : PRACTICE SHAPING

Docetaxel exhibits an overall survival benefit in hormone

sensitive metastatic disease in two studies and does not in one

Docetaxel added to ADT in hormone naïve metastatic disease

with “high volume” prolongs survival (CHAARTED)

De novo metastatic disease derives consistent benefit in both

positive studies

Marrow Toxicity remains a concern

Questions

• Is there meaningful benefit in low volume disease?

• How do we objectively select men who will benefit?

• Subsequent access to treatment important

• How do we address the ~20% of highly aggressive disease not

benefiting

Mechanisms of resistance to ADT may develop early1-3

ADT does not inhibit adrenal or intracrine/ paracrine androgen synthesis; inhibits testicular synthesis but less profoundly than abiraterone

A more robust ‘wild type’ androgen signaling driver of disease Abiraterone + Prednisone

improves OS in mCRPC4,5

reduces tumor burden in high-risk, localized PC6,7

These data suggest a potential role for inhibiting extragonadal androgen biosynthesis prior to the emergence of castration resistance

23

Rationale for Abiraterone added to ADT in mHNPC

1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746. 3. James N, et al. Lancet. 2016;387:1163-1177. 4. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 5. Ryan CJ, et al. Lancet Oncol. 2015;16:152-160. 6. Taplin ME, et al. J Clin Oncol. 2014;32:3705-3715. 7. Efstathiou E, et al. J Clin Oncol. 2015;33(suppl):15s. Abstract 5061.

Tumor Cell Density (%)

P < 0.0001 P < 0.0001

Tumor Epithelium Volume: Tumor Cell Density × Volume

Tumor Volume (cc)

P = 0.003

Efficacy end points

Co-primary:

• OS

• rPFS

Secondary: time to

• pain progression

• PSA progression

• next symptomatic

skeletal event

• chemotherapy

• subsequent PC therapy

ADT

+ Abiraterone acetate 1000

mg QD

+ Prednisone 5 mg QD

(n = 597)

ADT

+ placebos

(n = 602)

Patients

• Newly diagnosed adult

men with high-risk

mHNPC

Stratification factors• Presence of visceral

disease (yes/no)

• ECOG PS (0, 1 vs 2)

RANDOMIZED

1:1

• Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada

• Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results

LATITUDE Study Design

Fizazi et al NEJM 2017

Treatment arms: GS >=8 and bone lesions main criteria

ADT + AA + P(n = 597)

ADT + Placebos(n = 602)

Median age, years (range) 68.0 (38-89) 67.0 (33-92)

Gleason score ≥ 8 at initial diagnosis

98% 97%

Patients with ≥ 3 bone metastases at screening 98% 97%

Extent of diseaseBoneLiverLungsNode

97%5%

12%47%

98%5%

12%48%

Baseline pain score (BPI-SF Item 3)

0-12-3≥ 4

50%22%29%

50%24%27%

FFizazi et al NEJM 2017Fizazi et al NEJM 2017

Latitude: 38% risk reduction of death

0

0 6 12 18 24 30 36 42

20

40

60

80

100

Months

Ov

era

ll S

urv

ival (%

)

No. at risk

ADT + AA + P 597 565 529 479 388 233 93 9

602 564 504 432 332 172 57 2

Hazard ratio, 0.62 (95% CI, 0.51-0.76)

P<0.0001

ADT + AA + P, not reached

ADT + placebos, 34.7 mo

ADT + placebos

OS rate at 3 years:ADT + AA + P: 66%ADT + placebos: 49%

No. of events: 406 (48% of 852)

ADT + AA + P: 169

ADT + placebos: 237

Median follow-up: 30.4 months


53% risk reduction of radiographic progression or death

0

20

40

60

80

100

Pro

gre

ssio

n-F

ree S

urv

ival (%

)

0 4 8 12 16 2420 28 32 36 40

Months

No. at risk

ADT + AA + P 597 533 464 400 353 316 251 177 102 51 21

602 488 367 289 214 168 127 81 41 17 7

No. of events

ADT + AA + P: 239

ADT + placebos: 354

Hazard ratio, 0.47 (95% CI, 0.39-0.55)

P<0.0001

ADT + AA + P, 33.0 mo

ADT + placebos, 14.8 mo

ADT + placebos

27Fizazi et al NEJM 2017

ADT + AA + P

(n = 597)

ADT + placebos(n = 602)

n (%) n (%)

Patients eligible*n = 314 (53%)

n = 469 (78%)

Patients who received life- prolonging therapy

125 (40) 246 (52)

Docetaxel 106 (34) 187 (40)

Enzalutamide 30 (10) 76 (16)

AA-P 10 (3) 53 (11)

Cabazitaxel 11 (4) 30 (6)

Radium-223 11 (4) 27 (6)

*Patients who discontinued treatment and were eligible for subsequent therapy.

Subsequent life-prolonging therapy for prostate cancerNot enough AA on control arm?


Docetaxel & ZA comparisons: patients

Trial includes localised and M1 HSPCLocalised receive AA for 2years

STAMPEDE ARM G REPORT 2017

30

STAMPEDE Patient characteristics

1% WHO PS 2 [s]

21% WHO PS 1 [s]

67yr Median age [s](min 39, max 85)

52% Metastatic [s](88% Bony mets)

20% N+M0

28% N0M0

99% LHRH analogues [s]

41% Planned for RT [s](96% of N0M0 pts; 62% of N+M0 pts)

5% Previous local therapy

Balanced by arm

James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session

James et al NEJM 2017

Events262 Control | 184 abiraterone plus prednisone

HR 0.6395% CI 0.52 to 0.76P-value 0.00000115

SOC

SOC+AAP

OS – STAMPEDE “abiraterone plus prednisone comparison”


This represents a 37% improvement in survival


HR 0.2995% CI 0.25 to 0.34P-value 0.377x10-61

Events535 Control | 248 abiraterone plus prednisone

SOC

SOC+AAP

Failure Free Survival – STAMPEDE


This represents a 71% improvement in time to failure


Subsequent TreatmentsMore Frequent use of Docetaxel post AA

and limited use of AA in ADT arm


Abiraterone in 2017Conclusions : PRACTICE SHAPING

Abiraterone added to ADT in “high risk” hormone naïve

metastatic disease prolongs survival (LATITUDE)

Abiraterone exhibits an overall survival benefit in hormone

sensitive metastatic disease in two studies

De novo metastatic disease derives consistent benefit in both

positive studies

No new safety concerns with the use of Abiraterone

Questions

• Is the observed benefit based only on “biology” or “window of

opportunity?” as well : Consistently who gets more does better

• Is there meaningful benefit in ‘low risk’ and M0 disease?

• How do we objectively select men who will benefit from one of

the other agent?

• How do we address the ~20% of highly aggressive disease not

benefiting with either choice

Decision Making in mHNPCDocetaxel (6cs)

Low Cost

High Volume CHARTEED definition

Abiraterone acetate with consistent long term monitoring

androgen signaling driven biology is dominant

Fear of chemo frailty

The ‘Breast Cancer’ Model albeit without the molecular classification

Docetaxel 6cs followed by Abiraterone Acetate : TOO EARLY

BUT : Monitor Closely

Patients on both agents lived longer consistently on all trials

Different Mechanism of Action

Particularly High Volume disease may warrant more aggressive approach

High risk LATITUDE definition (majority) to be distinguished from High Volume CHARTEED definition: High volume is a subset of high risk

ADT

A minority of men with slowly progressive disease (eg gleason 7 but no tertiary 5)

Heart failure and comorbidities limiting survival

Strong evidence favouring AA+P

Toxicity profiles quite different and well known

Weak evidence favouring AA+P

No good evidence of a difference in OS

FavoursADT+AA+P

FavoursADT+DOC

Hazard ratio

Metastatic progression-free

survival

Progression-free survival

Failure-free survival

Symptomatic skeletal events

Cause-specific survival

Overall survival

Head-to-head data in 566 pts (Nov-2011 to Mar-2013)

Proportionately different time spent in each disease state

STAMPEDE points to “Equivalence” Is it a loss vs gain – balance

AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel

Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017 Sydes et al Annals of Oncology

Conclusions for now…HNPC treatment options

Intermittent ADT a valid option for biochemical recurrence of m0 HNPC

Continuous vs Intermittent ADT preferred for m HNPC

Six Cycles of Docetaxel 75mg/m2 or Abiraterone Acetate (continuously) combined with ADT recommended for m HNPC patients

Prostate Cancer Treatment Paradigm

in 2010

Local

therapy

Androgen deprivation

therapy (ADT)

Therapies after

ADT

Death

ADT

mCRPC

post-

docetaxel

mCRPC

symptomatic

mCRPC

mildly

symptomatic

mCRPC

asymptomatic

(failed ADT)

Hormone

sensitive

Docetaxel

A New Therapy landscape in ‘Advanced Prostate Cancer ‘

(2018)Death

ADT

supportive care

(denosumab/bisphosphonates)

Advanced metastatic Prostate Cancer

Hormone

Sensitive

Prostate Cancer

Localized / Metastatic

Sipuleucel-T

Abiraterone

Docetaxel Cabazitaxel

Radium 223

Enzalutamide

mHSPC

ADT +

Docetaxel

mHSPC

ADT +

Abiraterone

Apalutamide

Please see Important Safety Information throughout this presentation.Please see full Prescribing Information available at this presentation.

Non-Metastatic CRPC : Is this a real disease state?

40

Certain patients with prostate cancer receiving ADT will eventually develop

castration-resistant disease.1,2 Patients with CRPC who present with:

No evidence of detectable metastasis3

Non-metastatic3

or M0 CRPC4Rising PSA*

while on ADT3

Serumtestosterone levels

below 50 ng/dL3

No evidence of detectable metastases with convenitonal imagingnmCRPC includes local recurrence prostate bed + pelvic nodes

Please see Important Safety Information throughout this presentation.Please see full Prescribing Information available at this presentation.

• Apalutamide is an AR inhibitor that binds directly to the ligand-binding domain of the AR1

• Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription1

Apalutamide Mechanism of Action

41

Metastasis-Free Survival in nmCRPCimproved with Apalutamide

Apalutamide

Apalutamide+ ADT

FDA Approval on Valentine ‘s Day 2018

Proposed Treatment Algorithms for mCRPC reflective of lack of precision

NCCN Guidelines v2 2016; http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

Matthew R. SmithUS

Hideyuki AkazaJP

Gerhardt AttardUK

Tomasz M. BeerUS

Himisha BeltranUS

Arul M. ChinnaiyanUS

Johann De BonoUK

Charles G. DrakeUS

Rosalind A. EelesUK

Eleni EfstathiouUS

Stefano FantiIT

Karim FizaziFR

Silke GillessenCH

Susan HalabiUS

Axel HeidenreichDE

Maha H.A. HussainUS

Christopher J. Logothetis

US

Peter NelsonUS

William K. OhUS

Anwar PadhaniUK

Nicholas D. James

UK

Chris ParkerUK

Mark A. RubinUS

Oliver A. SartorUS

Jack A. SchalkenNL

Howard I. ScherUS

Avishay SellaIL

Neal ShoreUS

Eric SmallUS

Cora N. SternbergIT

Hiroyoshi SuzukiJP

Christopher SweeneyUS

Martin E. GleaveCA

Ian TannockCA

FrédéricLecouvetBE

Bertrand TombalBE

David OlmosES

Gedske DaugaardDK

Maria De SantisAT

Sten NilssonSE

Ian DavisAU

urologist medical oncologist othersradiation oncologist

APCCC St Gallen MeetingOffering Guidance

Therapeutic agents for “Advanced Prostate Cancer”/mCRPC

Trial Regimen Pts HR NSurvival

(months)Delta

(months)

IMPACT1 Sipuleucel-T CRPC 0.78 512 25.8 vs 21.7 4.1

TAX 3272 Docetaxel+Prednisonevs Mitoxantrone+Prednisone

CRPCChemonaive

0.76 1006 18.9 vs 16.5 2.4

TROPIC3 Cabazitaxel+Prednisonevs Mitoxantrone+Prednisone

CRPCPost-docetaxel

0.70 755 15.1 vs 12.7 2.4

COU-AA-3014 Abiraterone +Prednisone vs Prednisone

CRPCPost-docetaxel

0.74 1195 15.8 vs 11.2 4.6

ALSYMCA5 Alpharadin vs Placebo

CRPC 0.695 809 14.0 vs 11.2 3.6

AFFIRM6 Enzalutamidevs Placebo

CRPCPost-docetaxel

0.63 1199 18.4 vs 13.6 4.8

1. Kantoff PW et al. N Engl J Med 2010;363:411-22.2. Tannock IF et al. N Engl J Med 2004;351:1502-12.

3. de Bono JS et al. Lancet 2010;376:1147-54.

454. Fizazi K et al. Lancet Oncol 2012.5. Parker C et al. ASCO 2012 (LBA 4512).6. Scher H et al. N Engl J Med 2012;367:1187-97.

Survival prolongation on average 3.5 months!

Docetaxel in Metastatic Castrate Resistant Prostate Cancer

Tannock et al NEJM 2004

1Heinlein CA et al. Endocr Rev. 2004;25(2):276-308 2Hu R et al. Expert Rev Endocrinol Metab. 2010;5(5):753-764

PI3K/AKT/ERK/mTOR

PI3K/AKT/ERK/mTOR

NUCLEUS

AR

T/DHT

Androgen production by adrenal glands

and prostate tumor2

AR overexpression2

AR splice variants2

AR mutants2

Signaling cross-talk1,2

Upregulation of AR cofactors1,2

Up to 80% of CRPCs elevated AR gene copy number, 30% high-level amplification of the geneAR mutations common10-30% of the CRPC treated with antiandrogens

CRPC Remains Driven by Androgen Receptor Signaling – AR Alterations Selected During Therapy

Abiraterone Acetate: Androgen Biosynthesis Inhibitor

Μechanism of Action

Tip : Endocrine Side Effects

Low-dose steroid replacement minimizes mineralocorticoid-related

toxicity- NOT SUPRAPHYSIOLOGIC DOSING

Enzalutamide : Antiandrogenmechanism of action

Enzalutamide is an AR signalling inhibitor that inhibits AR signalling in three distinct ways:

DHT

1. Blocks AR binding 3. Blocks DNA binding and activation

EnzalutamideEnzalutamide AR

Cytoplasm Nucleus

2. Impairs nuclear translocation

Enzalutamide

Tran et al. Science 2009;324:787–90; Watson et al. Proc Natl Acad Sci USA 2010;107:16759–65.AR, androgen receptor; DHT, dihydrotestosterone

TIP: Crosses brain blood barrier

Centrally driven adverse event profile; fatigue

Steady State 28 day

COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC post docetaxel

De Bono et al. N Engl J Med.

21

HR = 0.646 (0.54-0.77) P < 0.0001

Placebo: 10.9 months (95% CI: 10.2-12.0)

Abiraterone acetate: 14.8 months (95% CI: 14.1-15.4)

100

80

60

40

20

Surv

ival

(%

)

00 3 6 9 12 15 18

Placebo

AA

Time to Death (Months)

CRPC, castrate resistant prostate cancer.

FDA Approved Apr 28, 2011EMEA Approved Sep 2011

Median age: 69 yrs≥ 75 years: 28%

Tip PSA increase should be a trigger for further evaluation but not discontinuation

AFFIRM Enzalutamide Improves Overall Survival in Metastatic CRPC post docetaxel

HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death

MDV3100: 18.4 months (95% CI: 17.3, NYR)

Placebo: 13.6 months (95% CI: 11.3, 15.8)

Surv

ival

(%

)100

80

60

Enzalutamide 800 775 701 627 400 211 72 7 0

Placebo 399 376 317 263 167 81 33 3 0

40

20

90

50

30

0

10

70

Scher et al NEJM 2012

FDA Approved Aug 2012EMA Dec 2012

Targeting Androgen Signaling Earlier Two large trials in line in chemo naïve

mCRPC : Both positive100

80

60

40

20

00

Ove

rall

Surv

ival

(%

)

9 21 30 48 6039Time to Death (Months)

24123 36 45 54

HR (95% CI): 0.81 (0.70-0.93)

p Value: 0.0033

Prednisone, 30.3 mos

Abiraterone, 34.7 mos

6 15 18 27 33 42 51 57

Ryan et al. NEJM 2014, Beer et al NEJM 2014

Su

rviv

al

(%)

60

50

40

30

20

10

0

90

80

70

100

0 3 6 9 12 15 18 21 24 27 30 33 36

Enzalutamide

Placebo

HR: 0.706 (95% CI: 0.60,0.84)P<0.0001

Placebo: 30.2 (95% CI 28.0, NYR)

Enzalutamide: 32.4

(95% CI 30.1, NYR)

Alpharadin Mechanism of action: microenvironment targeting?

Bonemarrow

Tumor

Range ofalpha particle(small volume)2-10 cell diameter

Minimal damage to surrounding bone marrowand tissue

BoneBone

surface

Radionuclide

Alpharadin increases Overall Survival in mCRPCpatients ineligible for or who refused chemo

Parker et al Lancet 2013Median Age

70

How to Train your Immune system…

Sipuleucel –T improves overall survival in mCRPC

Tips : No PSA response no rPFS improvement anticipatedSub-analysis in favor of prechemo – smaller volume disease with “stability”FYI two large ipilimumab trials negative in mCRPC Small et al 2010

Median age: 68 yrs≥ 75 years: 18%

TROPIC: Cabazitaxel improvesoverall survival vs Mitoxantrone in

post docetaxel mCRPC

De Bono et al. Lancet, 2010, 376:1147-54

Pro

po

rtio

n s

urv

ivin

g (%

)

100

80

60

40

20

0

Mitoxantrone

Cabazitaxel

0 6 12 18 24 30

28%

17%

Time (months)

HR 0.70 (95% CI 0.59–0.83)p <0.0001

FIRSTANA:

Overall survival no difference

Sartor et al. J Clin Oncol 2016

Conclusion : Cabazitaxel not superior to docetaxel in first line mCRPCCabazitaxel 20mg/m2 less toxic than 25mg/m2

FDA issued new dosing instruction : 20mg /m2 in 2017

Supportive Treatmentfor bone mCRPC

Bone HealthVit D (+Calcium) – a mandate for PCa patients

Zoledronic acid 4mg iv q 3-4 wks vsDenosumab 120mg /q 4wks

Both only approved for mCRPC in such regimen

Denosumab vs zoledronic acid in mCRPC

SIOG recommendations for senior men

Treatment recommendations for older men with prostate cancer should be based:

• health status (mainly driven by comorbidities)

• patient preferences

NOT on chronological age!!!

Droz JP et al, Lancet Oncology. 2015,

Treatment should be adapted tohealth status

Standard

treatment

Geriatric

intervention

• ‘Fit’: Same treatment as younger patients≈ 50% of men 70–75 years ≈ 25% of men 80–85 years

• ‘Vulnerable’: Geriatric intervention then standard treatment

• ‘Frail’: Geriatric intervention then adapted treatment or palliative treatment

• ‘Too sick’ Onlypalliative treatment

Treatment Selection for mCRPC

No available predictors of outcome No Clear selection Criteria between androgen signaling inhibitors

and docetaxel ....both abiraterone acetate and enzalutamide have proven survival benefit when given prior to docetaxel ..

• Alpharadin should be used only for bone metastases

• Sipuleucel –T is preferred pre chemo and on lower disease burden

• “ Vintage “ hormones are no longer recommended given lack of survival benefit data

Patient preference should be considered

Future Directions

Do not confuse motion with progress

Montalpert

Current Practice: Reactive Medicine

Regimen

+

+

Patient success

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Choice of TreatmentAccess to Treatment – Reimbursement status- Regulatory aspectsLevel I evidence : originating from randomised PhIII trials Personal Experience - Discipline

2015-17 Trial Progress ReportClinical Practice Change in mHNPC

The reemergence of Chemotherapy in advanced Prostate cancer

mHNPC data

Failure for microenvironment agents and immunotherapy in ALL mCRPC studies:

Orteronel ,Tasquinimod, Cabozantinib, Ipilimumab (2)

Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum

mHSPC positive data ( 2 positive trial)

mCRPCSaturation?Lack of Selection

Design of prostate cancer studies largely rely on

uniform prognostication

Moving the Therapeutic Dilemma Earlier

Local

therapy

Death

ADT

supportive care (eg

denosumab/bisphosphonates)

mCRPC

post-

docetaxel

mCRPC

symptomatic

mCRPC

mildly

symptomatic

mCRPC

asymptomatic

(failed ADT)

Hormone

sensitive

Sipuleucel-T

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Radium 223

EnzalutamidemHNPC

ADT +

Docetaxel

mHNPC

ADT +

Abiraterone

2017

Apalutamide

Agents• Docetaxel• Cabazitaxel• Sipeuleucel-T• Abiraterone• Enzalutamide• Rad 223

Giving Perspective :Pembrolizumab for MSI across solid tumors

Survival prolongation on average 3.5 months in mCRPCMost trials to date focused on drug development irrespective of risk category

Have we reached ‘Saturation’ in mCRPC ?

Registration Study Failures in mCRPC

Uniform Prognostication Approach

Cabozantinib, Tasquinimod and Ipilimumab (2),

And all Docetaxel + combinations (15)

Too many questions to be answered / lack of validation of companion

diagnostics

Galeterone

Too late Space taken / Saturation

Orteronel

Are we missing opportunities for our

patients and how can we rectify ?Ipilimumab in Post-Chemotherapy mCRPC

1.0

0.8

0.6

0.4

0.2

0.0

0 4 8 12 16 20 24 28 32 36

Pro

po

rtio

n A

live

IpilimumabCensored

PlaceboCensored

Months

Kwon, ED et al. Lancet Oncol. 2014.

HR 0·85, 95% 0·72–1·00; p=0·053

Steps in the right direction

Multi-institutional integrative clinical sequencing analysis- East Coast SU2C

Underscores Heterogeneity

~90% of mCRPC harbor clinically actionable molecular alterations

NEED FOR PROSPECTIVE VALIDATION TO PROVE A

POTENTIAL BENEFIT OF ANY ACTION

Robinson et al Cell 2015

A “feasibility” report paving the way for predictive biomarker identificationAnd a much needed classification

Somatic mutation landscape in far advanced mCRPC

Highly Burdened mutational landscape

A tall order to identify a driver ….

Cell. 2015 May 21;161(5)

DNA Repair Genes aberrations in mCRPC maybe ‘treatable’ with a PARP inhibitor :

A “retrospective” analysis providing insight – the path for a prospective validation

Mateo J et al. N Engl J Med 2015;373:1697-1708 Mateo et al 2015 NEJM

Pritchard, NEJM, 2016

GENETIC TESTING: SHOULD IT BE OFFERED

AND WILL IT AFFECT EARLY TREATMENT CHOICES ?

32

22 2 1 1 1 1 1 1

11 ATM

(13%)

10 CHEK2

(12%)

6 BRCA1

7%

RAD51D

ATR

GEN1NBN

PMS2

FAM175A

RAD51C

MSH6

MSH2BRP1

MRE11A

37 BRCA2

(45%)

12%

How to “Efficiently” target?

Would earlier treatment reduce “variables” that may be driving progression or resistance ?

What are the “variables” and how do they change over time and how do we track them?

Development of Biomarkers :Should a biomarker be ‘reflective’ of the

pathway of progression rather than a ‘by association’ event

Precision Medicine Requirements

National Research Council 2012

Precision Medicine Requirements Knowledge Network for

Biomedical Researchintegrating :

Molecular Characterisation& Clinical Data

New Taxonomy of Disease

Biomedical Research Clinical Medicine

Precision Medicine Delivered

Understand Anticipate

Cure/

Secondary

PreventionIntegrate KnowledgeIdentify / Classify findings

Enable Risk Assessment

Treat based on Taxonomy AND patient characteristics

Right treatment strategy at the right dose at the right time, with minimum ill consequences and

maximum efficacy

A need to acquire Knowledge to make most of information

Make the most of data – adapt to

your practice

Monitor patients diligently – details

matter

Listen to the need of the patient

For now : we can use available treatment strategy at the right dose, with minimum ill

consequences and strive for maximum efficacy

Working together to support ourPatients and their families

Questions

2016 question 1

An 80 yr old previously fit man with no comorbidities has recently started having back pain loss of weight and fatigue his PS is quickly deteriorating . Found to have de novo metastatic prostate cancer GS 8 with >20 bone lesions, PSA 800, LDH 1000 . What would be the preferred approach? a. Start Androgen Deprivationb. Start Androgen deprivation and bone modifying agentsc. Start Androgen deprivation and Docetaxeld. Start Androgen Deprivation and Abiraterone Acetate plus

low dose steroids e. C or D

2. Please propose the appropriate 1st line treatment for a gentleman of 78 yrswith no known comorbidities , who has mCRPC with multiple bone and lymphnode metastases . Patient remains fully active has no symptoms has a very busy social life. He is on treatment with lhrh analogue for 3 years and is now progressing by imaging and PSA criteria. Lymphnode size ranges from 2-3 cm . Novel agents are available and reimbursed or patient can afford

Pick all appropriate choicesa Novel Androgen Signaling Inhibitor : Abiraterone Acetate or Enzalutamideb 6-10 courses of Docetaxelc Alpharadind 6-10 courses of Cabazitaxele Sipuleucel – Td prednisone or dexamethasone low dose e Bicalutamide 50mg /qdf Denosumab or Zoledronic acid infusion added to one of choices of systemic treatment

3. A patient of 73 yrs old has received prior chemo with docetaxel and is now on treatment with a novel androgen signaling inihibitor ( abiraterone or enzalutamide) . For the past 12 months . He had initiated treatment because of a rising psa to 150 .

Initially his PSA regressed to 10 .His PSA is now progressing within the past 3 months ( 05/16 : 10 06/16: 12 07/16: 14)

Patient is feeling great and his imaging did not show any sign of progression Patient is concerned please advise regarding best option

a. Stop an androgen signaling inhibitor b continue the androgen signaling inhibitor and monitor closely imaging and clinical

symptoms while reassuring patient c continue androgen signaling inhibitor and add chemo with cabazitaxeld stop androgen signaling inhibitor and start treatment with cabazitaxel

e . Stop androgen signaling inhibitor and initiate alpharadinf change from one androgen signaling inhibitor to the other (abiraterone to

enzalutamide or vice versa depending on what he was on)g reassure patient nothing is wrong and send him home to continue monitoring only

psa every 3 months

4. A 68 yr old gentleman is diagnosed with a Gleason Score 7 (3+4) Prostate Cancer in 3/8 right lobe biopsy cores and none of 0 /6 left lobe biopsy cores . No comorbidities but hypertension. Please recommend treatmentoptions.Multiparametric Choose the most appropriate selectiona. Active Surveillanceb. XRT + ADT for 6 monthsc. XRT d. Radical Prostatectomy

presentación de powerpoint€¦ · hussain m et al. oral presentation, asco, chicago, 3 june 2012...

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