therapeutic landscape of metastatic prostate cancer: place ... · bone targeting agents . s(s)re in...

Therapeutic landscape of metastatic prostate cancer: place of

radionuclide therapy

Wouter Everaerts, MD, PhD

UZ Leuven

Lymph nodes:

• pelvic: locally advanced

• Outside pelvis: M1a

Bone M1b

Visceral mets M1c

- lung

- liver

- other organs

Metastatic prostate cancer:

definitions

“ De novo” metastatic:

Primary not treated

Recurrence after treatment

of primary tumour


definitions

Hellman , J Clin Oncol, 1995

Localised Pca

(no mets) Oligometastatic Polymetastastatic

Low volume High volume


definitions

Prognosis of subgroups of metastatic

PCA

Median

OS 5Y 3Y 8Y 4.5Y

Hormonale therapie in gemetastaseerd

prostaatkanker

Charles B. Huggins

Nobel lecture

December 13, 1966

”despite regressions of great magnitude, it is obvious that there are

many failures of endocrine therapy to control the disease”

ADT has been the standard therapy for M+ pCA for half a century

Androgen deprivation therapy

The effect of castration on advanced carcinoma of the prostate gland. Arch Surg., 1941

The effect of estrogens and androgen injection on serum phosphatases in metastatic

carcinoma of the prostate. Cancer Res., 1941

Andrew Schally

1977 Nobel prize

X LHRH analogs

Role of androgens in prostate cancer

X

Anti-Androgens

Improvements SRE, bone pain, spinal cord compression

NO OS benefit

Treatments options for prostate

cancer

Localised Biochemical recurrence

M+ Hormone sensitive

10–15 years +

Other cause

mortality

PCA mortality

Surgery

RT

AS/WW

ADT

CRPC: castration-resistant prostate cancer

Surgery

RT

ADT

AS/WW

mCRPC

CRPC: defined as a rising PSA, appearance of disease-

related symptoms or new radiographic lesions despite

castrate levels of testosterone

DISEASE MODIFYING AGENTS

Chemotherapy

Docetaxel: the start of a new era

Docetaxel improves OS in mCRPC patients: 327 study

• Open-label, multi-centre, phase III RCT; N=1006 chemo-naïve patients with progressive

mCRPC

Treatment Median OS HR (95% CI) P

Doc 3-wkly 18.9 mo 0.76 (0.62-0.94) 0.009

Doc wkly 17.4 mo 0.91 (0.75-1.11) 0.36

Mitoxantrone 16.5 mo reference -

months

Pro

babili

ty o

f O

S (

%)

0 6 12 18 24 30 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3-weekly Docetaxel weekly Mitoxantrone 3-weekly

Tannock IF et al. N Engl J Med 2004;351:1502-12

CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial

Docetaxel: the start of a new era

Cabazitaxel improves OS in mCRPC patients

progressing after docetaxel - TROPIC study

• Open-label, multi-centre, phase III RCT; N=755 pts with mCRPC with disease progression

during or after a docetaxel-containing treatment regimen

P

rob

ab

ility

of

OS

(%

)

Mitoxantrone

12.7 mo

Cabazitaxel

15.1 mo

100

80

60

40

20

0 Time (mo) 0 6 12 18 24 30

HR=0.70; 95% CI: 0.59-0.83; P<0.0001

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


cancer



mCRPC

10–15 years +

Other cause

mortality

PCA mortality

Surgery

RT

AS/WW

ADT

Docetaxel


Surgery

RT

ADT

AS/WW

mCRPC

Post docetaxel

Cabazitaxel

DISEASE MODIFYING AGENTS

Novel AR targeting therapies

Abiraterone blocks androgen production

PH

BE

/ZY

T/0

114/0

005

Cyp 17𝛼 hydrolase inhibitor

Role of abiraterone in CRPC

• COU-AA-301: post-docetaxel – M+, CRPC, after docetaxel

– Improved OS

– Improved PFS, PSA response, time to psa progression

• COU-AA-302: pre-docetaxel – M+, CRPC, asymptomatic or mildly symptomatic, pre-docetaxel

– Improved PFS and Improved OS

– Improved time to opiate use, time to psa progression, time to chemo

and time to ECOG PS deterioration

17 de Bono et al. NEJM 2011; 346(21): 1995-2005

Fizazi et al. Lancet Oncol. 2012; 13(10): 983-992

Ryan et al. N Engl J Med 2013; 368:138-148

Enzalutamide

• Enzalutamide directly targets three key stages of the AR signalling

pathway1,2

NUCLEUS

CYTOPLASM

Enzalutamide AR

AR

Enzalutamide

Enzalutamide

1. Blocks androgen binding to AR

2. Prevents nuclear translocation of AR

3. Impairs AR binding to DNA preventing modulation of gene expression

Testosterone DHEA

1. Tran C et al. Science 2009;324:787-90; 2. Hu R et al. Expert Rev Endocrinol Metab 2010;5:753-64

AR: androgen receptor; DHEA: didehydroepiandrosterone

Enzalutamide

• AFFIRM: post docetaxel – Progressive mCRPC, failed docetaxel

– Improved OS

– Improved time to SRE, rPFS, Qol, soft tissue response,

time to psa progression

• PREVAIL – Progressive mCRPC, failed docetaxel, asymptomatic or

mildly symptomatic

– Improved OS and rPFS

– Improved time to SRE, Qol, soft tissue response, time to

psa progression

Scher HI et al. N Engl J Med 2012;367:1187-97

Beer T et al. N Engl J Med. 2014;371:424-33


cancer



mCRPC

Asymptomatic

10–15 years +

Other cause

mortality

PCA mortality

Surgery

RT

AS/WW

ADT

Docetaxel

Abiraterone


Enzalutamide

Surgery

RT

ADT

AS/WW

mCRPC Mildly

symptomatic

mCRPC

symptomatic

mCRPC

Post docetaxel

Abiraterone

Enzalutamide

Cabazitaxel

BONE TARGETING AGENTS

S(S)RE in men with boneM+ from

prostate cancer

Pain

requiring

radiation

to bone

Pathologic

fracture

Spinal cord

compression

Surgery to

bone

33% 25% 4% 8%

Bisphosphonates: Zoledronic Acid

Clezardin P. 2013 BoneEy Reports

Zoledronic Acid in mCRPC: effects

on SRE

Saad et al. 2004 JNCI

NO OS benfit

Denosumab: Targeting RANK-L in

Bone M+

Yee A. et al. 2012 Clin int in aging

Denosumab: effects on SRE in

mCRPC

Fizazi K. Et al. 2011 Lancet

18% risk reduction

NO OS benfit

Pro’s and Con’s of Bone-targeting

agents

• Reduced morbidity

• Overall good tolerance

• Relatively cheap (115-300€/m)

• NO OS benefit

• ONJ (1-2%)

• Hypocalcemia (up to 13%)

• (Renal impairment)

𝛽 Radiopharmaceuticals

• Strontium-89 – Strontium vs placebo after radiotherapy:

• Improvement in time to pain (n=126) (Porter 1993)

• No improvement (n=95) (Smedeland 2003)

– Strontium versus radiotherapy • Similar pain control (n=284) (Quilty 1994)

• Better OS: 7 months vs 11 months (p<0.05) (n=101) (Oosterhof 2003)

• Samarium-153 – Samarium versus placebo

• Better pain control (n=118) (Serafini 1998) & (n=152) (Sartor 2004)

Radium-223 in mCRPC: ALSYMPCA trial

Symptomatic

mCRPC

≥ 2 bone M

No known visceral M

Post-decetaxel or

unfit for docetaxel

R

A

N

D

O

M

I

S

A

T

I

O

N

2:

1

Radium-223 (50Bq/kg) (6

CYCLES)

(n=614)

Placebo

(n=307)

Parker C. et al. 2013 NEJM

Radium-223 in mCRPC: ALSYMPCA trial: OS


Radium-223 in mCRPC: ALSYMPCA trial: SSRE


ALSYMPCA trial: Adverse events


Radium-223 and Docetaxel: ALSYMPCA

1. Sartor O. et. Al. 2016 Lancet Oncol 2. Sartor O. et. Al. 2016 Prostate

1. Effects of Radium are maintained irrespective of previous use of decetaxel 2. Chemotherapy following radium‐223 is feasible in patients with CRPC and

symptomatic bone metastases.

Radium-223 and concommitant

therapies in mCRPC: open label single

arm

Saad F. et al. 2016 Lancet Oncol

Radium-223 and concommitant

therapies in mCRPC: open label

single arm

Saad F. et al. 2016 Lancet Oncol

Similar grade 3-4

adverse events


cancer



mCRPC

Asymptomatic

10–15 years +

Other cause

mortality

PCA mortality

Surgery

RT

AS/WW

ADT

Docetaxel

Abiraterone


Enzalutamide

Radium 223

Denosumab/ Zoledronic acid

Surgery

RT

ADT

AS/WW

mCRPC Mildly

symptomatic

mCRPC

symptomatic

mCRPC

Post docetaxel

Abiraterone

Enzalutamide

Cabazitaxel

Body JJ et. Al. 2015 Nat. Rev. Urol

Treatment landscape for bone M+ in PCA

How to sequence therapies?

HORMONE SENSITIVE METASTATIC

PROSTATE CANCER

Adding treatments to stndard of care (ADT)

STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate

Cancer: Evaluation of Drug Efficacy

STAMPEDE

• Recruits men from 4 groups starting

long-term ADT

1. High risk localised (T3/4, PSA >40,

Gleason 8-10)

2. N+ PCA

3. Newly diagnosed M1

4. High risk recurrence post surgery or RT

STAMPEDE conclusions so far

• Docetaxel improves survival in hormone

naïve prostate cancer (HNPC)

• Abiraterone acetate improves survival in

HNPC

• ZA does not improve survival in HNPC

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

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

James N et al. nejm 2017; 377:338-351

Other studies

• Docetaxel improves survival in high

volume hormone naïve prostate cancer

(HNPC)

• Abiraterone acetate improves OS and

rPFS in high volume HNPC

• ZA does not improve survival or SRE in

HNPC ALLIANCE TRIAL: Smith MR et al. J Clin Oncol 2014;32:1143-1150

LATITUDE: Fizazi K et al. NEJM 2017; 377:352-360

CHAARTED: SWEENEY CJ et al. NEJM 2015;373:737-746


cancer



mCRPC

Asymptomatic

10–15 years +

Other cause

mortality

PCA mortality

Surgery

RT

AS/WW

ADT

Docetaxel

Abiraterone

Docetaxel


Enzalutamide

Radium 223

Abiraterone

Denosumab/ Zoledronic acid

Surgery

RT

ADT

AS/WW

mCRPC Mildly

symptomatic

mCRPC

symptomatic

mCRPC

Post docetaxel

Abiraterone

Enzalutamide

Cabazitaxel

Conclusions

• The treatment landscape of metastatic

prostate cancer is changing fast

• Radium223 is the only bone-tagerting

therapy that has shown OS benefit – Is safe and effective even in advanced disease

– Is ideally suited for combination therapies

– The timing of Radium223 is still debated

– Patients selection is critical: 6 courses completion

therapeutic landscape of metastatic prostate cancer: place ... · bone targeting agents . s(s)re in...

Documents