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The near future: molecular targeted therapies for metastatic prostate cancer
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The near future: molecular targeted therapies for metastatic prostate cancer

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  1. NEW PERSPECTIVES IN METASTATIC PROSTATE CANCER Rome, June 15, 2012 CINBO The near future: molecular targeted therapies formetastatic prostate cancer Mediterranean School of Oncology Alessandra Felici, Oncologia Medica A Istituto Regina Elena Rome

  2. 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)

  3. Epithelial targeting therapies • Stromal targeting therapies • Epithelial-stromal targeting therapies

  4. 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)

  5. 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)

  6. Androgen-independent prostate cancer Androgen-dependent prostate cancer Schalken, BJU, 2007

  7. Changes in gene expression with progression of prostate cancer Stavridi, Cancer Treatment Reviews, 2010

  8. 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)

  9. Chaperone protein Clusterin Hsp27 OGX-011 (custirsen) OGX-427

  10. Clusterin structure Zoubeidi A et al. Clin Cancer Res 2010;16:1088-1093

  11. 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

  12. 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

  13. Rocci, Cancer Res, 2005 Zoubeidi, Cancer Res, 2007

  14. First-Line OGX-427 + Prednisone vs Prednisone in mCRPC • OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression OGX-427 600 mg IV x 3. loading doses within 10 days, then 1000 mg IV weekly + Prednisone 5 mg PO BID Patients with progressive mCRPC who received no prior chemotherapy for metastatic disease (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.

  15. OGX-427/Prednisone in mCRPC: Results Chi KN, et al. ASCO 2012.

  16. OGX-427/Prednisone for mCRPC: Toxicity *1 case of grade 4 hemolytic uremic syndrome reported at Wk 7. Chi KN, et al. ASCO 2012.

  17. Stromal Targeting Therapies • Endothelin type A (ETA) receptor antagonist (Atrasentan) • Monoclonal antibodies against RANKL (Denosumab) • Antiangiogenic Agents

  18. Stromal Targeting Therapies • Endothelin type A (ETA) receptor antagonist (Atrasentan) • Monoclonal antibodies against RANKL (Denosumab) • Antiangiogenic Agents

  19. Antiangiogenesis Agents Bevacizumab (VEGFmAb) Lenalidomide (thalidomide analog) Aflibercept (VEGF Trap) Sunitinib (multitargeted small molecule VEGFR TKI) Sorafenib (multitargeted small molecule VEGFR TKI) Tasquinimod

  20. A Phase 2 Study of Estramustine, Docetaxel, and Bevacizumab in Men With Castrate-Resistant Prostate CancerResults 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 • TOXICITY • 69% neutropenia without fever • 25% fatigue • 9% thrombosis/emboli Picus, Cancer, 2011

  21. 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 ClinOncol, 2012

  22. 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 BamideleAdesunloye, ASCO 2012

  23. 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

  24. Dual antiangiogenic therapy + docetaxel and prednisone resulted in high PSA and tumor response. Toxicities were manageable.

  25. Multitargeted Tirosin Kinase Inhibitors Fizazi, BJU, 2010

  26. 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

  27. Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer All pts 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 Visceral mets Bone mets Pili, J ClinOncol 29:4022-4028, 2011

  28. °_+

  29. 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)

  30. 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

  31. Cabozantinib (XL184) in Chemotherapy-Pretreated mCRPC: Results from a Phase 2 Non-Randomized Expansion Cohort (Abstract n. 4513) Smith, ASCO 2012

  32. Key Eligibility Criteria:Prior Docetaxel (>225 mg/m2) and bone metastases documented on bone scanRadiographic 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

  33. Results and Toxicity

  34. Phase II CabozantinibSummary • 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

  35. Phase III trials in mCRCP with survival advantages

  36. FDA regulatory approvals in mCRCP in US

  37. 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