1. State-of-the-Art Management of Advanced Prostate Cancer
David I. Quinn, MD, PhD
Associate Professor of Medicine Division of Cancer Medicine and Blood Diseases The University of Southern California Medical Director USC Norris Cancer Hospital and Clinics Los Angeles, California
This program is supported by educational grants from

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3. Faculty Disclosure
David I. Quinn, MD, PhD, has disclosed that he has received consulting fees from AVEO, Bayer, Dendreon, Medivation, Novartis, Onyx, and Pfizer.
This slide lists the faculty who were involved in the production of these slides.

4. Reversible AR blockers[1,2]
Treatment Options for Prostate Cancer Have Snowballed After a 6-Yr Hiatus
Mitoxantrone[3]
Docetaxel*[5,6]
Sipuleucel-T*[8]
LHRH agonists*[1,2]
Abiraterone*[10]
Reversible AR blockers[1,2]
Cabazitaxel*[7]
Denosumab[9]
Zoledronic Acid[4]
MDV3100[11]
Radium-223[12]
1996
2002
2004
....
2010
2011
* Approved agent for PCa
AR androgen receptor; LHRH, luteinizing hormone-releasing hormone.
However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy
The Leuprolide Study Group. N Engl J Med. 1984;311: Crawford ED, et al. N Engl J Med. 1989;321: Tannock IF, et al. J Clin Oncol. 1996;14: Saad F, et al. J Natl Cancer Inst. 2002;94: Petrylak DP, et al. N Engl J Med. 2004;351: Tannock IF, et al. N Engl J Med. 2004;351: de Bono JS, et al. Lancet. 2010;376: Kantoff PW, et al. N Engl J Med. 2010;363: Fizazi K, et al. Lancet. 2011;377: de Bono JS, et al. N Engl J Med. 2011;364: Scher HI, et al. ASCO GU Abstract LBA Parker C, et al. ASCO GU Abstract 8.

5. Natural History of Prostate Cancer
Typical patient presentation as they move through different stages
Under UROLOGIST care
Under the care of ONCOLOGIST
Under ONCOLOGIST care
Androgen
deprivation
First-line therapy
Therapies after LHRH agonists and
antiandrogens
Death
Local
therapy
Salvage
therapy
Burden of disease
Asymptomatic
LHRH, luteinizing hormone-releasing hormone.
Symptomatic
Nonmetastatic
Metastatic
Castrate sensitive
Castrate resistant
Higano C, et al. In: Figg WD, et al. Drug management of prostate cancer; 2010.

6. 2005 Projected Male Population and Prostate Cancer Deaths
50,000
14,000,000
45,000
12,000,000
40,000
35,000
10,000,000
30,000
8,000,000
Estimated Deaths (Bars)
25,000
Population Projection
6,000,000
20,000
15,000
4,000,000
10,000
2,000,000
5000
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
Age Group (Yrs)
Chan JM, et al. J Urol. 2004;172:S13-S17.

7. 2045 Projected Male Population and Prostate Cancer Deaths
50,000
14,000,000
45,000
12,000,000
40,000
35,000
10,000,000
30,000
8,000,000
Estimated Deaths (Bars)
25,000
Population Projection
6,000,000
20,000
15,000
4,000,000
10,000
2,000,000
5000
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
Age Group (Yrs)
Chan JM, et al. J Urol. 2004;172:S13-S17.

8. Natural History of Prostate Cancer
Over 20 yrs, risk of prostate cancer mortality is very low (< 10%) in men yrs of age diagnosed with Gleason score 2-4 prostate cancer
Age at Diagnosis (Yrs)
55-59
60-64
65-69
70-74
Gleason Score 5
100 80 20
Survival Non–prostate cancer mortality Prostate cancer mortality 60 40 40 60 20 80
100
Gleason Score 6
100
Prostate Cancer Mortality 80 20 60 40
Alive, % 40 60 20 80
100
Gleason Score 7
Deceased, %
100
Other Cause Mortality 80 20
OS, overall survival. 60 40 40 60 20 80
100
Gleason Score 8-10 OS
100 80 20 60 40 40 60 20 80
100 5 10 15 20 5 10 15 20 5 10 15 20 5 10 15 20
Yrs Following Diagnosis
Albertsen P, et al. JAMA. 2005;293:

9. Charlson Comorbidity Index for Prostate Cancer
Condition
Assigned Weight
Metastatic solid malignancy 6
AIDS
Liver disease, moderate/severe 3
Hemiplegia 2
Renal disease, moderate/severe
Diabetes with end-organ damage
Any malignancy
Leukemia
Malignant lymphoma
Condition
Assigned Weight
Myocardial infarction 1
Congestive heart failure
Peripheral vascular disease
Cerebrovascular disease
Dementia
Chronic pulmonary disease
Connective tissue disease
Peptic ulcer disease
Liver disease, mild
Diabetes
Charlson ME, et al. J Chronic Dis. 1987;40: Daskivich TJ, et al. J Urol. 2011;186:

10. Prostate Cancer Mortality
Competing Risk of Mortality by Age, Cancer Stage, Grade, and Comorbidity
Cancer Stage T1c
Charlson
Index Number
Prostate Cancer Mortality 1
Other Cause Mortality
OS, overall survival.
≥ 2 OS
Albertsen PC, et al. J Clin Oncol. 2011;29:

11. Prospective Study to Predict Chemotherapy Toxicity in Older Adults
500 patients with cancer 65 yrs of age or older treated at 7 institutions
Prechemotherapy assessment
Demographics
Tumor/treatment variables
Laboratory test results
Geriatric assessment variables (function, comorbidity, cognition, psychological state, social activity/support, nutritional status)
Patients followed through chemotherapy course to capture grade 3-5 adverse events (NCI CTCAE, v3.0)
NCI CTCAE, National Cancer Institute common toxicity criteria for adverse events.
Hurria A, et al. J Clin Oncol. 2011;29:

12. Prospective Study: Predictive Model for Grade 3-5 Toxicity
Risk Factor
Prevalence, %
Grade 3-5 Toxicity, %
OR (95% CI)
Score
72 yrs of age older 54 60
1.85 ( ) 2
Cancer type: GI or GU 37 65
2.13 ( )
Standard chemotherapy dosing 76
2.13 ( )
Multiple chemotherapy drugs 70 55
1.69 ( )
Hb < 10/11 g/dL (male/female) 12 74
2.31 ( ) 3
Creatinine clearance < 34 mL/min 9 77
2.46 ( )
Hearing, fair/worse 25 62
1.67 ( )
≥ 1 fall in last 6 mos 18 67
2.47 ( )
IADL: taking medications with some help/unable 8 72
1.50 ( ) 1
MOS: walking 1 block, somewhat/quite limited 22 63
1.71 ( )
MOS: decreased social activity due to health 44 58
1.36 ( )
GI, gastrointestinal; GU, genitourinary; Hb, hemoglobin; IADL, instrumental activities of daily living; MOS, Medical Outcomes Study, OR, odds ratio.
Hurria A, et al. J Clin Oncol. 2011;29:

13. Prospective Study: Risk Score vs KPS for Predicting Chemotherapy ToxicityB
High
100
100 89 77 80 80
Medium 63 57
Patients With Grade 3-5 Toxicity (%) 60 54 60 54 50
Patients With Grade 3-5 Toxicity (%) 48 51
Low 40 32 40 25 20 20
KPS, Karnofsky performance status.
0-3
4-5
6-7
8-9
10-11
12-19
100 90 80 70
<70
Total Risk Score
MD-Rated KPS (%)
Hurria A, et al. J Clin Oncol. 2011;29:

14. CRPC: A Long-standing Problem
“Despite regressions of great magnitude, it is obvious that there were many failures of endocrine therapy to control the disease.”
Charles B. Huggins
Nobel Lecture December 13, 1966
CRPC, castration-resistant prostate cancer.
Huggins C. Cancer Res. 1967;27:

15. Evolving Terms for Failing Endocrine Therapy
Androgen (hormone) independent: AIPC
Inaccurate: PCa still responsive to androgen, hormones
Hormone refractory: HRPC
Inaccurate: PCa still responsive to low levels of androgen
Castration resistant: CRPC
Currently favored but can be pejorative, negative
Endocrine resistant: ERPC
Proposed as a politically correct version of CRPC
AIPC, androgen-independent prostate cancer; CRPC, castration-resistant prostate cancer; ERPC, endocrine-resistant prostate cancer; HRPC, hormone-refractory prostate cancer; PCa, prostate cancer.

16. History of Chemotherapy and Survival for CRPC
1.0
0.8
Median OS: ~ 8.5 mos
0.6
Probability of Survival
0.4
0.2
CRPC, castration-resistant prostate cancer; OS, overall survival. 20 40 60 80
100
Wks
Survival curves in randomized studies with 20 or more patients per arm.
Eisenberger MA, et al. J Clin Oncol. 1985;3:

17. Management of mCRPC: Chemotherapy
Standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on TAX-327 and SWOG studies[1,2]
TAX-327: Docetaxel improved survival and rates of response for pain, PSA level, and quality of life vs mitoxantrone/prednisone[1]
SWOG 99-16: Docetaxel/estramustine improved median survival by 2 mos vs mitoxantrone/prednisone[2]
100
100
P = .02 80 80
Docetaxel + estramustine (217 deaths; median: 17.5 mos) 60
Docetaxel q3w 60
OS (%)
OS (%) 40
CRPC, castration-resistant prostate cancer; mCRPC, metastatic CRPC; OS, overall survival; PSA, prostate-specific antigen.
Weekly docetaxel 40
Mitoxantrone + prednisone (235 deaths; median: 15.6 mos) 20 20
Mitoxantrone 3 6 9 12 15 18 21 24 27 30 33 12 24 36 48
Mos
Mos
1. Tannock IF, et al. N Engl J Med. 2004;351:
2. Petrylak DP, et al. N Engl J Med. 2004;351:

18. TROPIC: Phase III Registration Trial of Second-line Cabazitaxel in CRPC
Stratified by ECOG PS (0, 1 vs 2) and measurable vs nonmeasurable disease
Cabazitaxel 25 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 378)
Patients with
mCRPC progressing
on docetaxel
(N = 755)
Mitoxantrone 12 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 377)
CRPC, castration-resistant prostate cancer; ECOG, Eastern Cooperative Oncology Group; mCRPC, metastatic CRPC; OS, overall survival; PFS, progression-free survival; PO, orally; PS, performance status.
Primary endpoint: OS
Secondary endpoints: PFS, response rate, safety
de Bono JS, et al. Lancet. 2010;376:

19. TROPIC: OS (Updated ITT Analysis)
100
Median OS for MP vs CBZP: 12.7 vs 15.1 mos
HR : 0.72 (95% CI: ; P < .0001) 80 60
Patients Remaining Alive (%) 40
Censored MP
CBZP 20
CBZP, cabazitaxel plus prednisone; CI, confidence interval; HR, hazard ratio; ITT, intention to treat; MP, mitoxantrone plus prednisone; OS, overall survival
Combined median follow-up: 13.7 mos 6 12 18 24 30
Mos
Patients at Risk, n
Data cutoff: March 10, 2010 MP
CBZP
377
378
299
321
195
241 94
137 31 60 9 19
de Bono JS, et al. ASCO Abstract de Bono JS, et al. Lancet. 2010;376:

20. Phase III Trial of Sipuleucel-T Immunotherapy in mCRPC (IMPACT): OS
100
HR : 0.78 (95% CI: ; P = .03) 80
Sipuleucel-T
Placebo 60
Probability of Survival (%) 40
CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. 20
21.7 mos 12 24 36 48 60 72
Mos Since Randomization
Kantoff PW, et al. N Engl J Med. 2010;363:

21. Androgen-Signaling Axis and Inhibitors
ABI
ARI
Androgen
Biosynthesis
Inhibitors (ABI):
Ketoconazole
Abiraterone
TAK700
Second generation
AR inhibitors (ARI):
Enzalutamide
(MDV3100)
ARN509
ACTH, adrenocorticotropic hormone; AR, androgen receptor; ARE, androgen-response element; CRH, corticotrophin-releasing hormone; DHEA, dehydroe piandrosterone; DHEA-S, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.
Reprinted from Chen Y, et al. Lancet Oncology. 2009;10: ; with permission from Elsevier.

22. Abiraterone: Mechanism of Action
Pregnenolone
Deoxycorticosterone
Corticosterone
Aldosterone
CYP17: 17α-hydroxylase
17OH-Pregnenolone
11-deoxycortisol
Cortisol
x 2
CYP17: C17,20-lyase
DHEA
Androstenedione
Testosterone
Estradiol
DHEA, dehydroepiandrosterone.
< 1 ng/dL
x 3
< 2 ng/dL
< 80 ng/dL
Attard G, et al. J Clin Oncol. 2008;26:

23. COU-AA-301: Phase III Study of Abiraterone Acetate in mCRPC
Abiraterone acetate: selective inhibitor of androgen biosynthesis that blocks CYP17 activity
Primary endpoint: OS
Randomized 2:1
Abiraterone Acetate 1000 mg/day +
Prednisone 5 mg BID
(n = 797)
Patients with mCRPC progressing after 1-2 chemotherapy regimens, 1 of which contained docetaxel
(N = 1195)
Stratified by ECOG PS, worst pain over previous 24 hrs, previous chemotherapy, type of progression
BID, twice daily; ECOG, Eastern Cooperative Oncology Group; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PS, performance status.
Placebo +
Prednisone 5 mg BID
(n = 398)
Study stopped at planned interim analysis at 534 events because OS improvement crossed predetermined stopping boundary
de Bono JS, et al. N Engl J Med. 2011;364:

24. COU-AA-301: Overall Survival
Abiraterone acetate significantly improved OS vs placebo, with benefit consistent across nearly all patient subgroups
Group n
HR (95% CI)
Baseline ECOG 0-1
1068
0.64 ( )
BPI
< 4
659
0.64 ( )
≥ 4
536
0.68 ( )
Previous chemotherapy
1 regimen
833
0.63 ( )
2 regimens
362
0.74 ( )
Progression type
PSA only
363
0.59 ( )
Radiographic
832
0.69 ( )
Visceral disease
0.70 ( )
HR: 0.65 (95% CI: ; P < .001)
100
Abiraterone acetate: 14.8 mos (95% CI: ) 80 60
Survival (%) 40
Placebo: 10.9 mos (95% CI: ) 20
AA, abiraterone acetate; BPI, baseline pain intensity; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival; PSA, prostate-specific antigen. 3 6 9 12 15 18 21
Mos to Death AA
797
398
736
355
657
306
520
210
282
105 68 30 2 3
Placebo
de Bono JS, et al. N Eng J Med. 2011;364: Scher HI, et al. ASCO GU Abstract 4.

25. Abiraterone: Mechanism of Action
Hypokalemia
Hypertension
Fluid overload
Suppression of renin
ACTH
Pregnenolone
Deoxycorticosterone
Corticosterone
Aldosterone
Cortisol
11-deoxycortisol
17OH-Progesterone
17OH-Pregnenolone
CYP17: 17α-hydroxylase
CYP17: C17,20-lyase
x 5
Positive drive
Negative feedback
x 10
x 40
x 1.5
ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone.
x 3
x 4
x 2
DHEA
Androstenedione
Testosterone
Estradiol
< 1 ng/dL
x 3
< 2 ng/dL
< 80 ng/dL
Attard G, et al. J Clin Oncol. 2008;26: Reprinted with permission © 2008 American Society of Clinical Oncology. All rights reserved.

26. TAK-700 (Orteronel) in mCRPC: PSA Response and Safety
53% with PSA decreases ≥ 50% at 12 wks
Serious AEs in 25 patients (26%): hypokalemia (n = 3), acute renal failure (n = 3), pneumonia (n = 2), urinary tract infection (n = 2), hypotension (n = 2), neutropenia (n = 2), fatigue (n = 2)
Efficacy and tolerability demonstrated with TAK-700 administered with or without prednisone, suggesting feasibility of a steroid-free regimen
275
250
225
200
175
150
125
100
AEs, adverse events; BID, twice daily; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; QDAM, every day in the morning. .
PSA Change at 12 Wks (%) 75 50 25 x x x x
x x x x x x x x x
X x x x x x x
X x x
-25
-50
-75
-100
-125
Treatment
300 mg BID (n = 23)
400 mg BID + prednisone (n = 24)
600 mg BID + prednisone (n = 26)
600 mg QDAM (n = 24)
X Previous ketoconazole therapy
Agus DB, et al. ASCO Abstract 4531.

27. Oral 17,20-lyase Inhibitor, TAK-700, in mCRPC: Endocrine Responses18
120
Baseline 12 wks 16
100 14 12 80 10
Mean (SD) Testosterone (ng/dL)
Mean (SD) DHEA-S (ug/dL) 60 8 6 40 4 20 2
300 mg BID
400 mg BID + Pred
600 mg BID + Pred
600 mg QD
Overall
300 mg BID
400 mg BID + Pred
600 mg BID + Pred
600 mg QD
Overall
160
140
10,000
120
ACTH, adrenocorticotropic hormone; BID, twice daily; DHEA-S, dehydroepiandrosterone sulfate; mCRPC, metastatic castration-resistant prostate cancer; QD, once daily; SD, standard deviation.
8000
100
Mean (SD) ACTH (pg/mL) 80
6000 60
Mean (SD) Corticosterone (ng/dL)
4000 40 20
2000
300 mg BID
400 mg BID + Pred
600 mg BID + Pred
600 mg QD
Overall
300 mg BID
400 mg BID + Pred
600 mg BID + Pred
600 mg QD
Overall
Agus DB, et al. ASCO Abstract 4531.

28. Long-term Follow-up of Phase I/II Study of Enzalutamide in Advanced Prostate Cancer[1]
Enzalutamide (MDV3100): novel, oral AR antagonist
Blocks testosterone binding to AR, impedes movement of AR to nucleus, inhibits DNA binding
Slows tumor growth and causes cell death in cancers resistant to bicalutamide
Phase I/II trial conducted to determine safety, PK, and antitumor activity of enzalutamide[2]
N = 140 patients with progressive CRPC, pre- or postchemotherapy
Testosterone synthesis
Tumor death
Testosterone T T X
Enzalutamide AR
DNA binding and activation blocked 1
AR binding blocked 3 X X 2
Nuclear translocation impaired
Cell nucleus
No prednisone required
AR, androgen receptor; CRPC, castration-resistance prostate cancer; PCa, prostate cancer; PK, pharmacokinetics; T, testosterone.
Cohorts treated with sequentially escalating doses of enzalutamide ( mg/day)
1. Higano CS, et al. ASCO GU Abstract Scher HI, et al. Lancet. 2010;375:

29. Enzalutamide 160 mg PO daily
AFFIRM: Phase III Registration Trial of Enzalutamide in CRPC After Docetaxel
Randomized 2:1
Enzalutamide 160 mg PO daily
(n = 800)
Patients with
mCRPC progressing
on docetaxel
(N = 1199)
Placebo PO daily
(n = 399)
CRPC, castration-resistant prostate cancer; mCRPC, metastatic CRPC; PFS, progression-free survival; PO, orally; PSA, prostate-specific antigen; OS, overall survival.
Primary endpoint: OS
Key secondary endpoints: PSA response, soft-tissue objective response, radiographic PFS, time to PSA progression
Scher HI, et al. ASCO GU Abstract LBA1.

30. AFFIRM: Survival Improvement With Enzalutamide in CRPC
HR: (95% CI: ; P < .001) 37% reduction in risk of death
100
Survival (%) 90
Enzalutamide: 18.4 mos (95% CI: 17.3-NYR) 80 70 60 50 40 30 20
Placebo: 13.6 mos
(95% CI: )
CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. 10 3 6 9 12 15 18 21 24
Duration of OS (Mos)
Enzalutamide Placebo
211 81
72 33
7 3
0 0
Scher HI, et al. ASCO GU Abstract LBA1.

31. Radium-223 Targets Bone Metastases
Alpha-particles induce dsDNA breaks in adjacent tumor cells
Limited penetration of alpha emitters (2-10 cell diameters) results in highly localized tumor cell death with minimal damage to surrounding normal tissue
Range of alpha-particle
Radium-223
Bone surface
dsDNA, double-strand DNA.
Parker C, et al. ASCO GU Abstract 8. Perez CA, et al. Principles and practice of radiation oncology. 5th ed; 2007.

32. ALSYMPCA Phase III Trial of Radium-223 in mCRPC: OS
100 90
HR: (95% CI: ; P = ) 80
Survival, % 70 60
Radium-223 (n = 541)
Median OS: 14.0 mos 50 40 30
Placebo (n = 268)
Median OS: 11.2 mos
CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. 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 C, et al. ASCO GU Abstract 8.

33. Cabozantinib vs Placebo in mCRPC: Efficacy and Safety
Median PFS, Wks 21 6
Authors concluded cabozantinib has substantial antitumor activity in progressive mCRPC
Disease control at Wk 12: 68%
Measurable disease regression: 74%
Evidence of improvement on bone scan: 76%
Pain improvement: 67%
Moderate but manageable toxicity profile; similar to other TKIs
1.00
Cabozantinib (n = 14) Placebo (n = 17)
0.75
Proportion Progression Free
0.50
HR: 0.13 (log-rank P = .0007)
0.25
-12 10 20 30 40 50 60
12-Wk Lead-in Stage
PFS per mRECIST, Postrandomization (Wks)
HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; mRECIST, modified Response Evaluation Criteria in Solid Tumors; PFS, progression-free survival; TKIs, tyrosine kinase inhibitors.
Hussain M, et al. ASCO Abstract 4516.

34. A Treatment Algorithm for mCRPC
Maintain castration serum levels of testosterone and use denosumab or zoledronic acid with vitamin D and calcium if bone metastases are present
Symptomatic
Visceral disease No
Yes
Docetaxel
Mitoxantrone
Abiraterone acetate (Level 2B)
Palliative radiotherapy or radionuclide (radium-223?) for symptomatic bone metastases
Clinical trial
Sipuleucel-T
Secondary hormone therapy
Antiandrogen
Antiandrogen withdrawal
Ketoconazole or abiraterone acetate (level 2B)
Steroids
DES or other estrogen
Clinical trial
DES, diethylstilbestrol; mCRPC, metastatic castration-resistant prostate cancer.
Abiraterone acetate
Cabazitaxel
Salvage chemotherapy
Docetaxel rechallenge
Mitoxantrone
Secondary hormone therapy
Sipuleucel-T
Enzalutamide
Clinical trial
Mottet N, et al. Eur Urol. 2011;59: NCCN. Clinical practice guidelines in oncology: prostate cancer. v Yap TA, et al. Nat Rev Clin Oncol. 2011; 8:

35. Castration-Resistant Prostate Cancer
173,000
100,000
64,000
Localized PCa
Advanced PCa
CRPC
Tumor Volume M0 M1
Diagnosis
CRPC, castration-resistant prostate cancer; PCa, prostate cancer; PSA, prostate-specific antigen.
Primary PSA failure
Second PSA failure = CRPC
Androgen Deprivation Therapy

36. Time of M0 to M1 and Death in Progressive, Nonmetastatic CRPC
Time to Bone Metastasis
Time to Death
1.0
1.0
Cumulative incidence function
Kaplan-Meier estimate
0.9
0.9
95% CI
95% CI
0.8
0.8
0.7
0.7
0.6
0.6
Probability of Bone Metastases
0.5
Probability of Death
0.5
0.4
0.4
0.3
0.3
CI, confidence interval; CRPC, castration-resistant prostate cancer.
0.2
0.2
0.1
0.1
25 mos
46.8 mos 6 12 18 24 30 36 42 48 54 60 66 6 12 18 24 30 36 42 48 54 60 66
Mos Since Randomization
Mos Since Randomization
Smith MR, et al. Cancer. 2011;117:

37. Timing of Disease Progression in Prostate Cancer
Castration-Resistant Prostate Cancer M0
M1 Asymptomatic
M1 Symptomatic
A continuum, but not equal in time M0 M1
M1+
Mos

38. Fracture-Free Survival Diminishes With Cumulative ADT Exposure
Over a 4-year period
19.4% fractures on ADT
12.6 % fractures not on ADT
Fracture-free survival reduced with increasing number of GnRH agonist doses over 10-years
At ≥ 9 doses of GnRH agonist fracture-free survival is similar to orchiectomy
Longer, deeper androgen deprivation is THE new reality
ADT, androgen deprivation therapy.
Shahinian VB, et al. N Engl J Med. 2005;352:

39. Conclusions Promising new therapies are emerging
Time from CRPC to death expected to increase
Prostate cancer death rate expected to increase
Bone is a significant target of ADT and prostate cancer
Agents that produce “deeper” blockade of the androgen receptor pathway may have more profound effects on bone
ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer.

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