1. Newly Diagnosed Metastatic Castration Resistant Prostate Cancer
2016 ASCO/NCCN Prostate Cancer Satellite Symposium
Clinical Care Options
Newly Diagnosed Metastatic Castration Resistant Prostate Cancer

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3. Faculty
Andrew Armstrong, MD, ScM, FACP Associate Professor of Medicine and Surgery Duke Cancer Institute Divisions of Medical Oncology and Urology Duke University Medical Center Durham, North Carolina Andrew Armstrong, MD, ScM, FACP, has disclosed that he has received consulting fees from Astellas/Medivation, Bayer, Dendreon, Eisai, and Janssen; speaker fees from Dendreon and sanofi-aventis; and funds for research support from Active Biotech/Ipsen, Astellas/Medivation, Bayer, Dendreon, Gilead, Janssen, Novartis, Pfizer, and sanofi-aventis.

6. IMPACT: Sipuleucel-T Immunotherapy Improved OS in mCRPC
Median survival benefit for Sip-T: 4.1 mos
100
HR: 0.78 (95% CI: ; P = .03) 80
Sipuleucel-T (n = 341)
Placebo (n = 171) 60
Percent Survival (%)
25.8 mos
mCRPC, metastatic castration-resistant prostate cancer; Sip-T, sipuleucel-T. 40
21.7 mos 20 12 24 36 48 60 72
Survival (months)
Kantoff PW, et al. N Engl J Med. 2010;363:

7. IMPACT: Survival Benefit From Sipuleucel-T Associated With Lower Baseline PSA
Baseline PSA, ng/mL
≤ 22.1
(n = 128)
>
>
> 134.1
Median OS, mos
Sipuleucel-T
41.3
27.1
20.4
18.4
Control
28.3
20.1
15.0
15.6
Difference
13.0
7.1
5.4
2.8
HR (95% CI)
0.51
( )
0.74
( )
0.81
( )
0.84
( )
PSA, prostate-specific antigen.
Earlier use of sipuleucel-T prior to abiraterone/enzalutamide is preferred, given lack of short-term benefits on PSA, disease control, and possible improved survival impact earlier in the disease course
Schellhammer PF, et al. Urology. 2013;81:

8. Sipuleucel-T FDA approved April 2010
Toxicities are mild, infusion related: fever, chills
Consideration of spinal imaging (MRI) in men with high-volume spinal metastases given risk of disease progression in the short term
Ideally used early with lower volume disease or before numerous other therapies
No impact on PSA or radiographic response, PFS
NCCN category 1 recommendation if asymptomatic to minimally symptomatic (no opiates for cancer pain), no liver metastases, life expectancy > 6 mo, ECOG 0-1
ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen.
NCCN Guidelines® for Prostate Cancer, v

11. PREVAIL: Enzalutamide in Chemo-Naive CRPC
Overall Survival
rPFS
N = 1717; randomized 1:1 ENZ vs PBO
All subgroups benefited
rPFS: 3.9 mos (PBO)  NYR (ENZ) (15-19 mos)
PSA PFS: 2.8 mos (PBO) 11.2 mos (ENZ)
OS updated 2015: 35.3 vs 31.3 mos (HR: 0.77; P = .002)
PSA 50/90% or greater decline in 78/47% (ENZ)
RECIST responses in 59% (ENZ)
Time to chemo: 28 mos (ENZ) vs 10.8 mos (PBO)
QoL responses in 40 vs 23%; TTQoL decline 11.3 mos (ENZ) vs. 5.6 mos (PBO)
CRPC, castration-resistant prostate cancer; ENZ, enzalutamide; NYR, not yet reached; PBO, placebo; PSA, prostate-specific antigen; QoL, quality of life.
Beer TM, et al. N Engl J Med. 2014;371: Beer TM, et al. ASCO Abstract 5036.
Loriot Y, et al. Lancet Oncol. 2015;16:

12. PREVAIL: Pattern of Disease Spread And Activity of Enzalutamide in mCRPC
rPFS
mCRPC, metastatic castration-resistant prostate cancer. OS
Evans CP, et al. Eur Urol. 2016;[Epub ahead of print].

13. PREVAIL: Enzalutamide Safety
Beer TM, et al. N Engl J Med. 2014;371:

14. Posterior Reversible Encephalopathy Syndrome (PRES)
PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension.
A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).
Discontinue enzalutamide in patients who develop PRES.

15. Abiraterone Acetate + Prednisone X X
Cholesterol
Desmolase
Renin
Pregnenolone
Progesterone
Deoxy-
corticosterone
Corticosterone
Aldosterone X
CYP17
17α-hydroxylase
11β-Hydroxylase
17α-OH-
pregnenolone
17α –OH-
progesterone
11-Deoxy-
cortisol
Cortisol
ACTH X
CYP17
C17,20-lyase
Autocrine and paracrine (adrenal) pathways
5α-reductase
DHEA
Androstenedione
Testosterone
DHT
CYP19: aromatase
Estradiol
Attard G, et al. JCO. 2008;26:

16. Abiraterone Acetate in Chemo-Naive mCRPC
OS 30.3 mos (PBO) 34.7 mos (ABI); HR 0.81; P = .0033
Superiority over prednisone previously demonstrated post-docetaxel and in chemo-naive men with mCRPC
Dose: 1000 mg daily + prednisone 5 mg bid
Improved OS accompanied by improvements in QoL, pain, PFS, response rates, and fewer adverse events than placebo
Prevention of pain, PS deterioration, need for chemotherapy improved pre-docetaxel
Abiraterone acetate with prednisone is now FDA approved for men with mCRPC prior to docetaxel
Has not been evaluated in men with chemo-naive mCRPC and visceral mets
AE, adverse event; mCRPC, metastatic castration-resistant prostate cancer; QoL, quality of life.
Ryan CJ, et al. Lancet Oncol. 2015;16: Ryan CJ, et al. N Engl J Med. 2013;368:

17. Abiraterone Acetate: Safety Profile
Ryan CJ, et al. Lancet Oncol. 2015;16:

18. Differences in drug characteristics
Abiraterone
Enzalutamide
Oral
yes
Prednisone required no
Drug interactions (CYP)
Lowers seizure threshold
Potential liver toxicity
less
Risk for hypertension
Risk for CV events,
atrial fib
Dose
250 mg x 4
40 mg tablets x 4
Empty stomach
CV, cardiovascular.

19. Timing and Selection of Secondary AR-Directed Therapies
Choice of abiraterone vs enzalutamide cannot be dictated based on differences in efficacy
Similar OS, PFS from cross-trial comparisons
Enzalutamide has been evaluated in men with visceral metastases in the chemo-naive setting
Both are category 1 recommendations in NCCN guidelines
Therefore choice is based on differential toxicity
Abiraterone acetate for seizure-prone men and those more frail, elderly (> 75 years old) men at high risk for falls
Enzalutamide for men with significant CV risk factors, contraindications to prednisone, brittle diabetes, and metabolic syndrome
Significant cross-resistance, so initial choice is likely most important one
CV, cardiovascular.

20. Practical Aspects of Enzalutamide Use
Prescription is for four 40-mg capsules taken once daily, with or without food
I recommend home BP monitoring given the 7% risk of severe HTN with enzalutamide (160/100) of unclear cause
Exercise encouraged to reduce fall risk
No driving restrictions given rare seizure risk but important to avoid enzalutamide in patients with a prior history of seizures or epilepsy or those men at very high risk of seizures (eg, brain tumors, prior major strokes, CNS metastases, taking concurrent medications that lower seizure threshold)
BP, blood pressure; CNS, central nervous system; HTN, hypertension.
NCCN GL (DFC, 6/1/16): Speaker: This slide says capsules, and slide 21 says tablets. Nothing listed on slide 21 for abiraterone (capsule vs tablet), but slide 24 lists tablets. Can you edit to make consistent?

21. Practical Aspects of Abiraterone Acetate With Prednisone Use
Prescription is for mg tablets taken once daily, 1 hour prior to food intake or 2 hours after food (water OK)
Taking with food increases bioavailability substantially, may increase toxicity
I recommend home BP monitoring given the 5-10% risk of severe HTN with abiraterone (160/100) due to mineralocorticoid excess
Eplerenone may reverse this (mineralocorticoid antagonist)
Exercise encouraged to reduce fall risk, fatigue
Liver function and electrolyte, renal monitoring every 2 wks during the first 3 months, then every 12 wks
Treatment of fluid retention, hypokalemia is common
Pre-treatment cardiac evaluation reasonable in patients with significant underlying CHF, CAD, or arrhythmias

22. Bone Scans in CRPC Difficult to interpret Images osteoblast activity
Healing may appear more intense!
New lesions are best measures of progression vs flare (within clinical context)
Confirmation scans showing continued additional new lesions required—flare is common (40% with abiraterone/enzalutamide!)
Prostate Cancer Working Group 2 Guidelines are new criteria for determining progression
Often will be performed on site and centrally along with clinical read
Thus, misclassification of progression is common!
Baseline
Wk 13
CRPC, castration-resistant prostate cancer.
Wk 25
Scher HI, et al. J Clin Oncol. 2008;26:
Scher HI, et al. J Clin Oncol. 2016;34:

23. ALSYMPCA: Phase III Study Design
TREATMENT PHASE
PATIENTS
STRATIFICATION
Radium-223 dichloride
(55‡ kBq/kg) +
best standard of care†
N = 921
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel*
Total ALP: < 220 U/L vs. ≥ 220 U/L
Bisphosphonate use: Yes vs No
Prior docetaxel: Yes vs No
6 injections
at 4-week intervals
2:1
Placebo (saline) +
best standard of care†
CRPC, castration-resistant prostate cancer.
NCCN GL (DFC, 6/1/16): Removed “(ALpharadin in SYMptomatic Prostate Cancer)” from title.
PRIMARY ENDPOINT: OVERALL SURVIVAL
136 centers in 19 countries
Planned follow-up is 3 years
*Unfit for docetaxel includes pts who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable.
†Best standard of care defined as a routine standard of care at each center, eg, local external-beam radiotherapy, corticosteroids, antiandrogens, estrogens (e.g., diethylstilbestrol or estramustine), or ketoconazole.
‡NIST update 2016.
Parker C, et al. New Engl J Med. 2013;369:

24. ALSYMPCA Updated Analysis: OS
100
Radium-223 (n = 614)
Placebo (n = 307)
Median OS (mos)
14.9
11.3
Hazard Ratio
0.70
95% CI
P value
< .001 90 80 70 60
Median Δ: 3.6 mos
30% reduction in risk of death
Patients (%) 50 40 30 20
Radium-223 dichloride (n = 614)
Placebo (n = 307) 10
Month 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-223
614
578
504
369
274
178
105 60 41 7 1
Placebo
307
288
228
157
103 67 14 4 2
Parker C, et al. New Engl J Med. 2013;369:

25. ALSYMPCA: Predictors of Radium-223 Benefit?
Parker C, et al. New Engl J Med. 2013;369:

26. ALSYMPCA Updated Analysis: Select Adverse Events
All Grades
Grades 3 or 4
Patients with AEs
n, (%)
Radium-223
n = 600
Placebo
n = 301
n= 301
Hematologic
Anemia
187 (31)
92 (31)
77 (13)
39 (13)
Neutropenia
30 (5)
3 (1)
13 (2)
2 (1)
Thrombocytopenia
69 (12)
17 (6)
38 (6)
6 (2)
Non-Hematologic
Bone pain
300 (50)
187 (62)
125 (21)
77 (26)
Diarrhea
151 (25)
45 (15)
9 (2)
5 (2)
Nausea
213 (36)
104 (35)
10 (2)
Vomiting
111 (18)
41 (14)
7 (2)
Constipation
108 (18)
64 (21)
6 (1)
4 (1)
AE, adverse event.
Safety of taxane chemotherapy following radium-223 not well characterized
Parker C, et al. New Engl J Med. 2013;369:
Parker et al NEJM 2013

27. Radium-223: Efficacy and Safety According to Previous Docetaxel Treatment
Hoskin P, et al. Lancet Oncol. 2014;15:

28. Radium-223: Summary Administration: Clinical Benefit:
Once every 4 wks for 6 infusions
60-second IV infusion
Given by radiation oncologist or nuclear medicine radiologist
Enteric excretion
No pre-medication, no post-medication
CBC check before each treatment
Clinical Benefit:
Primary endpoint of improvement in symptomatic SRE
3.6-mo benefit in OS
Should be considered in symptomatic men with bone-predominant mCRPC
Consider spinal imaging for epidural disease in men with high burden of disease and rapid progression; palliative EBRT should be used if high risk for spinal cord compression
EBRT, external beam radiation therapy; CBC, complete blood count; mCRPC, metastatic castration-resistant prostate cancer.

29. NCCN Guidelines
Radium-223 is an NCCN category 1 recommendation for men with symptomatic bone-predominant CRPC
Can be used before or after docetaxel given similar survival benefit
Pts should be followed carefully for bone marrow toxicity prior to dosing and over time
Concurrent use of hormonal therapies, external beam palliative radiation, steroids are reasonable given the lack of drug interactions and safety issues
CRPC, castration-resistant prostate cancer.
NCCN Guidelines for Prostate Cancer, v

30. Conclusions: mCRPC
ADT should be continued despite “castration resistance”
Use of bone anti-resorptive agents should be considered
In eligible patients, sipuleucel-T is best given early in the course of CRPC
Enzalutamide, abiraterone, and radium-223 are all options prior to chemotherapy in individual patients
ADT, androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; mCRPC, metastatic castration-resistant prostate cancer.

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