Until 2004, CRPC was consistently a rapidly lethal disease.

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Joanna Eaton
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1 Until 2004, CRPC was consistently a rapidly lethal disease. the entry in systemic disease is declared on a an isolated PSA recurrence after local treatment so!!! The management of CRPC and MCRPC is different The main problem remains the hetrogenety of that population

2 there is a second-line ormonal manipulation? Switching GnRH agonist/antagonist Antiandrogen withdrawal syndrome But there has never been published reports of OS benefit so!!!

3 Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer Background and Rationale A randomized trial showed that mitoxantrone plus low-dose prednisone relieved pain and improved the quality of life more frequently than did prednisone alone but none found that this approach improved survival Study Design 1006 pts Stratified by Pain level PPI >2 or AS >10 vs PPI <2 or AS <10 Kanofsky <70 vs >80 R A N D O M I Z E Docetaxel 75mg/m 2 Q3 wks + Prednisone 5 mg bid Docetaxel 30mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12mg/m 2 Q3 wks + Prednisone 5 mg bid he primary end point was overall survival. Tannock IF et al. N Engl J Med 2004;351:

4 Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer Results Median duration of follow-up was similar among the three groups: months in the group given docetaxel every 3 weeks months in the other two groups. Kaplan Meier Estimates of the Probability of Overall Survival in the Three Groups Tannock IF et al. N Engl J Med 2004;351:

Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer 2003 Docetaxel Q3W (n=335) Docetaxel Weekly (n=334) Mitoxantrone (n=337) n (%) dead 166 (50%) 190 (57%) 201

5 Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer 2003 Docetaxel Q3W (n=335) Docetaxel Weekly (n=334) Mitoxantrone (n=337) n (%) dead 166 (50%) 190 (57%) 201 (60%) Median Survival* 18.9 ( ) 17.4 ( ) 16.5 ( ) Hazard Ratio* 0.76 ( ) 0.91 ( ) Results update 2006 p-value Docetaxel Q3W (n=335) Docetaxel Weekly (n=334) Mitoxantrone (n=337) n (%) dead 273 (81.5%) 269 (80.5%) 291 (86.4%) Median Survival* 19.3 ( ) 17.8 ( ) 16.3 ( ) Hazard Ratio* 0.79 ( ) 0.87 ( ) * 95% confidence interval indicated p-value Tannock IF et al. N Engl J Med 2004;351: and ASCO2006

Overall Study Design of COU-AA-302 Patients Progressive chemo-naïve mcrpc patients (Planned N = 1088) Asymptomatic or mildly symptomatic R A N D O M I Z E D 1:1 AA 1000 mg daily Prednisone 5 mg BID

6 Overall Study Design of COU-AA-302 Patients Progressive chemo-naïve mcrpc patients (Planned N = 1088) Asymptomatic or mildly symptomatic R A N D O M I Z E D 1:1 AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Placebo daily Prednisone 5 mg BID (Actual n = 542) Efficacy end points Co-Primary: rpfs by central review OS Secondary: Time to opiate use (cancerrelated pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration TTPP Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs. 1 Ryan et al. N Engl J Med 2013; 368(2):

7 No OS benefit up to now!

8 Interim analysis results of COU-AA-302: rpfs

9 Interim analysis results of COU- AA-302: Subsequent therapy Ryan, et al. N Engl J Med 2013;368:138 48

10 mcrpc Heterogeneous disease Berthold DR, et al. J Clin Oncol 2008;26:242 45

11 Survival (%) Pre-treatment PSADT predicts OS 1.00 PSADT >6 months PSADT 4 6 months PSADT 2 3 months PSADT 1 2 months PSADT <1 month and 3-6 Med OS NYR mean OS 25 and 22.5 months 0.25 < 1 mo months 0 Log-rank p< Armstrong AJ, et al. Clin Canc Res 2007;13: Survival (months) < 3 mo months

TAX 327 Survival: pain vs no pain/minimal Docetaxel q3w (n = 335) Docetaxel qw (n = 334) Mitoxantrone (n = 337) n 183 183 184 NO PAIN Median survival 23.0 21.1 19.8 Hazard ratio 0.73 0.

12 TAX 327 Survival: pain vs no pain/minimal Docetaxel q3w (n = 335) Docetaxel qw (n = 334) Mitoxantrone (n = 337) n NO PAIN Median survival Hazard ratio p value n PAIN Median survival Hazard ratio p value No subseguent therapy with established efficacy Berthold DR, et al. J Clin Oncol 2008;26:242 45

13 Decreased antitumor activity of docetaxel after abiraterone? TAX327 (DOC q3w) Phase I-II ABI DOC PSA decrease 50% 45% 25.7% Time to PSA progression (median) 7.7 mo 4.6 mo Median overall survival 20.8 mo 12.5 mo Abiraterone administered prior to docetaxel in CRPC patients may decreases the efficacy of first-line docetaxel Mezinski & De Bono Annal Oncol 2012 (epub ahead of print) Tannock et al. NEJM 2005, 351:

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III

metastases No known visceral metastases Postdocetaxel or unfit for

Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O

(50 kbq/kg) + Best standard of care Placebo (saline) + Best

14 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT

15 ALSYMPCA Overall Survival HR 0.695; 95% CI, P = % Placebo, n = 268 Median OS: 11.2 months Radium-223, n = 541 Median OS: 14.0 months 0 Month Radium Placebo

16 Overall Study Design Enzalutamide Patients Progressive chemo-naïve mcrpc patients (Planned N = 1680) R A N D O M I Z E D 1:1 ENZALUTAMIDE 160 mg/die Placebo daily Efficacy end points Co-Primary: rpfs OS Secondary: Time to initiation of chemotherapy Time to first skeletalrelated event A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy

17 Overall Study Design TAK-700 Patients Progressive chemo-naïve mcrpc patients (Planned N = 1680) R A N D O M I Z E D 1:1 TAK mg/bid +P Placebo/bid+P Efficacy end points Co-Primary: PFS OS Secondary: Time to initiation of chemotherapy Time to first skeletalrelated event

18 FIRSTANA Study Design Phase III Progressive mcrpc 1170 Pts Stratification - ECOG PS 0-1 vs 2 - mesurable disease Yes vs no - Region Primary Objective: To demonstrate the superiority of cabap vs docep Secondary Objectives: To evaluate safety in the 3 treatment arms. To compare efficacy of cabazitaxel for: Progression Free Survival (PFS) (RECIST 1.1) Tumor progression free survival (RECIST 1.1) Tumor response (RECIST 1.1), PSA response PSA-Progression free survival (PSA-PFS). Pain response in patients with stable pain at baseline Pain progression free survival Time to occurrence of any skeletal related events To compare Health-Related Quality of Life To assess Milan, the... pharmacokinetics and pharmacogenomics of cabazitaxel. R A N D O M I Z A T I O N Cabazitaxel i.v. 25mg/m2 q21 Prednisone 10 mg daily Cabazitaxel i.v. 20mg/m2 q21 Prednisone 10 mg daily Docetaxel i.v. 75mg/m2 q21 Prednisone 10 mg daily

19 Conclusion How to identify patients who require hormonal treatment from those who require docetaxel upfront? The studies of enzalutamide, abiraterone and TAK- 700 have as control arm prednisone Timing of chemotherapy What workup?

20 Conclusion Some patients need chemotherapy at the forefront of - how to identify them? Different population between TAX 327 and COU AA 302 What s the best sequence? The sequence abiraterone -> enzalalutamide and vice versa does not seem to be active

When exogenous testosterone therapy is. adverse responses can be induced.

When exogenous testosterone therapy is. adverse responses can be induced. Theoretical tips It has been reasoned that discontinuation of ADT in nonorchiectomized patients may have detrimental effect on patients with CRPC as discontinuation of ADT can result in renewed release