Cathomas - Prostate cancer.ppt [Compatibilit · What will not be discussed • Pathology •...
Transcript of Cathomas - Prostate cancer.ppt [Compatibilit · What will not be discussed • Pathology •...
Prostate cancer
SAMO Masterclass
Richard Cathomas
Onkologie Kantosspital Graubünden
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
po
rtio
no
fS
ub
jects
Wit
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SR
E
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