alessandra felici, oncologia medica a istituto regina elena rome the near future: molecular targeted...
TRANSCRIPT
Alessandra Felici, Oncologia Medica A
Istituto Regina Elena
Rome
The near future: molecular targeted therapies for
metastatic prostate cancer
NEW PERSPECTIVES IN METASTATICPROSTATE CANCER
Rome, June 15, 2012CINBO
Med
iterr
anea
n S
choo
l of O
ncol
ogy
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
Schalken, BJU, 2007
Androgen-independent prostate cancer
Stavridi, Cancer Treatment Reviews, 2010
Changes in gene expression with progression of prostate cancer
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(custirsen)
OGX-427
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, 2005Zoubeidi, Cancer Res, 2007
Chi KN, et al. ASCO 2012.
Patients with progressive mCRPC who received no prior
chemotherapy for metastatic disease
(N = 33)
Primary endpoint: PD at 12 wks
Secondary endpoints: PSA decline, measurable disease response, PFS, TTP, CTC count, serum/plasma HSP27
OGX-427 600 mg IV x 3. loading doses within 10 days, then 1000 mg IV weekly +
Prednisone 5 mg PO BID
Prednisone 5 mg PO BID*
*Crossover allowed upon disease progression
OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression
First-Line OGX-427 + Prednisone vs Prednisone in mCRPC
Chi KN, et al. ASCO 2012.
Outcome, n (%) OGX-427/Prednisone Prednisone
Disease progression at 12 wks (n = 17) (n = 15)
•No disease progression 12 (71; 95% CI: 0.440,0.897)
6 (40;95% CI:0.163,0.677)
•Disease progression 5 (29) 9 (60)
Best PSA decline from baseline (n = 22) (n = 20)
•≥ 80% 2 (9) 1 (5)
•≥ 60% 11 (50) 4 (20)
•≥ 30% 13 (59) 6 (30)
•Any 17 (77) 11 (55)
Measurable disease response (n = 9) (n = 12)
•CR 1 (11) 0
•PR 3 (33) 0
•SD 1 (11) 7 (58)
•PD 0 2 (17)
OGX-427/Prednisone in mCRPC: Results
Chi KN, et al. ASCO 2012.
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.
OGX-427/Prednisone for mCRPC: Toxicity
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
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
QuickTime™ e undecompressore TIFF (Non compresso)
sono necessari per visualizzare quest'immagine.
QuickTime™ e undecompressore TIFF (Non compresso)
sono necessari per visualizzare quest'immagine.
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
TOXICITY
• 69% neutropenia without fever
• 25% fatigue
• 9% thrombosis/emboli
Picus, Cancer, 2011
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)
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
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
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
46 (85.2%) has maximal PSA decline of >50%
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-3-carboxamide derivative that bind S100A9 protein
• Growth inhibition: up-regulation of TSP-1; down-regulation of HIF-1 α protein, androgen receptor protein, glucose transporter-1 protein
• Anti-angiogenic response: decrease tumor tissue level of VEGF
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
Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic
Metastatic Castrate-Resistant Prostate Cancer
Pili, J Clin Oncol 29:4022-4028, 2011
All pts
Visceral mets
Bone mets
°_+
Epithelial-Stromal Targeting Therapies
• Novel Agents that Interfere with Androgen Signaling (Abiraterone, TAK-700, MDV3100)
• Targeted Agents (Dasatinib, Cabozantinib)
• Immunotherapy (Sipuleucel-T, Ipilimumab, PROSTVAC-VF)
• 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)
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 scanRadiographic progression within 6 months of last taxane dose
Bone Scan Response by Independent Radiology Review
Two dose level explored sequentially: 100 mg po QD (N=93); 40 mg po QD (N=51)
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
QuickTime™ e undecompressore TIFF (Non compresso)
sono necessari per visualizzare quest'immagine.
FDA regulatory approvals in mCRCP in US
QuickTime™ e undecompressore TIFF (Non compresso)
sono necessari per visualizzare quest'immagine.
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