1. Update on the Treatment of Prostate Cancer
David M. Nanus, MD
Chief, Division of Hematology and Medical Oncology
Weill Medical College of Cornell University
New York Presbyterian Hospital

2. Demographics 238,590 estimated new cases in 2013
% of all cancers in males
most common cancer in men
Lifetime risk: 16% (1 in 6)
29,720 estimated deaths
- 9.7% of cancer deaths in males
- second to lung cancer in men

3. Death from other causes Death from Prostate cancer
Clinical
Metastases
Non-Castrate
Clinically
Localized
Disease
Rising
PSA
Castrate
Metastatic
Disease
Castrate
Rising
PSA
Adapted from Scher et al.

4. PSA – Like a Clint Eastwood Movie
The Good
PSA-based early detection decreases mortality
The Bad
Not perfectly sensitive or specific
 Over-detection compounded by Over-treatment
The Ugly
Treatment arbitrary, variable, often unnecessary and increasingly costly

5. Screening Recommendations
Shared decision making
Annual PSA and DRE
from age of 40 (AUA); age 50 (ACS)
High risk: (African American; 1rst degree relative)
Frequency
AUA: annually (based on initial PSA)
ACS: annually (every 2 year if PSA < 2.5 ng/ml)
Discontinue: life expectancy <10 years

6. The Changing Face of Prostate Cancer in the United States
Cooperberg et al. J Urol 2007; 178:S14

7. Significance of cancer: Determining need for treatment
Patient (age, comorbidities)
Gleason score
- sum of two predominant areas
Tumor characteristics
- Number of positive cores
- Percent positive within each core
Molecular profile

8. Active Surveillance Rationale Hypotheses
Surveillance in low risk patients is feasible and associated with a limited risk of progression
Progression can be quantitated
Predictors of progression and treatment can be identified
Screening results in the detection of very early stage/grade lesions - many indolent
Current staging/grading techniques accurate
Natural history prolonged and can be measured

9. Intervention Overall Survival Ca-Specific Survival N=452
97% at 10 years
N=452
5/452 patients
All PSADT ≤ 1.6 years
62% free of intervention at 10 y
Klotz L, et al. J Clin Oncol 2010;26:126–31

10. Defining the Triggers for Intervention
Change in PSA kinetics: PSADT <3 y
Progression on follow-up biopsy
Increase in Gleason grade
Increase in tumor volume
Increase in absolute cores involved with cancer
Increase in percent of positive cores >33%
Increase in absolute tumor length (mm)
Increase in percent of tumor tissue >50% within single core
Patient preference
Clinical/radiographic evidence of local/distant progression

11. What’s new in prostate cancer therapy?
Targeting the androgen axis
Immunotherapy
Chemotherapy
Bone targeted therapies
Molecular genetics
Circulating prostate cancer tumor cells

12. 3040 hormone naïve metastatic patients
Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), An international phase III trial
3040 hormone naïve metastatic patients
PS 0-2
PSA ≥ 5 ng/ml
treated with 7 months of goserelin + bicalutamide
1535 pts PSA ≤4 ng/ml
- randomized to CAD or IAD
Primary objective: non-inferior
Median Follow up: 10 years

15. Management of Castrate Resistant Metastatic Prostate Cancer
Androgen Signaling Axis Therapy
Abiraterone
Enzalutamide (MDV3100)
Chemotherapy
Docetaxel
Cabazitaxel
Mitoxantrone
Bone Targeted
Radium-223

16. Intra-cellular androgen Alternatively-spliced AR
Adapted from Harris et al. Nature Reviews Clin Onc 2009

17. CYP17 CYP17 Simplified view of cholesterol  testosterone synthesis
Occurs in: Testes,
Adrenal Gland,
Prostate cancer cells
cholesterol
pregnenolone
17α-hydroxy-
DHEA
androstenedione
Testosterone
DHT
CYP17
Mineralocorticoids
CYP17
Cortisol
Montgomery et al. Cancer Res 2008
Locke et al. Cancer Res

18. Abiraterone Acetate CYP17 CYP17 Oral irreversible inhibitor of CYP17
- 17α –hydroxylase
- C17,20-lyase
Inhibits testosterone production in testis, adrenal, and prostate
Abiraterone
Acetate
cholesterol
pregnenolone
17α-hydroxy-
DHEA
androstenedione
Testosterone
DHT
CYP17
Mineralocorticoids
CYP17
Cortisol
Montgomery et al. Cancer Res 2008
Locke et al. Cancer Res

19. COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisone
in men with progressive metastatic CPRC after docetaxel
Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone.
de Bono JS et al. N Engl J Med 2011;364:
Fizazi et al. Lancet Oncol 2013;13:983.

20. de Bono JS et al. N Engl J Med 2011;364:1995-2005.
Secondary End Points
de Bono JS et al. N Engl J Med 2011;364:

21. Hazard Ratios for the Risk of Death, According to Subgroup
de Bono JS et al. N Engl J Med 2011;364:

22. Asymptomatic or mildly symptomatic
COU-AA-302
Abiraterone 1000 mg/d
Prednisone mg bid
Chemo-naïve CRPC (n=1088)
Asymptomatic or mildly symptomatic
Placebo daily
Prednisone mg bid
Primary endpoint: Radiographic PFS, OS
Secondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS deterioration; progression

23. COU-AA-302: Updated interim results
Prednisone
Abiraterone + Prednisone
Radiographic PFS
8.3 mos
16.5 mos
HR 0.53;
p <
Overall Survival
30.1 mos
35.3 mos
HR 0.79;
p = *
> 50% PSA decline
69%
29%
Median Time to Chemotherapy
16.8 mos
26.5 mos
HR: 0.61
Median Time to Opiate Use
23.7 mos NR
HR 0.71
p =
* did not cross the prespecified boundary for significance (p = )
Ryan CJ et al. N M2013;368: GU ASCO 2013

24. Adverse Events of Special Interest.
Ryan CJ et al. N Engl J Med 2013;368:

25. AFFIRM: Enzalutamide (MDV3100)
Scher HI et al. N Engl J Med 2012;367:

26. Figure 1. Kaplan–Meier Estimates of Primary and Secondary End Points in the Intention-to-Treat Population. Shown are data for overall survival, the primary end point (Panel A), and for two secondary end points, the time to prostate-specific antigen (PSA) progression (Panel B) and radiographic progression-free survival (Panel C), in the enzalutamide group, as compared with the placebo group. CI denotes confidence interval.

27. Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups
Figure 2. Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups. Hazard ratios are based on a nonstratified proportional-hazards model. Dashes indicate that the median time to death had not been reached for the indicated subgroup. The size of the circles is proportional to the size of the subgroup. The horizontal bars represent 95% confidence intervals. The Eastern Cooperative Oncology Group (ECOG) grades the performance status of patients with respect to activities of daily living, with 0 indicating that the patient is fully active and able to carry out all predisease activities without restriction; 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature; and 2 indicating that the patient is ambulatory and up and about for more than 50% of waking hours and is capable of self-care but unable to carry out work activities. Scores on the Brief Pain Inventory–Short Form (BPI-SF) range from 0 to 10, with scores of 0 to 3 indicating that clinically significant pain is absent and scores of 4 to 10 indicating that clinically significant pain is present, and with higher scores indicating greater pain. LDH denotes lactate dehydrogenase, and PSA prostate-specific antigen.
Scher HI et al. N Engl J Med 2012;367:

28. Enzalutamide PREVAIL trial: Phase 3 CRPC before chemotherapy
TERRAIN trial: Phase 2 comparing Enzalutamide with bicalutamide in men who have progressed on LHRH analogue therapy or following surgical castration
Other studies:
Enzalutamide + docetaxel
Enzalutamide + abiraterone

30. Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone
de Bono et al, Lancet 2010:

31. Immunotherapy Cancer vaccines
Modulation of immune regulatory mechanisms
Blocking CTLA-4
Blocking PD-1 or PDL-1
Monoclonal antibody targeting of tumour growth

32. IMPACT Trial HR=0.759 (95% CI: 0.606, 0.951) P=.017 (Cox model)
Median Survival Benefit: 4.1 months
Sipuleucel-T (n=341)
Median Survival: 25.8 months
36-months survival: 32.1%
Control (n=171)
Median Survival: 21.7 months
36-months survival: 23.0%
Kantoff et al, ASCO GU 2010

33. Radium-223 Targets Bone Metastases
Radium-223 acts as a calcium mimic
Naturally targets new bone growth in and around bone metastases
Radium-223 is excreted by the small intestine Ca Ra
Parker et al; ECCO-ESMO 2011

34. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT
6 injections at 4-week intervals
PATIENTS R
A N D
OM I S
E D
2:1
STRATIFICATION
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel
Radium-223 (50 kBq/kg) + Best standard of care
Total ALP: < 220 U/L vs ≥ 220 U/L
Bisphosphonate use: Yes vs No
Prior docetaxel: Yes vs No
Placebo (saline) + Best standard of care
N = 922
Clinicaltrials.gov identifier: NCT
Parker et al; ECCO-ESMO 2011

35. ALSYMPCA Overall Survival
100
HR 0.695; 95% CI, P = 90 80 70 60
Radium-223, n = 541
Median OS: 14.0 months % 50 40 30
Placebo, n = 268
Median OS: 11.2 months 20 10
Month 3 6 9 12 15 18 21 24 27
Radium- 223
541
450
330
213
120 72 30
Placebo
268
218
147 89 49 28 7
Parker et al; ECCO-ESMO 2011

36. CRPC Therapeutic Options
Increase in median survival
Relative reduction in risk of death
Hazard ratio
(95% CI; P-value)
Abiraterone/P vs. placebo/P
3. 9 mos
35%
0.65
( ; P<0.001)
Enzalutamide vs. placebo
4.8 mos
37%
0.63
(P<0.0001)
Docetaxel(q3w)/P vs. Mitoxantrone/P
2.4 mos
24%
0.76
( ; P=0.009)
Cabazitaxel/P vs. mitoxantrone/P
2.8 mos
30%
0.70
( ; P<0.0001)
Sipuleucel T vs. placebo
4.1 mos
22%
0.78
( ;
P:0.03)
Alpharadin vs. placebo
31%
( ; P: )

37. Phase III Randomized Trials vs. Docetaxel + Prednisone
Primary Endpoint: Overall Survival
Trial Name
Arm B: DocPred plus
Mechanism
ASCENT-2
DN101
Calcitriol
CALGB 90401
Bevacizumab
VEGF
SWOG 0421
Atrasentan
Endothelin receptor antagonist
MAINSAIL
Lenalinomide
Anti-angiogenic; immune
VENICE
Aflibercept
Soluble VEGF fusion protein
ENTHUSE 33
Zibotentan
READY
Dasatinib
SRC kinase inhibitor
SYNERGY
OGX-11
Antisense to clusterin
(cell survival protein)
FIRSTANA
vs. Cabazitaxel (unTxed)
Taxane Chemotherapy

38. Molecular Markers Beyond the microscope
May be diagnostic, prognostic, and/or predictive
Gene fusions
TMRPSS2-ERG
Expression of abnormal proteins
Many may be targetable
Circulating Tumor Cells (CTCs)

39. Molecular Classification of Prostate Cancer
* Discoveries led by NYP-Weill Cornell Medical College

40. Frequency
Therapy
Ets gene fusion
50-60%
PARP inhibitor
PTEN/MAGI2
25-40%
PI3K inhibitor
BRAC2/ATM
20%
Spink1
10-15%
EGFr inhibitor
Aurora kinase A
5-40%
AURK inhibitor
SPOP
10% ?
BRaf fusion 1%
Raf inhibitor

41. Neuroendocrine or anaplastic prostate cancer
Frequency
Therapy
Ets gene fusion
50-60%
PARP inhibitor
PTEN/MAGI2
25-40%
PI3K inhibitor
BRAC2/ATM
20%
Spink1
10-15%
EGFr inhibitor
Aurora kinase A
5-40%
AURK inhibitor
SPOP
10% ?
BRaf fusion 1%
Raf inhibitor
Neuroendocrine or anaplastic prostate cancer

42. MLN8237 50 mg bid orally x 7 d on 21 day cycle Molecular biomarkers
Multi-institutional Phase II Trial of The Aurora kinase A inhibitor MLN8237 for Patients with Neuroendocrine Prostate Cancer
Inclusion Criteria:
Pathologic diagnosis
Clinical diagnosis: visceral metastases in absence of PSA progression, elevated serum neuroendocrine marker
MLN mg bid orally x 7 d on 21 day cycle
Molecular biomarkers
Tumor biopsies
CTC analyses
Exome/transcriptome sequencing

45. Bone Targeted Therapy

46. Smith MR et al. 2013 GU Cancers Symposium
CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal Related Events in Men with Prostate Cancer Metastatic to Bone
Eligibility:
> 1 bone metastasis, ADT therapy within 6 mos of enrollment
Therapy:
Zoledronic acid or placebo q 4 weeks
Median time to first SRE (skeletal-related event)
32.5 vs 29.8 mos (HR = 0.96 [ ]; P=0.74)
> Grade 3 toxicity same (15% vs. 12% in ZA and P)
Overall survival (HR= 0.89 [ ]; P=0.34)
Smith MR et al GU Cancers Symposium

47. Y denosumab Y Y Y Y Y Y Y Y Y Y Y Y Y

48. Targeted Therapy: Denosumab vs zoledronic acid for Skeletal Related Events risk-reduction in CRPC
Fizazi et al, Lancet 2011; 377: 813

49. Denosumab vs placebo to improve bone-metastases free survival
Smith et al, Lancet 2011

50. Management of Metastatic CRPC Sequencing???
Chemotherapy
Docetaxel, Cabazitaxel, Mitoxantrone
Androgen Signaling Axis Therapy
Abiraterone
Enzalutamide
Bone Targeted
Denosumab
Alpharadin

51. Prostate cancer clinical states model
enzalutamide
Prostate cancer clinical states model; framework for patient management and drug development. PSA, prostate-specific antigen. Data adapted.6,8
Scher H I et al. JCO 2011;29:

52. Prostate cancer clinical states model
enzalutamide
Prostate cancer clinical states model; framework for patient management and drug development. PSA, prostate-specific antigen. Data adapted.6,8
Scher H I et al. JCO 2011;29:

53. Cabozantinib (XL184): orally bioavailable tyrosine kinase inhibitor
against MET and VEGFr2 in men with CRPC
Smith D C et al. JCO 2013;31:

54. PFS in (A) randomly assigned patients with CRPC; and
(B) patients with CRPC by docetaxel pretreatment status
Kaplan-Meier estimates of progression-free survival (PFS) in (A) randomly assigned patients with castration-resistant prostate cancer (CRPC) and (B) patients with CRPC by docetaxel pretreatment status. Panel A shows the probability of PFS from week 12 random assignment for patients with CRPC randomly assigned to continued treatment with cabozantinib (n = 14) or placebo (n = 17). Panel B shows the probability of PFS for all patients with CRPC (n = 171) by docetaxel pretreatment status from first dose of cabozantinib. HR, hazard ratio.
Smith D C et al. JCO 2013;31:

55. Bone scan effects of cabozantinib treatment on study patients
Bone scan effects of cabozantinib treatment on study patients. Sequential whole-body technetium methylene diphosphonate bone scintigraphy is shown of four patients with advanced metastatic prostate cancer. Baseline scans show multiple areas of increased radiotracer uptake indicative of extensive bone metastases. Treatment with cabozantinib resulted in complete or partial resolution of bone scans at week 12. Bone scan resolution correlated with partial response of tumor lesions in soft tissue and pain relief in each patient.
Smith D C et al. JCO 2013;31:

56. Where We Are Now: Positive Phase 3 Trials in Met CRPC
Design HR
Endpoint
Comment
Canadian
N = 161
Mitoxantrone/prednisone vs
prednisone NR
Palliation in 29% vs 12% (duration 42 vs 18 wks)
Approval of mitoxantrone (also CALGB 9182)
TAX 327
N = 1006
Docetaxel/prednisone vs mitoxantrone/prednisone
0.76
OS 18.9 vs
16.5 mo
Docetacel/pred approved as new standard
SWOG 9916
N = 770
Docetaxel/estramustine vs mitoxantrone/prednisone
0.80
OS 17.5 vs
15.6 mo
Support docetaxel as new standard
ZAPCSG
N = 643
Zoledronic acid vs placebo
SRE 33.2% vs 44.2%
Zoledronic acid reduces SRE’s
IMPACT
N = 512
Sipuleucel-T vs Control
0.78
OS 25.8 vs
21.7 mo
Sip-T approved min symptomatic metCRPC
Dmab 103
N = 1904
Denosumab vs zoledronic acid
0.82
SRE-free 20.7 vs 17.1 mo
Denosumab approved
TROPIC
N = 755
Cabazitaxel/prednisone vs mitoxantrone/prednisone
0.70
OS 15.1 vs
12.7 mo
Cabazitaxel approved post-docetaxel
COU-AA-301
N = 1195
Abiraterone/prednisone vs
Placebo/prednisone
0.65
OS 14.8 vs
10.9 mo
Abi/pred approved post-docetaxel
ALSYMPCA
N = 922
Radium-223/BSC vs placebo/BSC
OS 14.0 vs
11.2 mo
Pending approval
AFFIRM
N=1199
Enzalutamide vs Placebo
0.63
OS 18.4 vs
13.6 mo
Enzalutamide approved post-docetaxel
COU-AA-302
N = 1088
0.43
16.5 mos vs
8.3 mo
Strong trend for OS