Chemotherapy For HighRisk Disease At RRP

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Chemotherapy For High-RiskDisease At RRP

• Mario A. Eisenberger, MD
• R. Dale Hughes Professor
• Oncology and Urology
• The Johns Hopkins University

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Clinically Localized DiseaseConsiderations

• Stage migration
• 80 are M0 at presentation
• Most get local treatment
• Early identification of high-risk

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Risk for Prostate Cancer Specific Mortality at 10
years Post Radical Prostatectomy
30 20 10 0
High Risk Intermediate Risk Low Risk
Prostate Cancer-Specific Mortality
0 1 2 3 4 5 6 7 8 9 10
Time (Years) Following Surgery
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Adjuvant Chemotherapy
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Biochemical Recurrence Free Survival in Patients
with Non-organ Confined Disease after Radical
Prostatectomy (The Johns Hopkins series).
  Adapted form M.Han et al (24)
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Postoperative Nomogram for Prostate Cancer
Recurrence
0
10
20
30
40
50
60
70
80
90
100
Points
10
Preop PSA
0.1
0.2
0.3
0.5
0.7
1
2
3
4
6
8
100
4
6
8
10
Gleason Sum
5
7
9
Inv.Capsule
Established
Extraprostatic Ext.
None
Focal
Pos
Surgical Margins
Neg
Yes
Seminal Ves. Invasion
No
Pos
Lymph Nodes
Neg
Total Points
0
40
80
120
160
200
240
280
84-Month Rec. Free Prob.
0.01
0.1
0.3
0.5
0.7
0.8
0.9
0.95
0.98
0.99
Kattan M et al
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Models for Adjuvant Approaches

• Neo-adjuvant (prior to surgery/radiation)
• Concomitant with radiation (chemotherapy ADT)
• Post-operative
• (radiation , chemotherapy, ADT)

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Surgical Adjuvant ADT for N patientsEST 3866
(Messing et al NEJM 1999)
Immediate Castration
Radical Prostatectomy
N
Observation ADT at the time Of Bone mets
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Prostate Cancer-Specific Survival by Treatment
ALIVE/DOC
D of DIS
MEDIAN
TOTAL
Treatment Arm
Immediate ADT
47
8
39
Not reached
Observation
51
25
26
12.3 yrs
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Rw Model for Risk of PSA Recurrence (Roberts W
et al Urology 2001)

• Rw LN (0/1)x1.43Surg.Margin (0/1)x 1.15
• modified Gleason(0-4)x0.71S.V.(0/1)x0.51

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EORTC Trial 22863 Survival EBRT versus EBRT
ADT
Bolla M, N Engl J Med. 1997 Jul 31337(5)295-300
Bolla M, Lancet 2002 Jul 13360(9327)103-106
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Combined ADTRT Ongoing Conclusions( T2b NxM0)

• Good Risk patients ? 4 months
• Intermediate Risk patients ? 6 months
• Poor Risk ? 2 - 3 years ( gt 1 year)
• T1c and T2a need ADT?

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Adjuvant Studies Radiation

• RTOG0521 (Sandler) Neo-adjuvant/adjuvant ADT
  Radiotherapy followed by docetaxel (Taxotere?) vs
  Neo adjuvant/adjuvant ADT Radiotherapy (n600
  pts)
• DFCI (DAmico) Neo-adjuvant/concomitant
  docetaxel 6 months Androgen Suppression
  Radiotherapy vs 6 months Androgen Suppression
  Radiotherapy (n350 pts)

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Post-Operative Adjuvant

• Adequate staging
• Selection of patients
• Facilitates assessments of risk for recurrence
  and study design
• Better patient / physician acceptance?

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Study Design (Partin et al 1995)
PSA relapse
RRP

• Prognostic factors
• Estimate probability
• of PSA relapse

• Evaluate PSA relapse
• Compare to matched
• controls

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RRP
Pilot Study
Central Pathology review
Rwgt2.84
Docetaxel 35mg/m2 Wkly x3 Every month X 6 months
Central Repository Bank

• PSA
• Other

Endpoint PSA gt0.2ng/ml (rising)
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Prognostic Factors for Biochemical Relapse
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Docetaxel Toxicity Profile
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Progression-Free Survival
Observed (95 C.I.)
Predicted by nomogram
With an overall median F/U of 28m (10.5-38.5),
46/76 evaluable pts progressed (60.5). The
observed median PFS was 15.7m (95 CI
12.8-25.1m) Predicted median Kaplan-Meier PFS
using a widely employed nomogram was 10m.
(Kattan JCO, 2005)
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Adjuvant ADT /- Mitoxantrone
cT3, T4 or N1 or M1
Randomization
Lupron flutamide Mitoxantrone x 4 (n46)
Lupron flutamide (n47)
Wang J, BJU Int. 2000 Oct86(6)675-80
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Adjuvant ADT /- Mitoxantrone Overall Survival
in Localized Prostate Cancer
80 vs 36 mos P0.044
Wang J, BJU Int. 2000 Oct86(6)675-80
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TAX-3501 (1,696 pts)
2nd P r o g r e s s i o n
Progression
ADT
Randomizat ion
Observation
ADT Docetaxel
RP
Progression
ADT
ADTdocetaxel
ADT leuprolide gel x 18 mos Docetaxel- 75mg/m2
q.3wks x 6 cycles
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TAX 35012X2 Factorial Design
24
Figure 1
1.0
gt3 years
0.75
lt3 years
Prostate Cancer Specific Survival
0.50
0.25
0.0
0
5
10
15
Years after PSA Recurrence
Number at risk by time from surgery to PSA
recurrence gt3 years 135
106 38
5 lt3 years 244
172 65
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Patients with a PSA lt 0.1ng/ml and at least one
of the following should be registered for central
pathology review
TAX 3501-Adjuvant Study for Patients with
Localized Disease After Prostatectomy

• Seminal vesicle invasion
• Or Positive nodes
• Or margins and Gleason grade gt 7
• If the cancer is outside of the gland (pT3) and
  Gleason grade 7

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Confirmation of Eligibility

• Central pathology confirmation
• Undetectable PSA 1-3 months after surgery
• No prior endocrine therapy
• Needs to be within 3 months of surgery.

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TAX 3501 Hypothesis
Immediate treatment
Deferred treatment
Tumor burden b
Tumor burden a
Tumor burden b 2 logs x a
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TAX 3501 Hypothesis
Deferred treatment
Immediate treatment
Tumor burden b
Tumor burden a
Tumor burden b 2 logs x a
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TAX 3501 Hypothesis
Immediate LHRH
Immediate LHRH docetaxel
Deferred LHRH
Deferred LHRH docetaxel
Hormone independent
Hormone independent
Hormone sensitive b
Hormone sensitive b
Hormone independent
Hormone independent
Hormone sensitive a
Hormone sensitive a
Tumor burden b 2 logs x a AND hormone
sensitive insensitive cells
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TAX 3501 Hypothesis
Immediate LHRH
Immediate LHRH Docetaxel
Deferred LHRH
Deferred LHRH Docetaxel
Hormone independent
Hormone independent
Hormone sensitive b
Hormone independent
Hormone sensitive b
Hormone sensitive a
Hormone independent
Hormone sensitive a
Tumor burden b 2 logs x a AND hormone
sensitive insensitive cells
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Biomarker Discovery
Serum Bank
Validation of Nomograms
Tumor Bank
TAX 3501
Global Study 1696 pts
Correlative Sciences
Natural History Data Base
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TAX 3501
Study Chair Mario A. Eisenberger M.D. Co-Chair
Adam Kibel M.D. Co-Chair Cora Sternberg
M.D. Steering Committee J.P. Aussel (SA) Evelyne
Ecstein-Fraisse M.D. (SA) Ronald DeWit
M.D. Isabelle Dubroca Ph.D biostatistician
(SA) Jonathan Epstein M.D. Martin Gleave M.D.
,Ph.D. Hartwig Huland M.D. Michael Kattan
Ph.D. Stephane Oudard M.D.
Sponsored by Sanofi-Aventis
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CALGB 90203 Phase III Study of Radical
Prostatectomy Alone vs. Neoadjuvant docetaxel
Estramustine in High Risk Localized Prostate
Cancer
RANDOMIZE
Radical Prostatectomy
High Risk Localized CaP
Primary Endpoint 5 year bPFS
Radical Prostatectomy
docetaxel 70 mg/m2 D2 LHRH a
N 450
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SWOG-9921 Adjuvant Therapy After RRP

• cT1-T2b
• ?
• RRP?
• pGS? 8 or
• pT3b,pT4, N1 or
• pG7and SM or
• Preop PSA gt 15
• PSA lt or 0.2

ADT x 2 years
Randomization
Mitox/Pred x 6 ADT x 2 years
n1,360, End point 30 increase in OS
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VA Cooperative Study 553 Adjuvant Randomized
Phase III Study in High Risk Disease
Docetaxel prednisone (4 months)
Patients Post RRP T3, G7-10, N0 700 pts

RANDOMIZE
Surveillance
At PSA progression in any arm, patients treated
with XRT or ADT
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Potential Systemic Adjuvant Approaches

• Bone targeted treatments
• Molecular targeted anti metastatic drugs
• Immunotherapy
• PSMA targeted MoAb
• PSA targeted drugs/vaccines
• Non suppressive endocrine approaches