1. Antonio ALCARAZ, MD PHD Professor of Urology University of Barcelona
E3805 CHAARTED Study
Antonio ALCARAZ, MD PHD
Professor of Urology
University of Barcelona

2. E3805
CHAARTED: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer
Abstract LBA2
Sweeney C, Chen Y-H, Carducci M, Liu G, Eisenberger M, Wong Y-N, Hahn N, Kohli M, Dreicer R, Vogelzang N, Picus J, Shevrin D, Hussain M, Garcia J, DiPaola R

3. A Quick Review of the History of Hormone Sensitive Metastatic Prostate Cancer

4. ASCO 2004, abstracts 3 and 4<br />mCRPC

5. Androgen Deprivation Therapy
Early Chemo+ADT: A debate in one slide – a need for randomized phase 3 trial
Pro
Attack de-novo testosterone independent clones early - allow ADT to keep PrCa in remission longer
Some patients at the time of progression are too frail for chemo.
Androgen Deprivation Therapy
Regression Re-emergence
Con
ADT will take cells out of cycle and be less responsive to cytotoxics
Some patients respond for a long time and never need chemotherapy

6. In vivo data Shionogi Mouse Model Box: Paclitaxel > AA at week 4
Triangle: AA > Paclitaxel at progression (wk 4)
Circle: AA + Paclitaxel Concurrent
Nadir reduction:
94% AA-P vs 99.5% concurrent (p=0.08)
Median TTP:
38 days versus 65 days, (P < 0.005)
Clin Cancer Res 2005;11:

7. ADT plus docetaxel greater tumor regression
ADT + Docetaxel
AR independent clones
AR dependent clones

8. Volume of disease at time of starting ADT consistently identifies pts more likely to progress early
SWOG: S8494 NEJM 1989: Leuprolide +/- Flutamide
Minimal Disease: Absence of mets in ribs, long bones, skull, soft tissue other than LN
Median OS Leuprolide Alone
Metastasis Burden
“Minimal”: months
“Severe”: months
N Engl J Med 1989; 321:419–24

9. Volume of disease at time of starting ADT consistently identifies pts more likely to progress early
Median OS Orch +/- Flutamide
Metastasis Burden
“Minimal”: months
“Extensive”: months
SWOG - S8894: NEJM 1998: Orchiectomy +/- Flutamide
Minimal disease: Nodal metastases and/or bone mets limited to pelvic and axial skeleton
Extensive disease included appendicular skeletal involvement
(with or without axial skeletal involvement), visceral (lung
or liver) metastasis, or both.

10. Improve OS from 1980’s to 1990’s Stage Migration
3 Sequential SWOG phase 3 trials
Pre-PSA era
S8494: Median OS: 33 months
(Accrue: 1985-’86)
S8894: Median OS: 35 months
(Accrue: 1989-’94)
PSA era
S9346 Median OS: 49 months
(Accrue: )
(No difference for African Americans
- unlike the other 2 studies)
Tangen et al J. Urology 2012

11. On therapy: PSA decline at 7 months identifies those destined for longer response to ADT
At Risk
PSA ≤ 0.2 ng/ml
0.2 < PSA ≤
PSA >
Hussain et al. J Clin Oncol, 2006

12. Volume of disease at time of starting ADT still identifies pts more likely to progress early even when limit to patients with PSA < 4ng/dL after 7 months of therapy
SWOG Intermittent vs Continuous: SWOG-9346
Med OS Continuous Arm: Minimal 6.9 yrs versus Extensive 4.4 years
Hussain et al NEJM 2013; 368:

13. Other efforts of early chemohormonal therapy in Hormone Sensitive Metastatic PrCa
ADT +/- keto+doc alt with vinblastine and estramustine
High-volume:
bone or visceral disease,
Low-volume
bone (ie, one or two areas of presumably pathologic uptake on bone scan),
local/nodal with prior definitive local therapy, and
local/nodal without prior definitive therapy.
? For high volume C-HT numerically better (p=0.29)
Millikan et al J. Clin Oncol 2008; 26:

14. Prostate Cancer Disease Landscape
Non – Metastatic Prostate Cancer
Localized Prostate Cancer
Local Disease with Rising PSA Post Radial Therapy
Non-Metastatic Hormone Sensitive
Non-Metastatic castration resistant (M0)
ADT
Intermittent ADT and develop mets on Rx break with normal testo
Progression
Patients at Diagnosis
Metastatic
Castration Resistant
Prostate Cancer
Metastatic Hormone Sensitive Prostate Cancer
Newly diagnosed
ADT

15. How common is hormone sensitive metastatic prostate cancer?
5% of a country PSA screened with de novo metastatic disease
Lower % in high socioeconomic (interval cancers)
Higher % in VA and county hosp population
230,000 in the USA = 11,000 pts
Possible major contributor of 30,000 deaths
Rapid recurrence after localized therapy
Hard to quantify and depends on practice patterns

16. Paths to CRPC and Pr Ca Death
1) De novo metastatic: most present with symptoms and presumably have high volume disease and most die of prostate cancer
~11,000 patients in USA
High volume: median OS months with ADT alone
Most will die of prostate cancer
Very few of these patients die of other diseases
Older patients (75yo) with competing risks for death who have low volume disease and live > 5 years with ADT alone

17. Paths to CRPC and Pr Ca Death
2) Localized disease:
95% of PrCa in PSA screened population
90% of 230,000 cases probably present with localized disease = 207,000 and get active surveillance, XRT (+/-ADT) or surgery
75% of 207,000 cured (or not need therapy / not relapse)
25% = 51,000 PSA relapse (estimate)
?5% of 230,000 get watchful waiting or primary ADT and not get AS or local Rx due to co-morbidities

18. Paths to CRPC and PrCa Death
2) Localized disease:
Estimate 80% of the 51K who relapse commence ADT with PSA rise
Die of something else (85% in NCIC PR-7 Int vs Cont PSA rise died of PrCa with 10 yr follow-up - Crook et al NEJM)
Develop CRPC and die of mCRPC (~18% of 51,000 = 9,000 over 15 year time - estimate)
Minority have rapid recurrence with mets on imaging despite PSA surveillance:
Estimate 10% of 51,000 = 5,100 (of 207,000 = 2.5% of local dz)
Few followed with PSA rise and ADT only with mets

19. ~20K mHSPC patients (estimates)
Estimated Incidence of mHSPC-eligible patients in US of 230K US prostate cancer patients
~20K mHSPC patients (estimates)
10K (denovo) + 10K (relapse after local Rx)
~20K of 30K prostate cancer deaths/year would be mHSPC
~10K of the deaths follow PSA relapse -> ADT -> CRPC PSA -> mCRPC -> death
Unknown as to how many of 20K are fit for docetaxel early

20. Registry Data
Median OS of 30 months and med age of 72 yrs in California registry of M1 HSPC
“Real world” data
Interesting to note chemofit study population ADT alone in CHAARTED median OS was 44 months with median age of 62 yrs
How much improvement with better CRPC Rx viable for oncogeriatric patient?

21. E3805 – CHAARTED Treatment Stratification
Extent of Mets
High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
Prior Adjuvant ADT
≤12 vs > 12 months
ARM A:
ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles
Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks
RANDOMIZe
Follow for time to progression and overall survival
Chemotherapy at investigator’s discretion at progression
ARM B:
ADT (androgen deprivation therapy alone)
Evaluate every 12 weeks
ADT allowed up to 120 days prior to randomization.
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but no daily prednisone

22. Study Endpoints Primary Endpoint Secondary Endpoints Overall survival
Rate of PSA < 0.2 ng/mL at 6 months and 12 months
Time to biochemical, radiographic or symptomatic PD
Time to radiographic or symptomatic progressive disease (PD)
Define adverse event profile and tolerability
Quality of life (FACT-P) until 12 months after randomization

23. Patient characteristics
ADT + Doc (N=397)
ADT alone (N=393) N %
Age (year)
Median 64 63
Range
36-88
39-91
Race
White
344
88.7%
330
87.3%
Other 44
11.3% 48
12.7%
Unknown 9 15
ECOG PS
276
69.7%
272
69.6% 1
114
28.8%
29.2% 2 6
1.5% 5
1.3%

24. Patient characteristics
ADT + Doc (N=397)
ADT alone (N=393) N %
Volume of Mets
Low
134
33.8%
142
36.1%
High
263
66.2%
251
63.9%
Gleason Score
4-6 21
5.9%
6.1% 7 96
26.9% 82
23.9%
8-10
240
67.2%
70.0%
Unknown 40 50
PSA (ng/mL) at time of ADT start
Median
56.0 
50.5 
Range

25. Patient characteristics
ADT + Doc (N=397)
ADT alone (N=393) N %
Prior Treatment
No localized Rx
289
72.8%
286
73.0%
Primary radiation 27
6.8% 33
8.4%
Prostatectomy 81
20.4% 73
18.6%
Missing 1
Adjuvant ADT 21
5.3% 15
3.8%
Median time from start ADT to randomization
Months (range)
1.1 (0-3.9)
1.2 (0-3.9)
No ADT prior to randomization 46
12% 45
11%

26. Primary endpoint: Overall survival
HR=0.61 ( ) p=0.0003
Median OS:
ADT + D: 57.6 months
ADT alone: 44.0 months

27. Causes of Death ADT + Doc (N=397) ADT alone (N=393) N %
Due to prostate cancer 84
83.2
112
83.6
Due to protocol Rx 1
1.0
0.0
Other cause 8
7.9 11
8.2
Unknown
Missing 2
Total
101
136

28. OS by extent of metastatic disease at start of ADT
High volume
Low volume
p=0.0006
HR=0.60 ( )
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 ( )
Median OS:
ADT + D: Not reached
ADT alone: Not reached
In patients with high volume metastatic disease, there is a 17 month
improvement in median overall survival from 32.2 months to 49.2 months
We projected 33 months in ADT alone arm with collaboration of SWOG9346 team

29. ADT + Docetaxel benefited all subgroups

30. Secondary Endpoints ADT + Doc (N=397) ADT alone (N=393) P-value
Hazard Ratio (95%CI*)
PSA <0.2 ng/mL at 6 months
27.5%
14.0%
<0.0001
PSA <0.2 ng/mL at 12 months
22.7%
11.7%
Median time to CRPC
- biochemical, symptoms, or radiographic (months)
20.7
14.7
0.56 (0.44, 0.70)
Median time to clinical progression
- symptoms or radiographic (months)
32.7
19.8
0.49 (0.37, 0.65)
*CI: confidence intervals

31. Therapy beyond progression
ADT + Docet (N=397) N
ADT alone
(N=393)
Biochem, Sympt, Radiog PD
145
174
Symptom or Radiograph PD 93
133
Docetaxel 49
129
Other Chemotherapy
Cabazitaxel 43 29
Mitoxantrone &/or Platinum 22 23
Hormonal Therapy
Abiraterone/Enzalutamide 92 79
Antiandrogen/ketocon 87 99
Immunotherapy
Sipuleucel T 20 18
Radiotherapy 54 67

32. Chemotherapy Doses Given
ADT + Docetaxel (N=397)
Arm A
Number of cycles N % 1 11
3.1 2 7
2.0 3 6
1.7 4 8
2.3 5 12
3.4
308
87.5
Total
352*
74% with no dose modifications
*Missing data on 45 pts due to form change (24 pts), never started Rx (6 pts), data missing (15 pts)

33. Non-Hematologic Toxicity (%)
ADT + Docetaxel (N=397)
Grade 3 4 5
Allergic reaction 2
<1 -
Fatigue
Colitis/Diarrhea 1
Stomatitis
Neuropathy-motor
Neuropathy-sensory
Thrombo-embolism
Sudden death
1 patient

34. Hematologic Toxicity (%)
ADT + Docetaxel (N=397)
Grade 3 4 5
Anemia 1
<1 -
Thrombocytopenia
Neutropenia 9
Febrile neutropenia 2
Infection with neutropenia
Worst grade heme and non-heme
toxicity per patient
16%
12%
1 patient

35. Conclusion
The combination of standard ADT and 6 cycles of docetaxel significantly improved overall survival compared to standard ADT alone in men with hormone sensitive prostate cancer

36. Clinical interpretation
6 cycles of docetaxel in addition to ADT represents an appropriate option for men with metastatic prostate cancer commencing ADT who are suitable for docetaxel therapy
The benefit in patients with a high volume of metastases is clear and justifies the treatment burden
longer follow-up is required for patients with low volume metastatic disease

37. What is the underlying biology of early docetaxel benefit?
Sweeney speculation:
Chemo did not make ADT more effective
ADT made chemo very effective
Recent insights into ADT + XRT
Better than XRT or ADT alone (clinical trials)1,2
Preclinical mechanistic work
AR signaling upregulates DNA repair enzymes
ADT down regulates DNA repair enzymes: XRT sensitize3,4
Question:
Does ADT down regulates chemoresistance genes?
1Warde et al. Lancet 2011, 2Bolla et al. Lancet 2002
3 Polkinghorn et al. Cancer Discovery 2013; 4Goodwin et al. Cancer Discovery 2013

38. Are these results believable?

39. GETUG-15

40. Comparison to GETUG15

41. Is the control group contemporary and representative?

42. How to adapt to practice?

43. What is extensive disease?

44. Selected early disease trials +/- docetaxel

45. Conclusions

46. Conclusions