1. Survival improvement with new drugs: a reality in prostate cancer?
Melhoria da sobrevida com as novas drogas: uma  realidade no carcinoma da próstata?
Survival improvement with new drugs: a reality in prostate cancer?
Eduardo Solsona
Servicio de Urología. IVO
RAMCV Valencia. España

2. Outline Presentation
- Survival analysis in patients with metastatic prostate cancer (mPCa). Phase III trials
First step: Androgen deprivation (ADT)
Second step: Androgen deprivation plus early Docetaxel (ADT+D)
Treatment optimization
Tretament impact on survival of mPCa patients (mathematic models)

3. Survival analysis in mPCa patients
Has survival improved in patients with mPCa since 1960?
Phase III trials with ADT (ORQ) (VACURG ).
- Trial 1 (stage IV) (853 pts): Placebo vs DES 5.0mg vs ORQ+P vs ORQ+DES
Md survival= 24ms
Byar DP Cancer (1975) 32: 1139

4. Survival analysis in mPCa patients
Recent phase III trials ( ): arm (ADT+ D)
Trial
Inclusion interval
Md FU ms
Md. Survival
(arm ADT+ D)
GETUG
2004-8
83.9
62.1ms
CHAARTED
53.7
57.6 ms
STAMPEDE 43
55-60 ms
VACURG vs ADT+D
Md survival ( )
Md survival ( )
Difference
24 ms ms
+36.4 ms
Analysis of Survival improvement:
1. First step (ADT)
2. Second step (ADT+D)
HR=0.76 ( ) p=0.005
Gravis G Eur Urol (2016) 70:256; Sweeney Ch.ESMO (2016); J
ames N D. Lancet (2016) 387: 1163

5. First step: ADT 24 ms 44.0-48.0 ms +22.2 ms
Recent phase III trials ( ): control arm (ADT)
HR=0.76 ( ) p=0.005
Trial
Md. Survival (ADT)
GETUG
48.6ms
CHAARTED
47.2ms
STAMPEDE
45-46ms
VACURG vs ADT
Md Survival
( )
( )
Difference
24 ms ms
+22.2 ms
Causes of survival improvement:
1. Efficacy of different ADT alternatives
2. Efficacy of recue therapies after ADT failure
Gravis G Eur Urol (2016) 70:256; Sweeney Ch. NEJM (2015) 373:737; James N D. Lancet (2016) 387: 1163

6. Survival improvement= 1.5 ms (1960-2004)
First step: ADT
Why this survival improvement?
1. Efficacy of new ADT alternatives
Strategy
Trial (pts)
HR (95%CI); significance
Benefit (ms)
Early vs Delay
Metanalysis (3064)
0.98 ( ); NO
Intermitent
vs Continuous
Metanalysis (4070)
1.02 ( ) NO
NSAA vs LHRH
Metanalysis (3060)
1.215 ( ) NO
Antagonists vs LHRH
Phase III tials
( M1)
0.65 ( ) NO
CAB vs LHRH
Metanalysis: Cochrane (5636)
0.871 ( ) YES
29.9 vs 28.4ms
+ 1.5 ms
Survival improvement= 1.5 ms ( )

7. Why this survival improvement?
First step: ADT
Why this survival improvement?
2. Efficacy of rescue therapies after ADT failure
Trial (yr)
Drug
Md. Survival
(drug vs control)
Difference
TAX 327 (2000-2)
DOCE vs MTX
18.9 vs 16.5 ms
2.4 ms
IMPACT (2003-8)
Sipu-T vs Placebo
25.8 vs 21.7 ms
3.6 ms
COU-AA 301 (2008-9)
DOCE → ABI + Pred vs Pred
15.8 vs 11.2 ms
4.6 ms
AFFIRM ( )
DOCE→ ENZ vs Placebo ms
2.8 ms
TROPIC (2007-8)
DOCE→ CBZ vs Placebo ms
ALSYMCA ( )
Rd-223 vs Placebo
ms (pre-D)
ms (post-D)
COU-AA 302 ( )
ABI+ Pred vs Pred ms
4.4 ms
PREVAIL ( )
ENZA vs Placebo ms
4.0 ms

8. - Therapeutic improvement:
First step: ADT
Why this survival improvement?
Summary
Survival improvement ( )= 22.2 ms
- Therapeutic improvement:
. CAB= +1.5ms
. TAX 327 (D)= +2.4ms
. COU-AA 301 (+ABI)= +4.6ms
Maximal therapy benefit= +8.5ms (40.4%)
- No therapeutic benefit= 13.7ms (60.6%)
. Co-morbidity control
. Possible lead time bias

9. Why this survival improvement?
First step: ADT
Why this survival improvement?
No therapeutic benefit: 3. Co-morbidity control
- Pts receiving ADT
Year
Pts
Md FU
Death
Died by tumor
Died by No tumor
VACURG
1960
266
≥72ms
82.5%
50.2%
49.8%
Hussain
1995
765
117.6ms
60.6%
76.6%
23.4%
GETUG
2004
192
83.9ms
70.4%
82%
18%
Pts died by intercurrencies decrease according to the year
Md survival by no cancer deaht is not available

10. Why this survival improvement?
First step: ADT
Why this survival improvement?
No therapeutic benefit: 4. Lead time bias
JH: 3096 PR ( )→ 422 (PSA failure)→123 M+ → 91 M1(eligeble)
- No Tto to M1 → early ADT→ NO active rescue therapy (2005)
- FU schedule: . PSA every 3 ms→ 1yr; every 6 ms→ 2yrs; after annually
. Progression PSA: PSA every 6ms & Bone scan annually
Makarov DV. J Urol. (2008) 179(1): 156–162

11. Lead time: Sure but no exactly quantified How much: 14.2 - 28.3 ms?
First step: ADT
Why this survival improvement?
No therapeutic benefit: 4. Lead time bias
Phase III trials CHAARTED/ GETUG (pts receiving ADT)
- mPCa pts with prior local Tx vs initial M1
GETUG
CHAARTED
M1 (ADT)
Pts
Md. OS
Prior local Tx 46
69.8ms
106
60.6ms
Initial
144
41.5ms
186
46.4ms
Difference
28.3ms
14.2ms
Lead time: Sure but no exactly quantified How much: ms?

12. Second step: ADT+ Early DOCETAXEL (ADT+D)

13. Second step: ADT+D
 4 Phase III trials comparing ADT vs ADT+ early DOCE (ADT+D)
Trial
Md. survival (control arm)
Md. survival (study arm)
Difference
GETUG*
48.6ms
62.1ms
+13.5 ms
CHAARTED
47.2 ms
57.6 ms
+10.4 ms
STAMPEDE**
45-46ms
55-60 ms ms
HR=0.76 ( ) p=0.005
Gravis G Eur Urol (2016) 70:256; Sweeney Ch. NEJM (2015) 373:737; James N D. Lancet (2016) 387: 1163

14. Second step: ADT+D CHAARTED: Subgroup analysis
Patients NO benefit with ADT+D:
- prior radical local Tx
- minimal disease
Sweeney Ch. NEJM (2015) 373:7

15. Second step: ADT+D GETUG: Subgroup analysis
Patients NO benefit with ADT+D:
- prior radical local Tx
- minimal disease
Gravis G Eur Urol (2016) 70:256;

16. Second step: ADT+D Subgroups which are not benefit by ADT+D
1. mPCa patients with prior local Tx
Trials
Pts
Local Tx
Md FU
Tto.
Md. Survival
GETUG 62
PR/RT
83.1 ms
ADT + D
NR (83.1ms* ADT  D)
CHAARTED
108
53.7 ms
68.3ms
Makarov 91 PR
120 ms
ADT
82 ms**
* ADT vs ADT+DOCEp (NR= no reached) (HR=0.83; , p=0.5); (Md OS series)
** No received active rescue treatment (2005)
Gravis G Eur Urol (2016) 70:256; Makarov DV. J Urol. (2008) 179(1): 156–162

17. Second step: ADT+D
Subgroups which are not benefit by ADT+D: 2. Pts with minimal disease
Extended disease: visceral &/or ≥4 or ≥1 extra-axial M1 (CHAARTED/ GETUG)
visceral &/or extra-axial M1 (Makarov/ Hussain)
Trials
Pts
Md. FU
Tto.
Md. Srvival
GETUG
202
83.9ms
ADT+D
NR (83.4ms* ADT)
CHAARTED
134
53.7ms
63.5ms
Hussain
406
117.6 ms
ADT
82.2 ms **
*ADT vs ADT+DOCE (NR= no alcanzado) (HR=1.02; ), p=0.9;
** Ptes seleccionados; No tto rescate con ABI; ENZ <2010)
GETUG
CHAATED

18. Treatment optimization
mPCa: response to ADT as prognostic factor
Minimal disease
Estudiop
Pts
No. (%)
Md. OS
GETUG*
385
202 (52.4)
83.4ms
Hussain **
1535
799 (52)
82.2ms
*Todos tto de rescate activos
** Pacientes seleccionados con PSA<4.0ng/ml tras ADT sin tto activo de rescate con ABI; ENZ
PSA<≤4ng/ml: OS= 69 ms
PSA>4ng/ml: OS= 16 ms
mPCa pts with PSA <4.0ng/ml after 3ms ADT &
minimal disease = survival than pts receiving ADT+D
Hussain M. JCO J Clin Oncol (2009) 27: ©

19. Impact of Treatment on mPCa Demography
Demography of mPCa pts
1. Initial M1: 3.8-4%
2. M1 after local Tx
% M+
(PR: Spratt, Zumteg, Ward, Han)
(RT: Kupelian, Coen, Zelefsky, Pollack)
NCDB
mPCa pts benefit by ADT+D
1. Initial M1 (4%) with extended disease (53.5%) (Getug, Chaarted, Hussain)
mPCa pts NO benefit by ADT+D
1. Pts with prior radical local treatment ( %)
2. Initial M1 (4%) with respond to ADT and mimimal ddiseae (46.5%)
Siegel RL. CA Cancer J Clin. (2016) 66:7

20. Treatment Impact on Survival: mathematical model
Model 1: M1 after local Tx (12.5%)
Initial M1 (13%) 11 → E. Extensa (53.5%) 6 pts
Local Tx (76%%) 74 pts
Pts benefit with ADT+DOCE= 21
Model 2: M1 after local Tx (27%)
NO Resp (15%) 15 pts
100 pts
Initial M1 (24%) 20 → E. Extensa (63.5%) 13 pts
Resp (85%) 85
Local Tx (76%%) 65 pts
Pts benefit with ADT+DOCE= 28
Benefit pts with ADT+DOCE= 21-28%
Benefit pts with ADT+DOCE in month/pt= ms
. CHAARTED: 21-28% x 17ms/100= ms/pt
. GETUG: 21-28% x 4.7ms= ms/pt

21. Take Home Messages
Since 1960 the survival benefit in pts with mPCa is important
2. The survival benefit is due to the oncological treatment 38.1% and to a better co-morbidity control and a potential lead time bias in 61.9%
3. In patients receiving ADT +DOCE, the survival benefit, as a whole, is concentrated in 21-28% of patients with a survival prolongation between 1 to 5mos/pt (mPCa)
4. This a very modest survival improvement as a whole of patients with mPCa, but in Oncology a great advance starts with little steps