Download Towards A New paradigm In The treatment Of prostate cancer

Towards a new paradigm in the
treatment of prostate cancer
Dra. Begoña Mellado
Hospital Clínic, Barcelona
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
AR is a prototype of lineage-survival oncogene
• Regulator of normal
prostate development
• Modulates:
differentiation,
cell cycle
survival
•Oncogenic:
Upregulated in CRPC
Garraway and Sellers, Nat Rev Cancer 2006
AR with DHT
Ligand
(Dimers)
Testosterone
5a-R
DHT
Activated AR gets in
the nucleus and
binds DNA
Hsp 70
RA (Inactive)
Hsp 90
Gene
expression
Androgen
Response Element
(ARE)
PSA
Mellado B, Clin Tras Oncol 2009
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
Chemotherapy in CRPC
1990s
2004
2010
Mitoxantrone-pdn
Docetaxel-pdn
Cabazitaxel-pdn
PALLIATIVE
BENEFIT IN OS
BENEFIT IN OS
1st line
2nd line
Treatments that have shown survival benefit in CRPC
Increase in
median OS,
months
Relative
reduction in
risk of death,
%
Abiraterone/P vs placebo/P1 (post docetaxel)
4.6
26
Abiraterone/P vs placebo/P2 (pre docetaxel)
5.2
21
Enzalutamide (MDV3100) vs placebo3
4.8
37
Docetaxel(q3w)/P vs mitoxantrone/P4
2.4
24
Cabazitaxel/P vs mitoxantrone/P5
2.4
30
Sipuleucel-T a vs placebo6
4.1
22
Radium Ra 223 dichloride vs placebo7
3.6
31
HR
(95% CI; P value)
0.74
(0.64–0.86; p<0.001)
0.79
(0.66-0.96; p=0.0151)
0.63
(0.53–0.75; p<0.0001)
0.76
(0.62–0.94; p=0.009)
0.70
(0.59–0.83; p<0.0001)
0.78
(0.61–0.98; p=0.03)
0.70
(0.58–0.83; p<0.0001)
CI, confidence interval; HR, hazard ratio; P, prednisone; q3w, every 3 weeks.
1. Fizazzi K et al. Lancet Oncol 2012;13:983–92; 2. Rathkopf DE et al. J Clin Oncol 2013;31(suppl. 6): abstr 5. 3. Scher HI et al. N
Engl J Med 2012;367:1187–97; 4. Tannock IF et al. N Eng; J Med 2004;2351:1502–12; 5. de Bono JS et al. Lancet 2010;76:1147–54;
6. Kantoff PW et al. N Engl J Med 2010;363:411–22; 7. Parker C et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512.
AR
AR
ETS
PTEN
Grasso et al. Nature 2012
AR AMPLIFICATION
Gaba et al, SEOM 2011
Model of CRPC progression
Nelson P S JCO 2012 feb ;30:644-646
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
Definition of Castration Resistance by The Prostate
Cancer Clinical Trials Working Group 2 (PCWG2)
• Serum castration lev- els of testosterone
(testosterone <50 ng/dL or <1.7 nmol/L)
• PSA and/or clinical progression to castration
•
progression despite anti-androgen withdrawal
for at least 4–6 weeks.
Scher HI, et al J Clin Oncol 2008;26:1148–59.
10- 20% of androgens are synthesized in suprarrenal glands
and can stimulate AR
Relative expression of steroidogenic enzymes in castration-resistant
metastases versus primary prostate tumors
Increased expression in primary tumor
Increased expression in CRPC
CYP17
Abiraterone acetate
• Pontent selective and irreverible
CYP17 (P450c17) inhibitor
- 17α –hydroxylase (IC50 = 4 nM)
- C17,20-lyase (IC50 = 2.9 nM)
• Weak antagonism of the androgen
receptor
3-Acetate-17-(3-piridil)
androste-5,16-dione
Abiraterone was designed in the early 1990s using
pregnenolone as a backbone to bind the active site of
CYP17A1 and inhibit its activity
Clinical impact of abiraterone in metastatic CRPC
PRE
POST
(asymptomatic/midly symptomatic)
docetaxel
COU-AA-302
Increase time to radiological progression
(16.5 vs 8.3 months, H· 0.53)
Trend to improve OS (NR vs 22 m.; HR:0.75)
25% reduction of risk of death
Delay the start of chemotherapy
(16.8 to 25.2 m)
Use of opiod, clinical deterioration
Ryan et al. New Eng J Med 2013
COU-AA-301
Improve OS (14.8 vs.10.9 m, HR:0.65).
35% reduction in risk of death
Improve time to progression
Quality of life
Pain
Skeletal related events
De Bono et et al. New Eng J Med 2011
Time to rPFS correlates with OS
rPFS may be a new surrogate endpoint to evaluate
treatment benefit in CRPC
Ryan et al NJM 2013
Ryan et al NJM 2013
Moving into earlier stages of prostate cancer
Potential “paradigm changes”…..
Re-definition of the concept of “castration”
Increase the chance of cure
of high-risc localized PC
Delay/prevention of M1
Modify from Scher et al. J Clin Oncol 2008
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
New hormononal therapies in CRPC
Enzalutamide
Clinical impact of enzalutamide in CRPC
PRE
POST
(asymptomatic/midly symptomatic)
docetaxel
PREVAIL
Increase time to radiological progression
Reduce risk of death
Delay the start of chemotherapy
Beer TM, et al. ASCO-GU 2014; Oral presentation.
AFFIRM
Improve OS
Increase time to radiological progression
Improve time to progression
Quality of life
Pain
Skeletal related events
Scher HI, N J M 2012
Other “anti-AR” therapies in CRPC
Other “anti-AR” therapies in CRPC
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
Gomez de Liaño A, Reig 0, Mellado B, Martin C,
Urgell Rul E , Maroto P.
Br J Cancer 2014
Towards a new paradigm in the treatment
of prostate cancer
• Prostate cancer as an example of hormone-dependent
disease
• AR and castration resistant progression
• Extra-testicular androgens and CRPC. Abiraterone
acetate
• Other new agents in CRPC
• Taxanes and AR
• What is after AR targeting????
Model of CRPC progression
Nelson P S JCO 2012 feb ;30:644-646
Epithelial to-mesenchymal-transition
-Embryological development, tissue repair, response to stimuli
-Reversible trans-differentiation of epithelial cells
Loss of epithelial markers (E-cadherine)
and acquisition of mesenchimal markers
(p.e. vimentine)
-“Share” characteristics with stem cells (stem cell like)
- IN CANCER: cell migration, metastasis, resistance to chemotherapy
IN PROSTATE CANCER:
androgen suppression and chemotherapy induce EMT
AR truncated isoforms
related to progression
Marin-Aguilera et al. Mol Cancer Ther 2014
Validation of docetaxel (D)-resistance profile in
localized high risk prostate cancer (LHRPC)
Neoadjuvant D+AD
followed by radical
prostatectomy 1
in vitro model
Radical
prostatectomy
specimens
LHRPC patients
93 genes of
D-resistance*
Radical
prostatectomy
*Taqman low-density arrays
1 Mellado et al. Br J Cancer 2009
Marin-Aguilera et al. 2013
63 (67.7%) out of 93 tested genes showed differential
expression genes differed between groups (P<0.05),
NFkB
AR
EMT/STEM CELL
Marin-Aguilera et al. Mol Cancer Ther 2014
Marin-Aguilera et al. Mol Cancer Ther 2014
ZEB-1+/CD44+ cells are present
in primary tumors
Marin-Aguilera et al. Mol Cancer Ther 2014
Conclusions
CRPC is a heterogeneous and dynamic disease
The persistence of AR activity is important in progression of the disease
The best sequence and/or combination of chemotherapy/new hormonal
agents is not known
There is a need to define subsets of CRPC based on biomarkers to
predict therapeutic benefit
The emergence of AR-independent progression during treatment
selection needs to be fully charactherized
Medical Oncology Department and
Laboratory of traslational Oncology.
IDIBAPS. Hospital Clinic
Mercedes Marin-Aguilera
Jordi Codony-Servat
Oscar Reig
Begoña Mellado
Natalia Jimenez
Pere Gascón
María Verónica Pereira
Pathology Department
Pedro L Fernández
Raquel Bermudo
Bioinformatics Platform Department
Juanjo J Lozano
Hospital Plató
Gemma Carrera
Urology Department
M José Ribal
Antonio Alcaraz
Lourdes Mengual
Other hospitals:
Albert Font. ICO Badalona
Enrique Gallardo. Parc Taulí Sabadell.