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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
Metastatic prostate cancer:
definitions
Hellman , J Clin Oncol, 1995
Localised Pca
(no mets) Oligometastatic Polymetastastatic
Low volume High volume
Metastatic prostate cancer:
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
Treatments options for prostate
cancer
Localised Biochemical recurrence
M+ Hormone sensitive
mCRPC
10–15 years +
Other cause
mortality
PCA mortality
Surgery
RT
AS/WW
ADT
Docetaxel
CRPC: castration-resistant prostate cancer
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
Treatments options for prostate
cancer
Localised Biochemical recurrence
M+ Hormone sensitive
mCRPC
Asymptomatic
10–15 years +
Other cause
mortality
PCA mortality
Surgery
RT
AS/WW
ADT
Docetaxel
Abiraterone
CRPC: castration-resistant prostate cancer
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
Parker C. et al. 2013 NEJM
Radium-223 in mCRPC: ALSYMPCA trial: OS
Parker C. et al. 2013 NEJM
Radium-223 in mCRPC: ALSYMPCA trial: SSRE
Parker C. et al. 2013 NEJM
ALSYMPCA trial: Adverse events
Parker C. et al. 2013 NEJM
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
Treatments options for prostate
cancer
Localised Biochemical recurrence
M+ Hormone sensitive
mCRPC
Asymptomatic
10–15 years +
Other cause
mortality
PCA mortality
Surgery
RT
AS/WW
ADT
Docetaxel
Abiraterone
CRPC: castration-resistant prostate cancer
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
Treatments options for prostate
cancer
Localised Biochemical recurrence
M+ Hormone sensitive
mCRPC
Asymptomatic
10–15 years +
Other cause
mortality
PCA mortality
Surgery
RT
AS/WW
ADT
Docetaxel
Abiraterone
Docetaxel
CRPC: castration-resistant prostate cancer
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