Mitoxantrone* 12.7

4 studies report a significant improvement of OS in CRPC after docetaxel failure.

Placebo* 11.2

Placebo 13.6

Alpharadin 14.0

Overall Survival

Cabazitaxel* 15.1

Abiraterone* 15.8

MDV3100 18.4

Placebo 11.2

Mitoxantrone* 3.1

Placebo* 6.6

Placebo 2.9

Cabazitaxel* 6.4

Abiraterone* 10.2

MDV3100 8.3

PSA-PFS

* Plus Prednisone

Study-Analysis

3 AGENTS with positive results but trials no comparable(differences in patients-characteristics, PSA level, presence of pain, criteria of

evaluation, progression criteria)

•There are no randomized trials comparing these 3 agents-No predictive models or biomarkers that are able to identify patients who are likely to benefit from any of these drugs

Choice of therapy is based on clinical expertise

Gleason Score, HT and OSTropic and EAP posthoc analysis

Conclusioni:•OS e PFS in patients treated with Cabazitaxel not related to:

– Gleason Score (0-7; 8-10)– Duration of HT pre-TXT (+/- 20 Months )

•Multivariate analysis: SHORT OS and PFS in pts with low PS (ECOG 2), high ALP and PAIN

Oudard et al, ASCO GU 2013

Univariable

Months of Prior Hormonal Therapy 0.96 (0.92, 0.99) 0.019

Time to PD Following Docetaxel 0.98 (0.89, 1.09) 0.75

Prior Cycles of Docetaxel 0.99 (0.93, 1.06) 0.80

Age 0.97 (0.93, 1.01) 0.11

Baseline PSA (/100) 0.93 (0.77, 1.11) 0.42

PSA Doubling Time 0.95 (0.84, 1.08) 0.46

Gleason Score 0.86 (0.64, 1.16) 0.33

Gleason Score, ≥8 versus ≤7 0.50 (0.26, 0.95) 0.033

Visceral Disease 2.74 (1.33, 5.65) 0.006

ECOG, 1 versus 0 1.28 (0.83, 1.98) 0.27

Prior Abiraterone 1.58 (0.55, 4.48) 0.39

Multivariable

Visceral Disease 4.16 (1.86, 9.30) <0.001

Gleason Score, ≥8 versus ≤7 0.36 (0.18, 0.72) 0.004

Future Oncology 2013

Predictors of poor response to ABI

• 408 mCRPC pts enrolled in 19 centres• Gleason at diagnosis:

– 8-10: 51.2%– 7: 36.1%– <7: 12.7%

• Median duration of ABI therapy: 6.1 months• Predictors of poor response to ABI:

– Univariate: age, Gleason, number of mets, baseline PSA, duration of HT, number of lines of chemo, duration of chemo

– Multivariate analysis: Gleason 8-10predict POOR response to ABI

Azria et al. ASCO GU 2012 (poster 149)

Is primary refractoriness to docetaxel a potentialpredictive variable?

Di Lorenzo et al (Eur Urol, 2013)

Cabazitaxel reduces the risk of death in primaryrefractory patients

Di Lorenzo et al (2013, Eur Urol)

Angelergues et al, Abst 5063, ASCO 2013

• Conclusions: patients treated with 2 prior Docetaxel lines, PSA response >30% with Cabazitaxel and treated with new hormonal agents after Cabazitaxel experienced prolonges OS.

• Conversely intake of new hormonal agents before Cabazitaxel rather after wasassociated with a reduced OS from the first Docetaxel.

• Prospective randomized trials are needed.

•125 pts treated with cabazitaxel and retrospectively analyzed.

•Median OS from the first docetaxel was 65 mo in patients treated with abiraterone/enzalutamide after Cabazitaxel vs 39 mo in patients receiving these agents before Cabazitaxel.

Esmo 2013

-Long term response to ENZALUTAMIDE: >12 MONTHS: 35%

-These pts had less disease burden

PS 2: HT

9% PS 2

Androgen levels

Serum Androgen is prognostic for OS in abiraterone patients

Prognostic model to predict OS in men receiving second line chemotherapy

(Halabi et al ASCO 2013)

-Data from Tropic trial (cabazitaxel patients) -A separate data set was used for external validation-Predictive score was used to classify patients in low and high risk groupsConclusions:•9 prognostic variables: ECOG PS, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior HT, hgb, PSA and ALP

•The median OS were 11 and 16 months in the high and low risk groups

Prognostic model to predict OS in men receiving abiraterone

(Chi et al ASCO 2013, abstr. 5013)-Data from COU-AA 301Following risk factors were associated with poor prognosis: 1) ECOG PS of 2 (HR 2.19),2) presence of liver metastases (HR: 2)3) Time from start of initial LHRH-agonist to start of Abir (<36 months) (HR:1.3)4) Low albumin (HR1.54)5)High ALP (HR:1,38)6) High LDH (HR: 2.31)CONCLUSIONS:Patients categorized in 3 risk groups: 0-1 good: OS 21.3 mo2 or 3 intermediate: OS 13.9 mo4 to 6: poor: OS 6.1 mo

Suggested choice in second line for mCRPC (expert opinion)

GLEASON SCORE ( >7) : cabazitaxelShort prior HT before CT ( 24): cabazitaxelPD during DOCETAXEL (primary ): cabazitaxelPD during DOCETAXEL ( acquired): both options

CT-CT-HT vs CT-HT-CT sequence: cabazitaxelPS: 2 abiraterone/enzalutamideVisceral metastases (liver): cabazitaxelHigh Serum androgen levels: abiraterone/EnzalutamideTOXICITY to prior treatment: abiraterone/enzalutamide

TO BE CONSIDER: AGE and Comorbidity : liver, hematologic, Hypertension and

cardiac disorders