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PAOLO CARLINI Oncologia Medica A Dipartimento di Oncologia Medica

PAOLO CARLINI Oncologia Medica A Dipartimento di Oncologia Medica. Classification scheme for prostate cancer based on hormonal sensitivity (Scher HI et al. Urology 1995;46:142-48). CRPC definition. FDA Regulatory Approvals in Metastatic CRPC. Estramustine-1981 Ancient History

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PAOLO CARLINI Oncologia Medica A Dipartimento di Oncologia Medica

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  1. PAOLO CARLINI Oncologia Medica A Dipartimento di Oncologia Medica

  2. Classification scheme for prostate cancer based on hormonal sensitivity(Scher HI et al. Urology 1995;46:142-48)

  3. CRPC definition

  4. 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

  5. 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

  6. SWOG 9916 Overall Grade > 3 Toxicity D/E M/P 20 18 16 14 12 % of patients 10 8 6 4 2 0 Pain Neurologic Metabolic Infection Hematologic GI Flu-like symptoms Cardiovascular Petrylak et al. Proc ASCO. 2004;23:2. Abstract 3.

  7. Median survival Hazard (months) ratio p-value 19.2 0.79 0.004 17.8 0.87 0.086 16.3 – – Overall survival data from March 2007, with 867 deaths among 1,006 randomly assigned patients. FU 48 months Berthold DR et al JCO 2008; 26: 242–5.

  8. FU 30 months FU 48 months Berthold DR et al JCO 2008; 26: 242–5.

  9. However, the design of the TAX327 study did not include a direct comparison of the weekly arm to the every-3-wk arm, precluding any valid conclusion about the supposed superior efficacy of the 3-wk regimen Berthold DR et al JCO 2008; 26: 242–5.

  10. PROGNOSTIC MODEL FOR PREDICTING SURVIVAL IN MEN WITH HORMONE-REFRACTORY METASTATIC PROSTATE CANCER

  11. Patients were categorised into THREE RISK GROUPS: GOOD RISK (ZERO TO ONE FACTOR), medianOS: 25.7 mo INTERMEDIATE (TWO FACTORS), medianOS: 18.7 mo HIGH RISK (THREE TO FOUR FACTORS), median OS: 12.8 mo

  12. Armstrong AJ et al. E J C ( 2 0 1 0 ) 5 1 7 – 5 2 5

  13. TAX 327 ANALYSIS SURVIVAL No pain vs pain → 21.3 mos vs 14.2 mos PSA<115ng/ml vs PSA≥115ng/ml → 20.4 mos vs 14.8 mos Berthold, JCO 2008

  14. TAX 327 Survival: pain vs no pain/minimal n 183 183 184 Median survival 23.0 21.1 19.8 Hazard ratio 0.73 0.95 p value 0.009 0.65 n 152 151 153 Median survival 14.9 15.1 12.8 Hazard ratio 0.85 0.8 p value 0.17 0.068 Docetaxel q3w (n = 335) Docetaxel qw (n = 334) Mitoxantrone (n = 337) NO PAIN PAIN ‘Asymptomatic patients may have adverse prognostic factors for survival that warrant the initiation of chemotherapy’ R. De Wit in British Journal Urology Supp 2008 ‘If a patient is eager to receive active treatment, there is no reason to withhold treatment until the patients develops symptoms’ R. De Wit in Eur Journal of Urology Supp 2006 Berthold DR, et al. J Clin Oncol 2008;26:242–45

  15. TAX 327 ANALYSIS Pre Treatment PSA-DT predicts Survival Armstrong, CCR 2007

  16. TAX 327 ANALYSISPSA-DT and Basal PSA predict Survival Armstrong, CCR 2007

  17. OS according to bone-pain intensity and PSA-DTRetrospective analysis in 145 CRPC pts treated by docetaxel Asymptomatic pts with a short PSA DT: start CT as soon as possible Oudard, BJUI 2009

  18. SURVIVAL ACCORDING TO BONE PAIN INTENSITY (MINIMAL OR NO PAIN, MILD PAIN, MODERATE OR SEVERE PAIN) Oudard, BJUI 2009

  19. SWOG trial: Petrylak DP et al NEJM 2004; 351: 1513–20 • Treatment continued until disease progression or unacceptable adverse effects occurred or until a maximum of 12 cycles of DOC + EMP • TAX 327 trial: Tannock IF et al NEJM 2004; 351: 1502–12 • Treatment continued until disease progression or unacceptable adverse effects occurred or until a maximum of 10 cycles of DOC /3w (5 cycles of DOC/w) .

  20. Armstrong et al, Clin Cancer Res; 16(1) January 1, 2010

  21. Complete Vs non complete treatmentOS 20.8 Vs 11.4 months Armstrong et al, Clin Cancer Res; 16(1) January 1, 2010

  22. Methods: Patients who initiated cycle 10 of therapy without progression in both studies were included. Per protocol, men on the TAX-327 study received 1 additional cycle, while men on the AT-101 study received up to cycle 17. Men in both arms of the AT-101 study were combined for analysis, as no significant differences in outcomes were observed. Overall survival (OS) was estimated from the cycle 10 D infusion date, using the Kaplan-Meier method. Results: The number of men receiving cycle 10 cycle was similar (Fisher's exact test p-value=0.60) between the two studies (166 or 49.6% in the TAX-327 study versus 99 or 44.8% in the AT-101 study), though of these men, death date information was more complete due to longer follow-up in TAX-327 (79.5% versus 34.4%). Six- and 12-month estimated survival from cycle 10 was 92.2% (95% CI: 86.9-95.4%) and 74.6% (CI: 67.2-80.5%) for TAX-327 patients, compared with 92.8% (CI: 85.5-96.5) and 63.4% (CI: 51.8-72.9%) for those on AT-101. Survival statistics were similar beyond cycle 10 within good, intermediate and poor risk groups. 38 (38.4%) men on the AT-101 study completed all 17 cycles. Of men on the AT-101 study, 24 and 13 had consistently declining PSA through cycles 13 and 17. Conclusions:A survival benefit was not detected with more than 10 cycles of DP chemotherapy in men with mCRPC in this hypothesis-generating exploratory analysis. A subset of men with mCRPC continue to have declines in PSA up to cycle 17 and thus may have ongoing benefit to continued chemotherapy administration. However, a randomized clinical trial is necessary to establish the optimal duration of therapy Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC). Meeting: 2011 ASCO Annual Meeting Abstract No:4582 Author(s): G. R. Pond

  23. Time to Response in TAX 327 >16% of men had transient worsening of PSA (>23% in pain, >27% in QoL)… …before going on to respond EARLY INCREASES IN SERUM PSA (UP TO 12 WKS) SHOULD BE IGNORED WHEN DETERMINING RESPONSE OR PROGRESSION. Berthold et al, Clin Canc Res 2008; 14: 2763-2767

  24. A considerable portion of CRPC patients experience an initial PSA surge/ flare-up under systemic chemotherapy. The incidence of a PSA surge/flare-up ranges according to the reported studies between 7.6% and 13.6%. Scher et al. recommended a 12-week period drug exposure based on their results on PSA progression-free survival and overall survival. (PCWG2: JCO 26(7),2008)

  25. Treatment with weekly docetaxel, which is less myelosupressive than three-weekly regimen is a reasonable treatment option in elderly and frail men with mCRPC. 2 010 B J U I N T E R N A T I O N A L | 1 0 6 , 4 6 2 – 4 6 9

  26. A decision tree for treating patients with metastatic disease. 2 010 B J U I N T E R N A T I O N A L | 1 0 6 , 4 6 2 – 4 6 9

  27. CRPC:Decision making in first line Clinical trial Observation Secondary hormone therapy Maintain castration levels of testosterone M0 Clinical trial additional hormone therapy Immunotherapy (Sipuleucel-T) ??? • Low baseline PSA • Slow PSADT Asymptomatic, slow growth • High baseline PSA • Rapid PSADT Asymptomatic Fast growth CT (DOCETAXEL) Clinical trial CT (DOCETAXEL)Palliative RT Zoledronic Acid Maintain castration levels of testosterone Symptomatic Bone M+ M+ Symptomatic disease Visceral M+ CT (DOCETAXEL)

  28. Second-line chemotherapy in metastatic docetaxel-resistant prostate cancer

  29. Docetaxel-Resistance (DR):It has been suggested to consider DR as the evidence of disease progression during therapy or within30–60 days of the last drug administration Mathew P et al. J Urol. 2007;178:S36–41. Beekman KW et al. Clin Prostate Cancer. 2005;4(2): 86–90.

  30. PRIMARY RESISTANCEis defined asprogressive disease without any evidence of response, andpatients who failed first-line DOC therapy (primary resistance)failed second-line taxane-based treatment.SECONDARY RESISTANCEis defined as progressive disease after an initial response: in some patients, re-exposure to DOC induced again a response , suggesting that a response to prior DOC could predict a subsequent response to taxanes.(Di Lorenzo G et al. BJU Int. 2011;107:234-9.) (Yonemori K et al. Breast Cancer Res Treat. 2005;89: 237–41.)

  31. DOCETAXEL-CASTRATION RESISTANT PROSTATE CANCER The majority of pts will have PD within 6 months 80% of pts MSKCC received 2° line CT → median survival 12 months from the start of 2° line treatment 40% of them received 3° line CT → median survival similar to that of pts in the second-line setting. Beekman KW, Clin Prostate Cancer 2005

  32. SECOND LINE CHEMOTHERAPY OPTIONS • DOCETAXEL RE-CHALLENGE • CABAZITAXEL • ABIRATERONE • SIPULEUCEL‑T • ALPHARADIN • CLINICAL TRIAL

  33. 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)

  34. 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 barriercompared 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

  35. Phase III TROPIC trial: Final Results 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  36. TROPIC: Phase III registration study146 Sites in 26 Countries mCRPC patients who progressed during and after treatment with adocetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles (n=377) *Oral prednisone/prednisolone: 10 mg daily Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression Primary endpoint:OS Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  37. Premedication in cabazitaxel group antihistamine, steroid, and H₂ antagonist administered by IV infusion at least 30 minutes prior to each dose of cabazitaxel Antiemetic prophylaxis was administered when necessary 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  38. Patient characteristics 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  39. Pre-protocol treatments 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  40. Primary endpoint:Overall survival (updated ITT analysis*) Censored MP CBZP Combined medianfollow-up: 13.7 months Numberat Risk MP CBZP 100 80 60 28% reduction in risk of death Proportion of OS (%) 40 20 0 0 6 12 18 24 30 Time (months) 377 378 299 321 195 241 94 137 31 60 9 19 * Data cut-off 3/10/2010 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  41. Overall survival benefit in all subgroups 0 0.5 1 1.5 2 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54 46

  42. Progression-free survival Censored MP CBZP Combined medianfollow-up: 13.7 months Numberat Risk MP CBZP 100 80 60 Proportion of PFS (%) 25% reduction in risk of progression 40 20 0 0 3 6 9 12 15 18 21 Time (months) 377 378 117 168 55 92 30 55 12 18 9 6 6 1 4 1 * Data cut-off 3/10/2010 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  43. Response rate and time to progression (TTP) MP(n=377) CBZP(n=378) Hazard ratio(95% CI) P-value Tumor assessment Response rate* (%) 4.4 14.4 – .0005 Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <.0001 PSA assessment Response rate* (%) 17.8 39.2 – .0002 Median TTP (months) 3.1 6.4 0.75 (0.63–0.90) .001 Pain assessment Response rate* (%) 7.8 9.2 – .6286 Median TTP (months) NR 11.1 0.91 (0.69–1.19) .5192 *Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively.NR=Not reached. 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  44. Most frequent treatment-emergentadverse events 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

  45. Hematological 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 2010 ASCO Genitourinary Cancers Symposium & ASCO 2010 De Bono JS et al Lancet 2010; 376: 1147–54

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

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