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CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS P. Carlini, Rome

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS P. Carlini, Rome.

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CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS P. Carlini, Rome

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  1. CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTSP. Carlini, Rome

  2. Although a variety of cytotoxic agents have been actively investigated for the treatment of patients with CRPC, most agents tested have demonstrated only marginal efficacy and, at best, have extended survival only 10–12 months. Mike Shelley, et al. Cochrane Database Syst Rev 2008

  3. Mike Shelley, et al. Cochrane Database Syst Rev 2008

  4. Mitoxantrone Mitoxantrone with prednisone is the only other cytotoxic regimen indicated for CRPC based on a palliative benefit (improvement in the McGill-Melzack bone pain score) rather than a prolongation of OS. PSA response, as defined above, occurs in approximately 20%– 30% of patients treated with mitoxantrone in the first-line setting and in 15% of patients treated in the second- line setting following docetaxel Kantoff PW et al J Clin Oncol 1999;17: 2506–2513. Tannock IF et al. J Clin Oncol 1996;14:1756 –1764. Berthold DR et al Ann Oncol 2008;19:1749 –1753. Rosenberg JE et al Cancer 2007;110:556 –563.

  5. FDA Regulatory Approvals in Metastatic CRPC Estramustine-1981 Ancient History Strontium89-1993 Reduction in new onset of painful bone lesions after XRT + isotope Mitoxantrone + prednisone-1996 Reduction in pain Samarium153-1997 Reduction in bone pain Zoledronic acid-2002 Skeletal related event reduction Docetaxel + prednisone-2004 Prolonged survival Sipuleucel-T-2010 Prolonged Survival Cabazitaxel + prednisone-2010 Prolonged Survival Denosumab-2010 Skeletal related event reduction Abiraterone + prednisone-2011 Prolonged Survival 2012: MDV3100 and radium-223 chloride Prolonged Survival

  6. Two randomised phase 3 trials have demonstrated a significant improvement in overall survival (OS) for docetaxel- based chemotherapy, compared with themitoxantrone-prednisone combination 30 months Petrylak DP et al NEJM 2004; 351: 1513–20. Tannock IF et al NEJM 2004; 351: 1502–12 Docetaxel given at the dose of 75 mg/m2 every 21 d is the sole regimen approved by the FDA and EMA for the treatment of mCRPC

  7. Treatment for docetaxel-resistant CRPC is becoming a major unmet need for patients with advanced prostate cancer because no standard treatment exists for this clinical situation Berthold DR et al J Clin Oncol 2005;23:8247– 8252.

  8. MECHANISMS OF RESISTANCE TO DOCETAXEL IN METASTATIC PROSTATE CANCER. Seruga B et a. NRCO 2011

  9. CELLULAR MECHANISMS OF RESISTANCE TO TAXANES Seruga B et a. NRCO 2011

  10. SECOND LINE CHEMOTHERAPY OPTIONS • DOCETAXEL RE-CHALLENGE • NEW TAXANES :CABAZITAXEL • NEW CHEMOTHERAPEUTIC AGENTS: • EPOTHILONES,, NEW PLATINUM- BASED REGIMENS, • NONTAXANE HALICHONDRIN B ANALOG MICROTUBULE INHIBITOR,

  11. NEW CHEMOTHERAPEUTIC AGENTS • NEW TAXANES: CABAZITAXEL, NAB-PACLITAXEL • EPOTHILONES:IXABEPILONE,PATUPILONE,SAGOPILONE • PLATINUM CHEMOTHERAPY DRUGS:SATRAPLATIN • NONTAXANE HALICHONDRIN B ANALOG MICROTUBULE INHIBITOR: ERIBULIN MESYLATE (E7389) • METRONOMIC CHEMOTHERAPY

  12. NEW TAXANES

  13. CABAZITAXEL The Oncologist 2012;17:543–549

  14. Cabazitaxel: a next generation taxane Both extracted from needles of the European Yew treeTaxus baccata Y X O Y X Docetaxel -OH -OCCH3 Cabazitaxel -OCH3 -OCH3 These 2 radicals confer very specific properties to cabazitaxel 99th AACR annual meeting, San Diego, April 2008 (abstract #3227)

  15. Cabazitaxel: selected to overcome taxane resistance Some patients do not answer to Docetaxel (acquired or constitutional resistance). This may be due to various mechanisms: affinity for multidrug resistant (MDR) membrane-associated P-glycoprotein (PgP) efflux pump, alterations of tubulin, overexpression Bcl-2, Aurora-A … Cabazitaxel: Poor affinity for the PgP efflux pump greater penetration of the blood brain barrier compared with docetaxel and paclitaxel Active in vitro and in vivo on tumors resistant to Docetaxel H R Taxane • Docetaxel and paclitaxel have a strong affinity for the PgP pump • If the PgP pump is surexpressed, it drives drug out of tumour cell Mita AC et al, Clin Cancer Res. 2009, 15, 723-730

  16. Preclinical data Activity against tumor cells and tumor models that are resistant to, or not sensitive tocurrently available taxanes¹,² As potent as docetaxel against sensitive cell lines and tumor models¹,² Phase I studies Dose-limiting toxicity was neutropenia Antitumor activity in mCRPC including docetaxel-resistant disease3 Cabazitaxel: preclinical & clinical data ¹ Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.² Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552. 3 Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.

  17. Primary endpoint:OS Secondary end-points: Progression-freesurvival (PFS), response rate, and safety De Bono JS et al. Lancet 2010; 376: 1147–54

  18. Baseline characteristics and treatment history of patients in the intention-to-treat population De Bono JS et al. Lancet 2010; 376: 1147–54

  19. Baseline characteristics and treatment history of patients in the intention-to-treat population De Bono JS et al. Lancet 2010; 376: 1147–54

  20. Primary endpoint:Overall survival (updated ITT analysis*) De Bono JS et al. Lancet 2010; 376: 1147–54

  21. Progression-free survival De Bono JS et al. Lancet 2010; 376: 1147–54

  22. De Bono JS et al. Lancet 2010; 376: 1147–54 Oudard S, Future Oncology, 2011

  23. TROPIC Update: at 2 years the same OS (HR 0.70 vs 0.72) OS: 15,1 Vs 12,7 mo Cut-off Sept 25, 2009) De Bono JS, The Lancet 2010 Oudard S, Future Oncology, 2011

  24. Intention-to-treat analysis of overall survival in subgroups of patients defined by baseline characteristics. De Bono JS et al. Lancet 2010; 376: 1147–54

  25. TROPIC Cabazitaxel: Haematological results * *Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator. • Higher rate of grade ≥ 3 neutropenia than in TAX 327 but patients enrolled in TROPIC had more advanced disease, were heavily pretreated and had weekly hematological testing The incidence of neutropenia varied significantly by region, with rates of neutropenia in North America exceeding those in the Europe De Bono JS et al. Lancet 2010; 376: 1147–54

  26. TROPIC Cabazitaxel: Most frequent adverse events De Bono JS et al. Lancet 2010; 376: 1147–54

  27. Deaths in patients who received at least one dose of study treatment De Bono JS et al. Lancet 2010; 376: 1147–54

  28. Conclusions: TROPIC Cabazitaxel demonstrated a statistically and clinically significant survival improvement compared with mitoxantrone in study population 15.1 months vs 12.7 months 28% reduced risk of death (HR=0.72, P <.0001) Survival benefit consistent across subgroups Secondary endpoints of PFS, RR, and TTP also significantly improved Safety profile was manageable Proactive management of side effects recommended (neutropenia/diarrhea) Cabazitaxel is the first treatment to show a survival benefit in patients with mCRPC after failure of docetaxel-based therapy 30

  29. TROPIC post-hoc analyses: impact of cabazitaxel on overall survival at 2 yrs in patients with aggressive disease Methods: Patients with poorly differentiated tumours and/or with visceral metastases at baseline were analyzed in term of OS • Aggressive disease was defined as the presence of poorly differentiated tumour histopathology at diagnosis, or presence of visceral metastases. • Visceral metastases are defined as the presence of lung, liver, adrenal or pancreatic lesions. Oudard S. at al. ESMO 2012 abs 933P

  30. Overall survival by differentiation at diagnosis Patients with poorly differentiated tumour histopathology showed significantly improved OS with CbzP compared with MP Oudard S. at al. ESMO 2012 abs 933P

  31. Overall survival by duration of hormonal therapy Cabazitaxel was associated with a significant survival advantage over MP in all subgroups, suggesting that duration of prior hormonal therapy does not affect the OS benefit associated with cabazitaxel Oudard S. at al. ESMO 2012 abs 933P

  32. In patients likely to poorly respond to abiraterone (eg, high Gleason score, rapid progression to CRPC with primary ADT, or progression during docetaxel therapy), cabazitaxel might be the first option in the second- line setting. For patients with less-aggressive mCRPC, cabazitaxel and abiraterone are reasonable treatment options. Heidenreich A et al European Urology 9 August 2012

  33. NAB-PACLITAXEL

  34. 2 cycles of 150 mg/in2 nab-paclitaxel weekly for 3 weeks during each 4-week cycle, followed by radical prostatectomy with bilateral lymphadenectomy. Journal of Urology 2009; 181, 1672 1677

  35. Post-chemotherapy prostate specific antigen was decreased in 18 of 19 (95%) Intracytoplasmic vacuolization occasional Intranuclear Inclusions. Journal of Urology 2009; 181, 1672 1677

  36. First-line Therapy : NAB-PACLITAXEL Kolevska et al2009: 100 mg/m2 was administered IV QW for 3 weeks of a 4-week cycle. ( 35pts) PSA response was achieved in 9 (25%) Clinical Benefit (response + SD) of 68%. Amato et al. 2012 in combination with leuprolide and bicalutamide (46 pts) After two years of therapy, tumor regression was achieved in 78% of patients with a median reduction of PSA level of >90%.

  37. EPOTHILONES:IXABEPILONE

  38. EPOTHILONES (1) The epothilones represent a novel class of cytotoxic agents that stabilizes microtubules, leading to cell cycle arrest at the G2/M phase of the cell cycle and triggering death, especially in rapidly growing cells Lee FY et al Clin Cancer Res 2001;7:1429 –1437 Detailed structural studies have identified a taxane binding site on the  -tubulin surface localized on the luminal (inner) surface of microtubules. Nogales E et al. Nature 1995;375:424–427

  39. EPOTHILONES (2) Epothilones also circumvent the overexpression of the multidrug resistance genes or proteins such as MDR-1 and MRP-1 Goodin S et al. J Clin Oncol 2004;22:2015–2025. These agents have also been shown to inhibit tumor growth in taxane-resistant cell lines, suggesting a lack of crossresistance between the two drug classes Lee FY et al. Cancer Chemother Pharmacol 2009;63:201–212. Altmann KH. Curr Pharm Des 2005;11:1595–1613 Sepp-Lorenzino L et al. Prostate Cancer ProstaticDis 1999;2:41–52.

  40. IXABEPILONE: Trials (1)

  41. IXABEPILONE: Trials (2)

  42. EPOTHILONES: PATUPILONE

  43. PATUPILONE

  44. Patupilone 2.5 mg/m2 weekly for 3 weeks of a 4-week cycle. Annals of Oncology 20: 492–497, 2009

  45. EPOTHILONES: SAGOPILONE

  46. SAGOPILONE Graff J et al.abstract 5141. J Clin Oncol 2008;26:284s.

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