1. The Role of the Medical Oncologist in the Treatment of Prostate Cancer
Daniel P. Petrylak, MD
Professor of Medicine
Columbia University Medical Center

2. When should you see an oncologist?
High risk localized disease
Rising PSA after local therapy
Hormone sensitive disease
Endocrine Resistant Disease

3. Natural History of Metastatic Prostate Cancer
Tumor Volume
and Activity
Time
Castration
Secondary
Hormonal Rx
Chemo Rx
This slide nicely illustrates the progression pattern over time.
Although surgery and radiation are potentially curative in clinically localized disease, as many as a third of these patients will progress.
At the time of disease progression, patients are offered hormonal therapy or ADT is often initiated earlier for high risk cases.
Although the majority of patients respond initially to castration therapy, many will eventually progress to an androgen independent state. Treatment options at this stage are limited and transient.

4. Ligand activated androgen receptor signaling remains a ‘driver’ in CRPC
Hypothesis:
Hormone-refractory prostate cancer (HRPC) frequently remains driven by a ligand-activated androgen receptor (AR).
This disease is not truly hormone refractory

5. Biological evidence for a continued hormone ‘driver’ in CRPC
High intratumoral androgens despite castration
Castration resistance:
– AR amplification/ mutations in CRPC increase AR activity
– ↑ AR mRNA expression alone → resistance in isogenic lines
– Aberrant activation of the androgen receptor

6. Abiraterone: Response
Response Parameter Untreated Prior Docetaxel
PSA >50%: 38/54 (70%) /34(47%)
>30%: 43/54 (80%) /34 (65%)
TTP PSA days days
RECIST /29(60%) NR

7. Abiraterone Clinical Trials
Abiraterone vs placbo in patients with CRPC prior to docetaxel
Abiraterone/prednisone vs placebo/prednisone in CPRC patients post chemotherapy. Close to accrual

9. Waterfall Plot of Best Percent PSA Change from Baseline
Chemotherapy-Naïve (N=65)
Post-Chemotherapy (N=75)
62% (40/65)
>50% Decline
51% (38/75)
>50% Decline

10. AFFIRM Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients
MDV3100 – 240 mg QD
Placebo QD 2 1
Primary Endpoint: 25% survival increase (12 to 15 months)
Sample size: ~1170 (780 and 390)
Statistics: 85% Power; p=0.05, two-sided
Biomarkers: CTC enumeration and profiling with outcome
Scher, H. (North America) and De Bono, J. Co-PI, Medivation

11. When is chemotherapy initiated?
At first PSA rise in non metastatic patients
At PSA rise in an asymptomatic patient
At PSA rise and scan progression in an asymptomatic patient
In a patient with symptomatic bone pain

12. Docetaxel HRPC Trials TAX 3271 N=1006 SWOG 99162 N=770 Randomize
Mitoxantrone 12 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Randomize
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles
N=1006
Docetaxel 75 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
SWOG 99162
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid
Q 21 days
N=770
Randomize
Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5*
Dexamethasone 20 mg, tid d 1 & 2
*Warfarin and aspirin
1. Tannock et al. N Engl J Med 2004:351; Petrylak et al. N Engl J Med 2004;351:

13. Overall Survival HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 # at Risk # of0%
20%
40%
60%
80%
100% 12 24 36 48
Months
# at
Risk
# of
Deaths
Median
in Months
D+E
338
217 18
M+P
336
235 16
HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
Petrylak et NEJM 2004

14. Probability of Surviving
Overall Survival — TAX 327
1.0
0.9
Docetaxel 3 wkly
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
Probability of Surviving
0.5
Median survival Hazard (mos) ratio P-value
Combined:
D 3 wkly:
D wkly:
Mitoxantrone – –
0.4
Overall survival favors administration of docetaxel q3 weekly (p=0.009) compared to mitoxantrone arm
0.3
0.2
0.1
0.0 6 12 18 24 30
Months
Tannock et al. N Engl J Med 2004:351;

17. Evidence for Angiongenis as a Target for Prostate Cancersis
Microvessel density correlates with prognosis in radical prostatetectomy specimens
Elevated levels of VEGF correlate with prognosis in CRPCa
bFGF expresse in epithelial and stromal cells

18. CALGB Study
Primary endpoint of improvement in median survival from 19 in docetaxel arm to 23 months in docetaxel/bevizcuzimab arm not met
Press Release Roche 2010

19. CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with HRPC
Arm A
Dexamethasone 8 mg po x 3 doses
Docetaxel 75 mg/m2 on d1 q21d
Prednisone 10 mg po daily
Placebo* IV on day 1 q 21 days
Eligibility
Metastatic PC
T <50 ng/ml
No prior chemo
Adequate hem, renal & liver function
RANDOMIZE
Arm B
Dexamethasone 8 mg po x 3 doses
Docetaxel 75 mg/m2 on d1 q 21d
Prednisone 10 mg po daily
Bevacizumab* 15 mg/kg IV on day 1q 21d
Stratification
Halabi
nomogram
N = 1020 patients
CALGB, ECOG, NCIC

20. Structure of Thalidomide and the 2nd-Generation IMiDs
Immunomodulatory drugs (IMiDs) are synthetic analogs that were created based on thalidomide as a parent structure
Various IMiDs have improved antitumor activities in vitro and different toxicity profiles compared with the parent compound

21. Best response by % change in PSA

22. MAINSAIL TRIAL Metastatic CRPC Chemo-naïve Disease Progression
Screening
CRPC Patients N= 1,015
Randomize 1:1
Docetaxel/Prednisone + Placebo Until Progression or Toxicity
N ~ 500
Docetaxel/Prednisone + Lenalidomide Until Progression or Toxicity
Follow-Up:
For Survival
For Other Treatments
Up to five years

23. TROPIC: Phase III Registration Study 146 Sites in 26 Countries
TROPIC slide deck. Slide6,10,13
mCRPC patients who progressed during and after treatment with a docetaxel-based regimen
(N=755)
Stratification factors
ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease
cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles
(n=378)
mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles
(n=377)
*Oral prednisone/prednisolone: 10 mg daily.
Primary endpoint: OS
Secondary endpoints: Progression-free survival (PFS), response rate, and safety
Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

24. Pre-Protocol Treatments
TROPIC slide deck. Slide16,17,43
MP (n=377)
CBZP (n=378)
Total prior docetaxel dose (mg/m²)
Median
529.2
576.6
Months from last docetaxel dose to progression
0.70
0.80
Number of patients progressed (%)
During last docetaxel treatment
27.6
30.4
<3 months since last docetaxel dose
48.0
41.8
≥3 months since last docetaxel dose
24.0
27.0
Radiation (%)
Curative
29.7
25.9
Palliative
29.2
35.4
Chemotherapy (%)
1 regimen
71.1
68.8
2 regimens
21.0
24.9
≥3 regimens
8.0
6.3

25. Primary Endpoint: Overall Survival (ITT Analysis)
TROPIC slide deck. Slide21
Proportion of OS (%) 80 60 40 20
100
0 months
6 months
12 months
18 months
24 months
30 months
15.1
12.7
Median OS (months)
0.59–0.83
95% CI
<.0001
P-value
0.70
Hazard Ratio
CBZP MP
Number at risk MP
377
300
188 67 11 1
CBZP
378
321
231 90 28 4

26. On-Study Laboratory Abnormalities Safety Population
MP (n=371)
CBZP (n=371)
All Grades (%)
Grade ≥3 (%)
Hematology
Anemia
81.4
4.9
97.3
10.5
Leukopenia
92.5
42.3
95.7
68.2
Neutropenia
87.6
58.0
93.5
81.7
Thrombocytopenia
43.1
1.6
47.4
4.0
Biochemistry
Alkaline Phosphatase
57.7
9.7
53.6
7.3
ALAT
18.9
0.3
25.9
1.1
ASAT
28.0
0.5
27.8
0.8
Hyperbilirubinemia
4.6
3.8
Creatinine
11.6
15.6
1.3

27. Total Deaths During Study Safety Population
TROPIC slide deck. Slide32
MP (n=371)
CBZP (n=371)
Total deaths during study
275 (74.1%)
227 (61.2%)
Due to progression
253 (68.2%)
197 (53.1%)
Due to AEs
7 (1.9%)
18 (4.9%)
Due to other reasons
15 (4.0%)
12 (3.2%)

28. Zometa 039: Skeletal-Related Event (SRE) Prevention Study
Bone metastases with progressive disease after ADT (N=639)
Randomize
Standard Care +
ZOMETA
Standard Care +
Placebo
Endpoint: SRE

29. Skeletal-Related Events
Pathologic fracture
Spinal cord compression/vertebral body collapse
Radiation or surgery to bone
Change in antineoplastic therapy

30. Proportionof Patients With SRE
Proportion of Patients With SRE (-HCM) at Month 15 by Treatment (Intent-to-Treat Patients)
0.8
0.7
0.6
45%
0.5
Proportionof Patients With SRE *
38%
0.4
34%
0.3
0.2
0.1
ZOMETA 8/4 mg
ZOMETA 4 mg
Placebo
*P<.05 vs placebo

31. Time to First SRE (–HCM) by Treatment
Median Time, Days*
ZOMETA 4 mg NR
Placebo 321
110
100 90 80 70 60 50 40 30 20 10
% Patients Without the Event
Time After the Start of Study Drug (Days)
*P=.011 ZOMETA 4 mg vs placebo

32. Study Design: International, Randomized, Double-Blind, Active-Controlled Study
Key Inclusion
Hormone-refractory (castration resistant) prostate cancer and bone metastases
Key Exclusion
Current or prior IV bisphosphonate treatment
Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950)
Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951)
This was a head-to-head comparison vs. active comparator, resulting in much higher sample size per arm (almost 1000) as compared to the historic zoledronic acid registration trial, which was placebo-controlled (about 220 per arm).
The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI.
The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphosphonate use for osteoporosis was allowed.
Zoledronic acid (ZA) was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance <30 mL/min were excluded per the Zometa® label.
There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study.
Subjects were stratified by
previous SRE (YES/NO),
current chemotherapy (within 6 weeks prior to randomization) (YES/NO),
Baseline PSA (<10 vs. ≥10 ng/mL).
All subjects were strongly recommended to take daily supplemental calcium (500 mg) and vitamin D (400 IU).
Calcium and Vitamin D supplemented in both treatment groups
Accrual period from May 2006 to December 2008
Analysis cut-off date October 2009
*Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine.
No SC dose adjustments made due to increased serum creatinine. 32

33. Time to First On-Study SRE
HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority)
P = (Superiority)
Risk Reduction
18%
1.00
0.75
Proportion of Subjects Without SRE
0.50
KM Estimate of Median Months
Efficacy analyses are vs. the most potent bisphosphonate used in clinical practice, and the only one approved for use in prostate cancer bone metastasis. This is NOT a comparison vs. placebo, as has been done in Novartis registration trial
The primary endpoint is represented on a Kaplan Meier curve.
Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to The P value was equal to for noninferiority and equal to for superiority.
The median time to first on-study SRE was 20.7 months for denosumab and was 17.1 months for zoledronic acid, a 3.6 mo difference.
The 2 most common components of SREs were fractures and radiation to bone.
727 subjects experienced a first on-study SRE; subject incidence was 341 (35.9%) in the denosumab arm and 386 (40.6%) in the zoledronic acid arm.
0.25
Denosumab
20.7
Zoledronic acid
17.1 3 6 9 12 15 18 21 24 27
Study Month
Subjects at risk:
Zoledronic Acid
951
733
544
407
299
207
140 93 64 47
Denosumab
950
758
582
472
361
259
168
115 70 39

36. Conclusions Standard of care for CRPCA is docetaxel/prednisone
Novel phase IIII studies are combining docetaxel with novel targeted agents
Carbazitaxel is approved as a second line therapy for castration resistant prostate cancer
New biological approaches are being evaluated in the second line setting

37. Questions Prostate cancer after hormone ablation is
Still hormone responsive
Does not respond to chemotherapy
Spreads to the bone in 90% of pateints
A and C

38. Question 2
A significant complication of treatments targeting bone (bisphosphophonates and denosamab) is
Osteonecrosis of the jaw
Hand foot syndrome
Rash
Diarrhea