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Cabazitaxel: Understanding the new taxoid for prostate cancer

Cabazitaxel: Understanding the new taxoid for prostate cancer. Cesar Rodriguez Valdes, M.D. James Graham Brown Cancer Center Department of Medical Oncology. Learning objectives. Brief overview of prostate cancer and the mechanism of action of taxanes.

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Cabazitaxel: Understanding the new taxoid for prostate cancer

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  1. Cabazitaxel: Understanding the new taxoid for prostate cancer Cesar Rodriguez Valdes, M.D. James Graham Brown Cancer Center Department of Medical Oncology

  2. Learning objectives • Brief overview of prostate cancer and the mechanism of action of taxanes. • Discuss the molecular properties of cabazitaxel. • Integrating concepts for second line therapy in castrate resistant prostate cancer. • Overview of advances in other study treatments.

  3. Prostate cancer • Prostate cells store large amounts of zinc. • Produce citrate for semen. • Requires large amounts of ATP. • Cancer cells do not accumulate zinc. • Lack ZIPI transporter. • Use stored energy for cell division. • Second most common malignant tumor in men. • 25% of new cancer diagnoses.

  4. Prostate cancer management • Important distinction in staging: prostate confinement. • Local and regional stages have a 100% 5-year survival. • Treatment for localized disease: • Surveilance (stage I) • Surgical resection or cryosurgery • Radiation therapy • Brachytherapy • External beam radiation • High intensity focused ultrasound (HIFU)

  5. Prostate cancer management • Metastatic disease is not curable. • Treatment achieves temporary disease control. • Treatment of metastatic disease: • Hormone ablation therapy. • Orchiectomy • Gonadotropin releasing hormone agonists. • Antiandrogens. • Estrogens • Chemotherapy Most become Refractory after 1-3 years.

  6. Overview of taxanes

  7. Overview of taxanes • Hydrocarbons (diterpenes) originating from pinetrees, butterflies or termites. • Disrupt microtubule function. • Stabilization against cold-induced. depolimerization. • Radiosensitizing

  8. Microtubule dynamics Hydrolysis and growth Dissociation and rescue Tubulin GTP- bound GDP- bound

  9. Molecular structure cabazitaxel docetaxel

  10. Advantages of cavezitaxel • Semi-synthetic taxane. • Cavazitaxel is more cytotoxic towards MDR1- expressing tumor cells. What is the MDR1 gene (ABCB1)? • Encodes an ATP-dependent P-glycoprotein. • Membrane protein that works as a drug efflux pump. • Has broad substrate specificity. • Responsible for decreased drug accumulation in multidrug-resistant cells. • Functions as a transporter in the blood-brain barrier.

  11. Taxanes for treating CRPC

  12. Vol 15 Oct 7,2004

  13. TAX 327 trial • Study type: randomized non-blinded Phase III multicenter trial. • 24 countries • Population: 1006 patients with metastatic CRPC. Study Objectives: • Primary goal: overall survival. • Secondary: pain control, PSA levels, quality of life.

  14. docetaxel q3 weeks - 75 mg/m2 every 3 weeks - prednisone 5mg PO twice daily mitoxantrone - 12 mg/m2 every 3 weeks - prednisone 5mg PO twice daily docetaxel weekly - 30 mg/m2 weekly - prednisone 5mg PO twice daily TAX 327 trial (cont’d) 1006 patients Metastatic CRPC on • Inclusion criteria • - confirmed diagnosis of metastates • progression of dz while on hormone treatment • Karnofsky of at least 60 • no cytotoxic pretreatments • 4 weeks of being off antiandrogens

  15. TAX 327 trial results

  16. Second-line therapy for CRPC

  17. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Final results of a multinational phase III trial. TROPIC trial A.O. Sartor, S. Oudard, el al.

  18. TROPIC trial • Phase III clinical trial

  19. TROPIC study design Cabazitaxel 25mg/m2 q 3 wk + oral prednisone 10 mg daily for 10 cycles N=378

  20. TROPIC trial (cont’d)

  21. TROPIC trial (cont’d) • Pre-protocol treatments

  22. TROPIC trial (cont’d) Kaplan-Meier overall survival curve Cabazitaxel + prednisone Cabazitaxel + prednisone

  23. TROPIC trial (cont’d) • Subgroup overall survival analyses

  24. TROPIC trial (cont’d) • Secondary endpoint: progression free survivial

  25. TROPIC trial (cont’d) • Secondary endpoint: response and time to progression

  26. TROPIC trial (cont’d) • Adverse events

  27. TROPIC trial (cont’d) • Adverse events

  28. TROPIC trial (cont’d) • Deaths during study

  29. TROPIC trial summary • Cabazitaxel has a statistical and clinical significant improvement in OS compared to mitoxantrone treated patients. • OS: 15.1 vs 12.7 months • 30% risk reduction of death (HR=0.7, P<0.0001) • Grade 3/4 side effects are more significant than mitoxantrone treatment. • More neutropenic fevers, diarrhea and deaths caused by treatment.

  30. Other promising treatments

  31. Sipuleucel-T • Patient’s antigen presenting cells (APC) co-cultured with a fusion protein of prostatic acid phosphates (PAP). • Granulocyte-macrophage colony stimulating factor. Phase III trials (D9901 and D9902A) with 225 CRPC patients. - IMPACT trial • Sipuleucel-T vs placebo • 33% reduction in risk of death (HR 1.50; 95% CI: 1.10, 2.05; p=0.011) • Median survival 23.2 months vs 18.9 months. • 72% of placebo patients who progressed received sipuleucel Higano et al.Cancer 2009

  32. Denosumab • Human monoclonal antibody designed to target RANKL ligand. • Leads to inhibition of osteoclast maturation. • Approved for postmenopausal women at risk of osteoporosis. Phase II study on patients with metastatic bone disease. • Urinary N-telopeptide (uNTx) levels in patients treated with denosumab vs biphosphonates. • Levels normalized in 71% and 29% respectively. Phase III trial (NCT00321620) with 1,901 CRPC patients. • Denosumab vs zoledronic acid. • Skeletal-related events. Di Lorenzo et al. Drugs 2010

  33. Di Lorenzo et al. Drugs 2010

  34. Thank you

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