Cabazitaxel: Understanding the new taxoid for prostate cancer

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