Transcript The near future: molecular targeted therapies for metastatic prostate

Mediterranean School of Oncology
NEW PERSPECTIVES IN METASTATIC
PROSTATE CANCER
Rome, June 15, 2012
CINBO
The near future: molecular
targeted therapies for
metastatic prostate cancer
Alessandra Felici,
Oncologia Medica A
Istituto Regina Elena
Rome
The Two-Compartment
Model
• Epitheliel compartment: prostate cancer
ephitelial cells
• Stromal compartment: bone
microenvironment (hematopoietic cells,
fibroblasts, endothelial cells, adipocytes,
macrophages, osteoblasts, osteoclasts
and mesenchymal stem cells + soluble
extracellular matrix rich in growth factors
and cytokines)
• Epithelial targeting therapies
• Stromal targeting therapies
• Epithelial-stromal targeting
therapies
Epithelial Targeting Therapies
• Chemotherapy (intrinsic defect in
epithelial cell apoptosis due to BCL2
overexpression and PTEN loss)
• Oligonucleotides antisense that target
clusterin (a chaperone protein involved
in cell proliferation and survival)
Epithelial Targeting Therapies
• Chemotherapy (intrinsic defect in
epithelial cell apoptosis due to BCL2
overexpression and PTEN loss)
• Oligonucleotides antisense that target
clusterin (a chaperone protein involved
in cell proliferation and survival)
Androgen-dependent
prostate cancer
Androgen-independent
prostate cancer
Schalken, BJU, 2007
Changes in gene expression with progression
of prostate cancer
Stavridi, Cancer Treatment Reviews, 2010
Epithelial Targeting Therapies
• Chemotherapy (intrinsic defect in
epithelial cell apoptosis due to BCL2
overexpression and PTEN loss)
• Oligonucleotides antisense that
target clusterin (a chaperone protein
involved in cell proliferation and
survival)
Chaperone protein
Clusterin
Hsp27
OGX-011 OGX-427
(custirsen)
Clusterin structure
Zoubeidi A et al. Clin Cancer Res 2010;16:1088-1093
Randomized phase II study of docetaxel and
prednisone with or without OGX-011 in patients with
metastatic castration-resistant prostate cancer
•
•
•
•
•
D/P ± OGX-011 640 mg iv weekly (82 pts)
PSA decline ≥ 50%: 58% arm A v 54% arm B
PFS: 7.3 v 6.1 mos (95% CI 5.3-8.8; 95% CI 3.7-8.6)
OS: 23.8 v 16.9 mos (95% CI 16.2-not reached; 95% CI 12.8-25.8)
Main side effects: fever, rigors, diarrhea, rash
Chi KN, J Clin Oncol, 2010
Randomized phase II trial of Custirsen (OGX-011) in
combination with docetaxel or mitoxantrone as second-line
therapy in patients with metastatic castrate-resistant prostate
cancer progressing after first-line docetaxel: CUOG trial P-06c
20 DPC
77% pain responses
PSA declines ≥50%: 60%
OS: 15.8 mos
Time to pain progression
(TTPP): 10.0 mos
22 MPC
46% pain responses
PSA declines ≥50%: 27%
OS: 11.5 mos
Time to pain progression
(TTPP): 5.2 mos
Saad, Clin Cancer Res, 2011
Rocci, Cancer Res, 2005
Zoubeidi, Cancer Res, 2007
First-Line OGX-427 + Prednisone vs
Prednisone in mCRPC

OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression
Patients with
progressive mCRPC
who received no prior
chemotherapy for
metastatic disease
OGX-427 600 mg IV x 3. loading doses
within 10 days, then 1000 mg IV weekly +
Prednisone 5 mg PO BID
(N = 33)
Prednisone 5 mg PO BID*
*Crossover allowed upon disease progression

Primary endpoint: PD at 12 wks

Secondary endpoints: PSA decline, measurable disease response, PFS, TTP,
CTC count, serum/plasma HSP27
Chi KN, et al. ASCO 2012.
OGX-427/Prednisone in mCRPC:
Results
Outcome, n (%)
OGX-427/Prednisone
Prednisone
(n = 17)
(n = 15)
12 (71; 95% CI: 0.440,0.897)
6 (40;95% CI:0.163,0.677)
5 (29)
9 (60)
(n = 22)
(n = 20)
• ≥ 80%
2 (9)
1 (5)
• ≥ 60%
11 (50)
4 (20)
• ≥ 30%
13 (59)
6 (30)
• Any
17 (77)
11 (55)
(n = 9)
(n = 12)
• CR
1 (11)
0
• PR
3 (33)
0
• SD
1 (11)
7 (58)
• PD
0
2 (17)
Disease progression at 12 wks
• No disease progression
• Disease progression
Best PSA decline from baseline
Measurable disease response
Chi KN, et al. ASCO 2012.
OGX-427/Prednisone for mCRPC:
Toxicity
Incidence of All Laboratory
Treatment-Emergent Events
OGX-427 +
Prednisone
(n = 22)
Prednisone
(n = 20)
Grade 3/4
Grade 3/4
Lymphopenia, n
4 (11%)
2 (10%)
Chills, n
1 (5%)
0
Hyperglycemia, n
3 (14%)
1 (5%)
Elevated creatinine, n
1* (5%)
0
Fatigue, n
1 (5%)
0
Hypertension, n
1 (5%)
0
Hyponatremia, n
1 (5%)
0
*1 case of grade 4 hemolytic uremic syndrome reported at Wk 7.
Chi KN, et al. ASCO 2012.
Stromal Targeting Therapies
• Endothelin type A (ETA) receptor
antagonist (Atrasentan)
• Monoclonal antibodies against RANKL
(Denosumab)
• Antiangiogenic Agents
Stromal Targeting Therapies
• Endothelin type A (ETA) receptor
antagonist (Atrasentan)
• Monoclonal antibodies against RANKL
(Denosumab)
• Antiangiogenic Agents
Antiangiogenesis Agents
– Bevacizumab (VEGFmAb)
– Lenalidomide (thalidomide analog)
– Aflibercept (VEGF Trap)
– Sunitinib (multitargeted small molecule
VEGFR TKI)
– Sorafenib (multitargeted small molecule
VEGFR TKI)
– Tasquinimod
A Phase 2 Study of Estramustine, Docetaxel, and
Bevacizumab in Men With Castrate-Resistant Prostate Cancer
Results From Cancer and Leukemia Group B Study 90006
RESULTS (79 pts)
• 75% had a ≥ 50% PSA decline
• 59% had a partial response
• Median PFS 8 months (1st end point)
• Overall median survival: 24 months
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TOXICITY
• 69% neutropenia without fever
• 25% fatigue
• 9% thrombosis/emboli
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Picus, Cancer, 2011
Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing
Docetaxel and Prednisone With or Without Bevacizumab in Men With
Metastatic Castration-Resistant Prostate Cancer: CALGB 90401
1050 pts with chemotherapy-naive progressive mCRPC
Docetaxel 75 mg/m2, PDN 5 mg bid ± beva 15 mg/kg, q21
OS: 22.6 v 21.5 mos H(R: 0.91; 95% CI 0.78 to 1.05; p=.181)
(primary end-point)
PFS: 9.9 v 7.5 mos (p<.002)
OR: 49.4% v 35.5% (p=.0013)
Grade 3/4 toxicities: 75.4% v 56.2% (p≤.001)
Kelly, J Clin Oncol, 2012
Phase II docetaxel, bevacizumab,
thalidomide and prednisone (60 pts)
•89,6% had <50 % PSA response
•Overall response 64%
•PFS: 18,3 mos
•OS: 28,2 mos
Bamidele Adesunloye, ASCO 2012
54 pts
46 (85.2%) has maximal PSA decline of >50%
30 pts had measurable disease: 1 CR and 25
PR by RECIST
PFS: 22 mos
90% alive at 12 mos
25 of study: 17 for radiographic progression, 8
for other reasons
Dual antiangiogenic
therapy + docetaxel
and prednisone
resulted in high PSA
and tumor response.
Toxicities were
manageable.
Multitargeted Tirosin Kinase Inhibitors
Fizazi, BJU, 2010
Tasquinimod
• Oral quinoline-3carboxamide derivative that
bind S100A9 protein
• Growth inhibition: upregulation of TSP-1; downregulation of HIF-1 α protein,
androgen receptor protein,
glucose transporter-1 protein
• Anti-angiogenic response:
decrease tumor tissue level
of VEGF
Phase II Randomized, Double-Blind, Placebo-Controlled
Study of Tasquinimod in Men With Minimally Symptomatic
Metastatic Castrate-Resistant Prostate Cancer
201 asymptomatic or mildly symptomatic pts with
bone-metastases (134 T, 67 placebo)
PFS at 6 mos: 69% vs 37% (median PFS: 7.6
mos vs 3.3 mos) p<.001
Time to symptomatic progression was longer in T
treated pts (p=0.039; HR:0.42)
Side effects: GI disorders, fatigue,
musculoskeletal pains, elevations of pancreatic
and inflammatory biomarkers
All pts
Visceral mets
Bone mets
Pili, J Clin Oncol 29:4022-4028, 2011
°
_+
Epithelial-Stromal Targeting
Therapies
• Novel Agents that Interfere with
Androgen Signaling (Abiraterone, TAK700, MDV3100)
• Targeted Agents (Dasatinib,
Cabozantinib)
• Immunotherapy (Sipuleucel-T,
Ipilimumab, PROSTVAC-VF)
Cabozantinib (XL184)
• Is a potent targeted therapy that inhibits MET and VEGFR2
• MET pathway activation promotes tumor growth, invasion and
metastasis.
• Overexpression of MET and/or its ligand HGF are associated with
prostate cancer metastasis.
• In preclinical studies, androgen ablation upregulates MET signaling.
Hussain, ASCO 2011
Cabozantinib (XL184) in Chemotherapy-Pretreated
mCRPC: Results from a Phase 2 Non-Randomized
Expansion Cohort (Abstract n. 4513)
Smith, ASCO 2012
Key Eligibility Criteria:
Prior Docetaxel (>225 mg/m2) and bone metastases documented on bone
scan
Radiographic progression within 6 months of last taxane dose
Two dose level explored sequentially:
100 mg po QD (N=93); 40 mg po QD
(N=51)
Bone Scan Response by Independent Radiology Review
Results and Toxicity
Phase II Cabozantinib
Summary
• Cabozantinib 100 mg QD demonstrates
robust clinical activity in docetaxel-pretreated
mCRPC patints:
– 67% complete or partial bone scan responses
– 80% regression of measurable disease
– 46% madian pain improvment in patients with pain
score <4
• 56% decrease or discontinued narcotics
• Activity regardless of prior abiraterone and/or cabazitaxel
therapy
• Preliminary evidence supports clinical activity at 40 mg
QD
• Manageable AEs
Phase III trials in mCRCP with
survival advantages
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FDA regulatory approvals in
mCRCP in US
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Conclusions
• Despite the significant advances in treatment
options for patients with CRPC, their
prognosis remains poor.
• Targeting multiple signaling pathways may
yield better results
• A big challenge is the inability to tailor therapy
individually based on the unique
characteristics of a particular cancer
• Every patient with CRPC should be
encouraged to participate in clinical trial