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Castrate Resistant Prostate Cancer Second Line Therapy

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Castrate Resistant Prostate Cancer Second Line Therapy

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    1. Castrate Resistant Prostate Cancer Second Line Therapy Ali Mohamed, MD No financial disclosures

    2. Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that almost 1.6 million new cases of cancer will be diagnosed in 2011. The most common cancers are prostate in men and breast in women; lung and colorectal cancers are the second and third most common cancers in both men and in women. Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that almost 1.6 million new cases of cancer will be diagnosed in 2011. The most common cancers are prostate in men and breast in women; lung and colorectal cancers are the second and third most common cancers in both men and in women.

    3. Incidence rates of prostate cancer have changed substantially over the last 20 years: rapidly increasing from 1988 to 1992, declining sharply from 1992 to 1995, remaining stable from 1995 to 2000, and decreasing from 2000 to 2007, due, in part, to changes in prostate cancer screening with the prostate-specific antigen (PSA) blood testing. Incidence rates for both lung and colorectal cancers in men have been declining for many decades.Incidence rates of prostate cancer have changed substantially over the last 20 years: rapidly increasing from 1988 to 1992, declining sharply from 1992 to 1995, remaining stable from 1995 to 2000, and decreasing from 2000 to 2007, due, in part, to changes in prostate cancer screening with the prostate-specific antigen (PSA) blood testing. Incidence rates for both lung and colorectal cancers in men have been declining for many decades.

    4. Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing; this decrease has been estimated to account for nearly 40% of the overall decrease in cancer death rates in men. The death rate for stomach cancer, which was the leading cause of cancer death early in the 20th century, has decreased considerably since 1930. Death rates for prostate and colorectal cancers have also been declining. Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing; this decrease has been estimated to account for nearly 40% of the overall decrease in cancer death rates in men. The death rate for stomach cancer, which was the leading cause of cancer death early in the 20th century, has decreased considerably since 1930. Death rates for prostate and colorectal cancers have also been declining.

    6. First Line Therapy Mitoxantrone and prednisone provides palliation, tumor regression and reduce PSA level* Docetaxel plus prednisone when compared with mitoxantrone plus prednisone led to superior survival rate (18.9 vs 16.5 months)** *Tannock IF, et al. J Clin Oncol. 1996 Jun **Tannock IF, et al. N Engl J Med. 2004 Oct 7.

    7. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

    9. Results:

    11. Response to treatment and disease progression

    12. Adverse events reported in patients who received at least one dose of study treatment

    13. 2011 May 26;364(21):1995-2005. Abiraterone and increased survival in metastatic prostate cancer.

    15. Mechanism of Action

    16. Study Design Multinational, phase 3, randomized, double, placebo-controlled study (05/08-07/09) 1195 patients, 2:1 ratio (abiraterone plus prednisone : placebo plus prednisone) Inclusion criteria: Prostate cancer that had previously been treated with docetaxel Disease progression (Prostate Cancer Working group or rising PSA or new radiographic evidence) Ongoing androgen deprivation with serum testosterone < 50ng/dl ECOG performance status < 2 Albumin > 3 g/dl, AST/ALT < 2.5 upper normal

    17. Figure 1. Kaplan–Meier Estimates of Overall Survival, Time to PSA Progression, and Progression-free Survival According to Radiographic Evidence in the Intention-to-Treat Population.Figure 1. Kaplan–Meier Estimates of Overall Survival, Time to PSA Progression, and Progression-free Survival According to Radiographic Evidence in the Intention-to-Treat Population.

    20. 2010 Jul 29;363(5):411-22. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

    22. Figure 1. Enrollment and Outcomes.Figure 1. Enrollment and Outcomes.

    23. Figure 2. Kaplan–Meier Estimates of Overall Survival. Panel A shows the results of the primary efficacy analysis of treatment with sipuleucel-T as compared with placebo (hazard ratio for death in the sipuleucel-T group, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). Panel B shows the results of the analysis with and without censoring at the time of the initiation of docetaxel therapy after study treatment. After censoring at the time of docetaxel initiation, a consistent treatment effect with sipuleucel-T was observed (hazard ratio, 0.65; 95% CI, 0.47 to 0.90; P=0.009). Statistical approaches to assess the effects of subsequent treatment vary; no consensus exists on how to address the confounding effects.Figure 2. Kaplan–Meier Estimates of Overall Survival. Panel A shows the results of the primary efficacy analysis of treatment with sipuleucel-T as compared with placebo (hazard ratio for death in the sipuleucel-T group, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). Panel B shows the results of the analysis with and without censoring at the time of the initiation of docetaxel therapy after study treatment. After censoring at the time of docetaxel initiation, a consistent treatment effect with sipuleucel-T was observed (hazard ratio, 0.65; 95% CI, 0.47 to 0.90; P=0.009). Statistical approaches to assess the effects of subsequent treatment vary; no consensus exists on how to address the confounding effects.

    24. Figure 2. Hazard Ratios for the Risk of Death, According to Subgroup. Hazard ratios are based on a nonstratified proportional-hazards model. The Eastern Cooperative Oncology Group (ECOG) grades the performance status of patients with respect to activities of daily living, with 0 indicating that the patient is fully active and able to carry on all predisease activities without restriction; 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work; and 2 indicating that the patient is ambulatory and up and about more than 50% of waking hours and is capable of all self-care but unable to carry out any work activities. Dashes indicate that the median time to death had not been reached for the indicated patient subgroup. The size of the circles is proportional to the size of the subgroup. BPI denotes Brief Pain Inventory–Short Form, CI confidence interval, and PSA prostate-specific antigen.Figure 2. Hazard Ratios for the Risk of Death, According to Subgroup. Hazard ratios are based on a nonstratified proportional-hazards model. The Eastern Cooperative Oncology Group (ECOG) grades the performance status of patients with respect to activities of daily living, with 0 indicating that the patient is fully active and able to carry on all predisease activities without restriction; 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work; and 2 indicating that the patient is ambulatory and up and about more than 50% of waking hours and is capable of all self-care but unable to carry out any work activities. Dashes indicate that the median time to death had not been reached for the indicated patient subgroup. The size of the circles is proportional to the size of the subgroup. BPI denotes Brief Pain Inventory–Short Form, CI confidence interval, and PSA prostate-specific antigen.

    26. Summary NCCN considered Cabazitaxel and Abiraterone as a category 1 recommendation for second line therapy after docetaxel failure There is no randomized trails, predict models or biomarkers to identify patients who are likely to benefit from either approach. Decision largely based on the drug safety and patient preference More data needed to clarify the value of Sipuleucel-T treatment Mitoxantrone still an option for palliative treatment Our understanding of the biological basis of disease progression, have led to new treatments that will further improve survival in these patients (MDV3100, TAK-700 & Ipilimumab*). Lassi K, Dawson NA. Update on castrate-resistant prostate cancer: 2010. Curr Opin Oncol. 2010;22:263–7 Clinical Trialsgov identifier NCT01193257 PREVAIL study

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