Huidige behandelingsmogelijkheden bij castratie resistent … › files › posteaun › Bergman...

Huidige behandelingsmogelijkheden bij castratie resistent prostaatcarcinoom en

de effecten op overleven en kwaliteit van leven

André Bergman, internist-oncoloog

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1. Introductie prostaat kanker

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2. Hoe wordt prostaatkanker behandeld?

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3. Welke behandelingen hebben wij voor mCRPC?

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4. Nieuwe behandelmogelijkheden in 2017-2018

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5. Conclusies


• Een op de tien mannen zal gediagnosticeerd worden met prostaatkanker



• Ongeveer 30% van de prostaat kankerpatiënten presenteert met- of ontwikkeld metastasen




• Ondanks hoge response kans op Androgeen deprivatie therapie (ADT), zal uiteindelijk castratie resistentie ontwikkelen.





• Gemetastaseerd castratie resistent prostaatcarcinoom (mCRPC) is geassocieerd met morbiditeit en mortaliteit






• In de laatste twee decennia zijn er meerdere, levensverwachting verlengende behandelingen ontwikkeld






• In de laatste twee decennia zijn er meerdere, levensverwachting verlengende behandelingen ontwikkeld

• Op dit moment zijn er meerdere nieuwe behandelingen in ontwikkeling

DeMarzo et al, Nat Rev, 2007


• Multistep disease:

• Prostatic Intraepithelial Neoplasia (PIN)

• Adenocarcinoma

• Metastatic disease

Shen M M , and Abate-Shen C Genes Dev. 2010

How does prostate cancer develop?


• Heterogeneous disease

• Multifocal disease: average

of five genetically

independent tumors

Nelson et al NEJM 2003


HSP HSP P

P

P P

5α-reductase

Testosterone

DHT

DNA binding at

Androgen-response element

Co-activator

recruitement

Target gene

activation:

• PSA

• Growth

• Survival

AR signaling in Prostate Cancer


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5. Conclusies

Decreased prostate cancer growth after

surgical castration or estrogens supletion

Increased prostate cancer growth after

androgen supplementation

Huggins et al. Cancer Res 1: 293-297, 1941

Charles Huggins

Nobelprice medicine 1966

Testosterone suppression in prostate

cancer treatment


Testosterone synthesis inhibitors

ng/dL

300 - 1200

50

20

10

Normal levels

Castration level HRPC HRPC

Hormone Refractory

Prostate Carcinoma


cancer treatment


Testosterone synthesis inhibitors

ng/dL

300 - 1200

50

20

10

Normal levels

Castration level

CRPC

CRPC

Castration Resistant Prostata Carcinoma


cancer treatment


Primary prostate

cancer

℞ curative intention: • Prostatectomy

• Radiotherapy


Primary prostate

cancer

Loco-regional lymph

node metastasis ℞ curative intention: • Prostatectomy

• Radiotherapy


Primary prostate

cancer

Loco-regional lymph

node metastasis

Distant lymph node,

organ or skeletal

metastasis


• Radiotherapy


Primary prostate

cancer

Loco-regional lymph

node metastasis

Distant lymph node,

organ or skeletal

metastasis


• Radiotherapy

℞ paliative intention: • Lowering serum

testosterone levels


Primary prostate

cancer

Loco-regional lymph

node metastasis

Distant lymph node,

organ or skeletal

metastasis

Castration resistant


• Radiotherapy

℞ paliative intention: • Lowering serum

testosterone levels


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5. Conclusies

TAX327: Tannock et al1 SWOG9916: Petrylak et al2

Docetaxel 3 weekly vs mitoxantrone 3 weekly:

• PSA response: 45% vs 32%

• Overall Survival: 18.9 vs 16.5 m

Docetaxel is the “gold-standard” of

mCRPC treatment

1. Tannock IF et al. N Engl J Med 2004; 351: 1502-1512, 2. Petrylak et al. et al. N Engl J Med 2004; 351: 1513-1520

Docetaxel combination studies

• Fase III-studies do not find added value of docetaxel modulation:

NePro: docetaxel ± oraal bifosfonaat (risedronate)

MAINSAIL: docetaxel ± lenolidamide

ASCENT-II: doceaxel ± calcitriol

VITAL-II: docetaxel ± GVAX vaccin

SWOG S0421: docetaxel ± atrasentan

Enthuse: docetaxel ± zibotentan

CALLGB90401: docetaxel ± bevacizumab

Venice: docetaxel ± aflibercept

Ready: docetaxel ± dasatinib

SYNERGY: docetaxel + OGX-011 (Custirsen)

“Docetaxel is a bad bride!”


mCRPC treatment


mCRPC treatment

Docetaxel

Hormone sensitive disease Castration resistant disease


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

Docetaxel and ADT in hormone sensitive metastasized prostate cancer

CHAARTED:

• 790 hormone sensitive metastasized patients (M1b, c)

• 27% had local therapy and 4% adjuvant ADT

• Randomized between ADT and ADT + 6 cycles of docetaxel


CHAARTED


OS benefit 13,6 months


CHAARTED




High-Volume disease:

Visceral metastases and/or ≥4 bone lesions Low-Volume disease

James ND et al. Lancet 2016; 387: 1163-1177


STAMPEDE trial:

• 2,369 locally advanced, lymph nodes only, newly diagnosed

metastatic and relapsing prostate cancer patients

• Randomized between ADT and ADT + 6 cycles of docetaxel

(zoledronic acid)

Docetaxel and ADT in hormone sensitive

metastasized prostate cancer

STAMPEDE trial

Docetaxel: Survival

Presented By Nicholas James at 2015 ASCO Annual Meeting



STAMPEDE trial

Overall Survival

benefit: 10 months

Docetaxel: Survival – M1 Patients



STAMPEDE trial


Overall Survival

benefit: 22 months



Overall Survival

Failure-free survival

Effect of addition of docetaxel to standard of care of M1 disease

Meta-analysis of GETUG-15, CHAARTED and STAMPEDE (3,206 M1 patients)

Vale et al. Lancet oncol, 2016;17:143-256



Overall Survival

Failure-free survival

Effect of addition of docetaxel to standard of care of M1 disease

Conclusion: The addition of docetaxel to ADT should be considered

standard care for men with M1hormone-sensitive prostate cancer who

are starting treatment for the first time.

Meta-analysis of GETUG-15, CHAARTED and STAMPEDE (3,206 M1 patients)

Vale et al. Lancet oncol, 2016;17:143-256

The worse the prognosis, the higher the benefit from docetaxel?

VA

CSP

SP

CG

12

CH

AA

RTE

D

STA

MP

ED

E M

1

CH

AA

RTE

D

GETU

G1

5

GETU

G1

2

STA

MP

ED

E M

0

RTO

G 0

52

3

Intermidate

risk localized

High-risk

localized

N1/minimal M1 High-volume

M1

Be

ne

fit

fro

m d

oc

eta

xe

l PFS not improved PFS improved OS improved

Docetaxel


Docetaxel

What treatment options do we have now?

1. Introduction prostate cancer

Cabazitaxel

Treatments after docetaxel progression

De Bono et al, Lancet 2010; 376: 1147-1154

Docetaxel

Cabazitaxel

ketoconazol (Nyzoral®)

o CYP17A1 inhibitor

o Liver toxicity

abiraterone (Zytiga®)

o CYP17A1 inhibitor

o Little side effect

o Prednisone


Abiraterone

Casus 1: Patient behandeld met abiraterone

Treatments should not be stopped for PSA progression alone

CV CV 72 year old patient

• 2007 cT4N0M1b Gleason 7 prostate cancer. iPSA

290 ng/ml. Start ADT

• 2013-12 rising psa and progression bone

metastases. mCRPC

• 2014-4 Start abiraterone/P

Prior to abiraterone/P December 2013


PSA DT 13.7 months Start abiraterone/P

PSA

72 year old patient

• 2007 cT4N0M1b Gleason 7 prostate cancer. iPSA

290 ng/ml. Start ADT

• 2013-12 rising psa and progression bone

metastases. mCRPC

• 2014-4 Start abiraterone/P

• 2016-1 No PSA response, followed by PSA rise



Start abiraterone/P

Alkaline phosphatase

PSA DT 13.7 months Start abiraterone/P

PSA



CV CV Prior to abiraterone/P December 2013

After 3,5 years of abiraterone/P September 2017


Enzalutamide

Scher et al, N Engl J Med 2012; 367: 1187-1197


Maximum PSA change on enzalutamide treatment after progressing on

docetaxel and abiraterone

13 (21%)

Badrising et al. Cancer 2014;120:968-975

Evidence for Cross-resistance between abiraterone and enzalutamide



13 (21%)


AFFIRM 54%




13 (21%)


AFFIRM 54%


Median PFS 12 weeks (CI 11.1-20.0)



13 (21%)


AFFIRM 54%


Median PFS 12 weeks (CI 11.1-20.0)

AFFIRM 36.1 weeks

Ionizing Radiation: α vs β Particles

α β

Relative particle mass 7000 1

Initial energy (MeV) 3–8 0.01–2.5

Range in tissue (μm) 40–90 50–10000

LET (KeV/μm) 60–230 0.015–0.4

Charge +2 –1

Ion pairs/μm 2000–7000 5–20

DNA hits to kill cell 1–5 100–1000

α particle β particle LET, linear energy transfer Henriksen G, et al. J Nucl Med. 2003;44(2):252-9

Radium-223

Parker et al. NEJM 2013, 369: 213-223


EAU Guidelines Recommendations on Metastatic Prostate Cancer

PSA response on Radium-223 treatment is a rare event

85 year old patient

• 2006 cT3N1Mx Gleason 9 prostate cancer. iPSA

32 ng/ml. Start bicalutamide

• 2009 Start ADT

• 2013 rising psa and bone metastases. mCRPC

and start abiraterone/P

• 2016-8 progression bone metastases. Start

Radium-223

Prior to Radium-223

August 2016

CT-scan:

One LN 14 mm



Start Radium-223

6 cycles

PSA Start Radium-223

6 cycles

Alkaline phosphatase



85 year old patient

• 2006 cT3N1Mx Gleason 9 prostate cancer. iPSA

32 ng/ml. Start bicalutamide

• 2009 Start ADT

• 2013 rising psa and bone metastases. mCRPC

and start abiraterone/P

• 2016-8 progression bone metastases. Start

Radium-223

• 2017-2 PSA response after 6 courses

CT-scan February 2017: Still one LN of 14 mm



Start Radium-223

6 cycles

12 cycles

PSA Start Radium-223

6 cycles

12 cycles Alkaline phosphatase



Prior to Radium-223

August 2016

After 12 times Radium-223 July 2017

Study Agent Control arm OS benefit

(months)

TAX327 (2004)1 Docetaxel + P Mitoxantrone + P 2.9

TROPIC (2010) 2 Cabazitaxel + P Mitoxantrone + P 2.4

COU-AA-301 (2011) 3 Abiraterone + P Placebo + P 3.9

AFFIRM (2012) 4 Enzalutamide Placebo 4.8

ALSYMPCA (2013) 5 Radium-223 Placebo 3.6

mCRPC:

Post docetaxel

1. Tannock IF et al. N Engl J Med 2004; 351: 1502-1512, 2. De Bono J et al. Lancet 2010; 376: 1147–54; 3. De Bono J et

al. N Engl J Med 2011;364:1995-2005; 4, Scher HI et al. N Engl J Med. 2012, 367: 1187-97; 5. Parker C et al. N Engl J

Med. 2013, 369(3):213-23.



(months)

COU-AA-302 (2013) 1 Abiraterone + P Placebo + P NR

PREVAIL (2014) 2 Enzalutamide Placebo 2.2

mCRPC:

Pre docetaxel

1. Ryan CJ et al. N Engl J Med. 2013, 368: 138-148; 2. Beer TM et al. N Engl J Med. 2014; 371: 424-433.


(months)

CHAARTED (2015) 1 ADT + Docetaxel ADT alone 13.6

STAMPEDE (2016) 2

(M1 only)

ADT + Docetaxel + P ADT alone 22

1. Sweeney CJ et al. N Engl J Med. 2015, 373: 737-746; 2. James ND et al. Lancet. 2016; 387: 1163-1177.

mHSPC:


Docetaxel

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223 Enzalutamide

Abiraterone


Docetaxel


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5. Conclusies

Metastasized hormone sensitive disease

LATITUDE study

• 1199 patients with newly

diagnosed, high-risk, metastasized

and hormone sensitive disease

• High-risk disease (2 out of three): • Gleason score of ≥ 8

• ≥ 3 lesions on bone scan

• Visceral lesions


Are we going to add abiraterone/P to androgen deprivation therapy in stead of docetaxel?

• The results of the LATITUDE and STAMPEDE (abiraterone arm) were presented at ASCO 2017

• Both studies show survival benefit with abiraterone compared to docetaxel

Docetaxel Abiraterone

Recurrence (CHAARTED only)

Primary metastases

CHAARTED LATITUDE

Locally advanced

Recurrence

Primary metastases

STAMPEDE docetaxel

STAMPEDE

docetaxel/zoledronic acid

STAMPEDE abiraterone

Overall study design of LATITUDE

Presented By Karim Fizazi at 2017 ASCO Annual Meeting

LATITUDE study

Dual primary endpoint:

OS: not reached

Radiographic PFS: 33 vs 14.8 months

34.7 months

NR




LATITUDE study

Dual primary endpoint:

OS: not reached

Radiographic PFS: 33 vs 14.8 months 14.8 months

33.0 months


CHAARTED vs LATITUDE: ADT alone

CHAARTED LATITUDE

months months

mOS 44.0 34.7

TT Rad Prog 14.8

TT CRPC 11.7

TT PSA Prog 7.4

TT Clin Prog 19.8

TT Pain Prog 16.6

TT Chemotherapy 38.9

TT Subs Therapy 21.6

LATITUDE poor prognostic population compared to CHAARTED

CHAARTED vs LATITUDE: Docetaxel/Abiraterone/P

CHAARTED LATITUDE

maanden △ maanden △

mOS 57.6 13.6 NR -

TT Rad Prog 33.0 18,2

TT CRPC 20.2 8,5

TT PSA Prog 33.2 25,8

TT Clin Prog 33.0 13,2

TT Pain Prog NR -

TT

Chemotherapy

NR -

TT Subs Therapy NR -

“PSA driven end points” can not be compared between

chemotherapy and anti hormonal therapy (PCWG3)

Abiraterone comparison: patients



STAMPEDE study

• 1917 patients with

metastasized/locally advanced

and hormone sensitive disease

• Randomized between ADT alone

and ADT + Abiraterone (100 mg

daily + prednisolone 5 mg daily


3. Novel indications in 2017 and 2018

Sydes MR et al Ann Oncol 2018: 29: 1235-1248

Comparison between the docetaxel and abiraterone arm of STAMPEDE

Sydes MR et al Ann Oncol 2018: 29: 1235-1248

Wo

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ve

rse

ev

en

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rad

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rep

ort

ed

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en

tire

tim

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l

Comparison between the docetaxel and

abiraterone arm of STAMPEDE


What treatment options do we have now?

Docetaxel

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223 Enzalutamide

Abiraterone


Docetaxel

Abiraterone


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5. Conclusies

• Circa 1 op de 10 mannen wordt gediagnosticeerd met prostaatkanker

5. Conclusies


• Prostaatkanker is een heterogene ziekte

5. Conclusies



• Een derde van patiënten zal met gemetastaseerd prostaatkanker worden gediagnosticeerd

5. Conclusies




• Testosteronverlagende therapie is de behandeling van keuze

5. Conclusies





• Mannen met uitgebreide ziekte die gaan beginnen met testosteronverlaging hebben baat bij de toevoeging van docetaxel of abiraterone

5. Conclusies






• Uiteindelijk zal castratie resistente ziekte (mCRPC) ontstaan

5. Conclusies







• Docetaxel was de eerste levensverlengende behandeling voor mCRPC patienten

5. Conclusies







• Docetaxel was de eerste levensverlengende behandeling voor mCRPC patienten

• Er zijn nu meerdere behandelingen voor mCRPC beschikbaar

5. Conclusies

Dank voor uw aandacht!

Huidige behandelingsmogelijkheden bij castratie resistent … › files › posteaun › Bergman...

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