Prostate cancer

SAMO Masterclass

Richard Cathomas

Onkologie Kantosspital Graubünden

richard.cathomas@ksgr.ch

SAMO Masterclass10.04.2014

Setting the stage

1. Metastatic vs non-metastatic

Silberstein JL et al. Transl Androl Urol 2013

CRPC: castration-resistant prostate cancer

2. Hormone-naive prostate cancer

What will not be discussed

• Pathology

• Localized prostate cancer

• PSA relapse after localized treatment

• Non-metastatic castration resistantprostate cancer

Metastatic prostate cancer

• Hormone-naive

• Castration resistant• Castration resistant

• Supportive treatments

mCRPC

Metastatic Prostate Ca until 2010

ADT (androgen deprivation) Docetaxel2°ADT

Metas. Hormone-naive PCa:Androgen deprivation therapy (ADT)

• Standard first line treatment for all patients withadvanced prostate cancer

• Response rate: 80-90% of patients

• Median progression free survival: 18 - 24 months

Important questions:

• Start of ADT ? – at time of diagnosis of mets

• Antiandrogen monotherapy? –less effective

• Complete androgen blockade? – generally no

• Intermittent ADT ? – less effective

• NEW 2014: early docetaxel?

Docetaxel in hormone-naive PCaCHAARTED study, ASCO 2014

• 790 pts, randomized phase III; ECOG-SWOG

• 60% with „high volume“ extent

– ≥ 4 bone mets (≥1 outside spine/pelvis), visceral mets

• ADT vs ADT + docetaxel 75mg/m2 6 cycles

– Start within 120 days; no prednisone

• OS „high volume“: 49 vs 32 Monate (HR 0.60)

• ADT + Docetaxel new standard if:

– Fit for docetaxel

– High volume according to definition

– Start within 3 months of diagnosisSweeny et al. Abstract LBA2 ASCO 2014

Met.Castration-resistant PCa: mCRPC• Definition:

• progression of disease on castrate levelsof testosterone (measure testosterone!)

• continue castration (lifelong)

Evaluation:

• Disease burden: extent, visceral mets

• Disease dynamic: PSA DT, LDH, Pathology

• Symptomatic

• Time on prior ADT

Metastatic castration-resistant prostatecancer (mCRPC)

• Treatments: overview

• Resistance mechanisms

• Sequence vs Combinations

• Docetaxel q3w 19.2 Monate

• Docetaxel q1w 17.8 Monate

• Mitoxantron 16.3 Monat

Docetaxel - TAX 327

• Mitoxantron 16.3 Monat• 1006 pts; Cross-Over 30 %

Tannock et al. NEJM 2004; Berthold et al JCO 2008Armstrong et al, JCO 2007;25:3965-70

Five substances with prolongation of overallsurvival in phase III trials since 2010

– Sipuleucel T

– Cabazitaxel– Cabazitaxel

– Abiraterone

– Radium 223

– Enzalutamide

Substance 1°EP Indication Median OS

HR; p-value

Publication

Sipuleucel-T(Provenge®)

Survival mCRPC

80% pre-D

+ 4.1 Mte

0.78; 0.03

NEJM 2010

Cabazitaxel(Jevtana®)

Survival mCRPC

Post-Doc

+ 2.4 Mte

0.7; <0.0001

Lancet 2010

Abiraterone(Zytiga®)

Survival mCRPC

Post-Doc

+ 3.9 Mte

0.65;<0.0001

NEJM 2011

Abiraterone(Zytiga®)

Survival

rPFS

mCRPC

pre-Doc

OS: 0.75

rPFS:0.43

NEJM 2013

Enzalutamide(Xtandi®)

Survival mCRPC

Post-Doc

+ 4.8 Mte

0.63;<0.0001

NEJM 2012

Enzalutamide(Xtandi®)

Survival

rPFS

mCRPC

Pre-Doc

+ 2.2 Mte

0.7;<0.0001

NEJM 2014

Radium 223(Xofigo®)

Survival mCRPC

Post Doc

+ 3.6 Mte

0.69; 0.0018

NEJM 2013

Increased survival in the era ofmodern treatment for mCRPC

Omlin AG et al. Eur Urol 2013

Sipuleucel-T

Drake CG. Nat Rev Immunol 2010

- Active cellular immunotherapy: „vaccine“- Very complex logisitics- Not available in Europe

More convenient immune therapies in the future?

Kantoff et al N Engl J Med 2010;363:411-422

Cabazitaxel• tubuline-binding taxane

• activity in docetaxel and paclitaxel refractory celllines

• penetrates blood-brain barrier

• Intravenous every 3 weeks (6-10 cycles)• Intravenous every 3 weeks (6-10 cycles)

• Post Docetaxel setting: 75% Taxane refractory

• Current dose 25mg/m2– Ongoing phase III trial 20mg vs 25mg/m2

• Toxicity:– More: neutropenia

– Less: alopecia, nail changes, dysgeusia, neuropathy

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

CYP17 Inhibition - Abiraterone

De Bono et al NEJM 2011Ryan et al NEJM 2013

Abirateron

Abirateron

Oral daily continuous, + 10mg prednisonePre/Post DocetaxelSide effects: Hypokalemia, Hypertension, Edema

Enzalutamide

AR-pathway:Triple blockade

Oral daily continous

No need for prednisone

Pre/post docetaxel

Side effects:-Fatigue-Seizures (rare)

Scher et al. NEJM 2012; Beer TM et al. NEJM 2014

Radium 223• Radium 223 acts as calcimemtic

• naturally targets bone growth in and around bonemetastases

• excreted by small intestine

• Alpha emitter: short penetration, only a few cell-diameters (2-10)diameters (2-10)

• Intravenous 1x/month by nuclear medicine (x6)

Negative phase III trials!Substance Mechanism Phase III Publication

DN-101 High doseVitamine D

Doc vsDoc + DN-101

J Clin Oncol2011

NEG

Bevacizumab Angiogenesis Doc vsDoc + Bevacizumab

J Clin Oncol2012

NEG

Lenalidomide Immuno-modulation

Doc vsDoc + Lenalidomide

ESMO2012

NEG

Aflibercept Angiogenesis Doc vs ASCO GU NEGAflibercept Angiogenesis Doc vsDoc + Aflibercept

ASCO GU2013

NEG

Dasatinib Src-Inhibitor Doc vsDoc + Dasatinib

ASCO GU2013

NEG

Atrasentan Endothelin ARec Antago.

Doc vsDoc + Atrasentan

ASCO2012

NEG

GVAX Vaccine Doc vsDoc + GVAX

ASCO GU2009

NEG

Zibotentan Endothelin ARec Antago.

Doc vsDoc + Zibotentan

J Clin Oncol2013

NEG

CabazitaxelAbirateroneAbiraterone

mCRPC

Overview mCRPC 2014

ADT (androgen deprivation) Docetaxel2°ADT

Radium 223Enzalutamid

AbirateroneEnzalutamidRadium 223(Sipuleucel-T)

?

TasquinimodIpilimumabPARP Inhib.

Docetaxel

Resistance mechanisms

• Castration resistance

• Cross-resistance Abi-Enz• Cross-resistance Abi-Enz

• Cross-resistance Taxane – Abi/Enza

Mechanisms for castration resistance

Abiraterone

Possible cause for Abi-Enza cross resistance

Seruga B et al. Nat Rev Clin Oncol 2011

Enzalutamide

Abi – Enza Cross Resistancecave: small retrospective analyses; post-docetaxel

• Enza Abi

– PSA RR 3-8%

– PFS 3-4mts

• Abi Enza

– PSA RR 25 – 30%

– PFS 4mts

– OS 7 mts

– OS 7-11 mts

Schrader Eur Urol 2013

Noonan Ann Oncol 2013;24:1802-1807

Loriot Annals of Onc 2013;24:1807-1812

Cross resistance: Taxane – Abi/Enza ?

Thadani-Mulero M et al. Cancer Res 2012;72:4611-4615

Possible treatment choices

First line options

• Abiraterone

• Enzalutamide

• Docetaxel

Second line options

Docetaxel-naive

• Docetaxel

• All other options not• Docetaxel

• Radium (bone mets only)

• Trial

• All other options nottested/registered

Prior docetaxel

• Cabazitaxel

• Abiraterone

• Enzalutamide

• Radium 223 (bone mets)

• Trial

Decision aids for first line treatment

• No predictive (bio-)markers

• Possible clinical factors

– Duration of response to primary ADT

– Tumour load: Visceral metastases, Symptoms

• Possible patient factors:

– Age, PS, co-morbidities, co-medication

• Account for possible cross resistance (?)

Response to primary ADT:an important prognostic marker

Angelergues A et al. ASCO GU 2014

SWOG 9346

Hussain M et al. J Clin Oncol 2006;24:3984-3990

?Also a predictive marker: novel hormone agents less effective?

Importance of monitoring

• Best benefit for patient: use all available options• Change of treatment: not too early – not too late

• PSA Measurements:• Monthly, BUT :• Cautious interpretation in first 12 weeks• PSA only no reason for change

• CT und Szintigraphy:• Generally every 12 weeks, consider prolongation of

interval in asymptomatic pts and excellent PSA responders

• MRI Long-Spine• At baseline in case of extensive bone disease and very

early in case of symptoms

What about combinations?• No proven benefit over sequential treatment

• Good candidates + ongoing trials:

– Enzalutamide plus abiraterone

– Radium plus abiraterone or enzalutamide– Radium plus abiraterone or enzalutamide

– Enzalutamide + taxane

– Abiraterone + taxane

• Beware:

– Radium + docetaxel: need to dose reduce docetaxel

Bone health:Denosumab vs Zoledronat in mCRPC

1.00

Pro

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no

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Wit

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SR

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0.75

Denosumab

Zoledronic acid

HR 0.82 (95% CI: 0.71, 0.95)P = 0.0002 (Non-inferiority)P = 0.008 (Superiority)

No change:-Overall survival

0Pro

po

rtio

no

fS

ub

jects

Wit

ho

ut

SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

Study Month

Fizazi K et al. Lancet 2011;377:813–22.

-Overall survival-Progression free survivalInclusion criteria

– mCRPC

– Bone metastases

Don‘t forget Calcium + Vit D!

Prolongation of time to SRE with new treatments

Radium 223Parker et al ASCO 2012+ 5.5 Monate

MDV3100DeBono et al ASCO 2012+ 3.4 Monate

Take home messages• Define disease setting before taking decisions

• Met. Hormon-naive PCa: ADT

– Consider Docetaxel for extensive disease

• Met. Castration-resistant PCa:

– Sequential treatment: but sequence not defined

– Cross resistance: not complete but be aware

– Treat as long as possible: but switch early enough

– Interdisciplinary management – and TRIALS