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The near future: molecular targeted therapies for metastatic prostate cancer

Explore the latest advancements in targeted therapies for metastatic prostate cancer at the Mediterranean School of Oncology, focusing on epithelial and stromal compartment treatments and their impact on patient outcomes.

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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

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