Download 09 Nevin Murray Prostate Cancer

Navigating Prostate
Cancer Therapy
Nevin Murray MD
Clinical Professor of Medicine, UBC
Medical Oncologist, BCCA
Disclosures
In compliance with accreditation, we require the following disclosures to the session audience:
Research Support/P.I.
N/A
Employee
N/A
Consultant
N/A
Major Stockholder
N/A
Speakers Bureau
N/A
Honoraria
AstraZeneca, Bristol Myers Squibb, Astellas
Scientific Advisory Board
AstraZeneca, Bristol Myers Squibb, Astellas
Presentation includes discussion of the following off- label use of a
drug or medical device: N/A
Prostate Cancer Demographics
In Canada in 2015
24,000 new cases (#1 overall)
4,100 deaths (#3 in men)
In B.C. in 2013
3,800 new cases (#1 overall)
600 deaths (#3 in men)
Prostate Cancer Screening
Review of new studies
Why does a clear consensus escape us?
Randomized trials but no easy answer.
Current recommendations
And what to do in Family Medicine
Summary
Gary Larson – Far Side
The evidence
Comes from 2 Randomized Studies
Europe ERSPC
USA PLCO
NEJM March 2009
ERSPC
European Randomized Screening Trial of Prostate Cancer
162,400 men in core group 55-69 years
Median follow-up 11 years
Control group not screened
Screened group: PSA every 4 years x 2
• PSA threshold 3ng/ml (2.5-4ng/ml)
DRE dropped
control
Positive diagnosis rate
screened
6%
9.6%
(63% increase)
Schroder et al. N Engl J Med, 360,(13), 2009 & March 2012
Results: ERSPC trial
Large stage shift
(% of positive)
control
13%
8.2%
High risk
Metastases
screened
8%
3%
(48% decrease)
Non-palpable
(T1c)
41%
54%
(31% increase)
Schroder NEJM March 2009 & March 2012, Supplemental material on line, adjusted for null stage
Update: ERSPC trial
And this translates into a reduction in prostate
cancer deaths
Screened 0.4% (n=299)
Control 0.5% (n=462)
Schroder: NEJM March 15, 2012
RR 0.79 p=0.001
Update: ERSPC trial
NNInvite
NNDiagnose
781
27
(was 1440)
(was 48)
In those actually screened
Mortality reduction ratio 0.71
But no hint of an overall survival benefit
Mortality ratio 0.99 [CI 0.97-1.01]
Schroder EAU Paris 2012
Update: PLCO trial
Cumulative number of deaths
Prostate Cancer Mortality
Screened
Control
Study year of death
Redrawn from Andriole JNCI On line 2012
Why the differences?
In the US the baseline opportunistic
screening rate was
45% in the prior 3 years (lifetime rate unknown)
rising to 52% in the control arm by year 6
and 86% in the screening arm
So it was a trial of more screening versus
~50% screening
Indicative of an underlying problem
PSA is not a great test!
Significant
overlap
No level free
of cancer
risk
Holmström,BMJ 2009;339:b3537
PSA: No safe level
Thompson. JCO VOLUME 23 NUMBER 32 NOVEMBER 10 2005
PSA screening in Family Practice
93% are screening
Bluman et al
Primary Care Physician Education and Engagement in the Promotion of Recommended Cancer Screening in BC
Report On Province-wide Cancer Screening Needs Assessment
UBC Division of Continuing Professional Development, Faculty of Medicine & The BC Cancer Agency
Widely available through Google search
What is the BCCA policy?
May 2012
We recommend: Considering PSA Testing
Start age: asymptomatic men 50-55 years
estimated life expectancy > 10 years
well informed about the risks of over-diagnosis
and over-treatment
BCCA web site: Google “BCCA PSA Screening”
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Genitourinary/Prostate/PSAScreening/Recommendations.htm
1: Asymptomatic men 50-55 years
Tempting to get a baseline level at 45-50
But not evidence based
Costly
Many false positives
Possibly indicated in the high risk
• Family history
• African ethnicity
2: Well informed about the risks of
over-diagnosis and over-treatment
This is really difficult
It is impossible to do properly in 5 minutes
Is it actually required ethically?
• Do we do this for cholesterol testing?
• An ‘easy out’ to say no!
• Most authorities say it is required
Patient information brochures are available
• And should be read before the blood is drawn
Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the
early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010 MarApr;60(2):70-98.
Minimum components of consent
Risks of PSA testing
False negative and false positive PSA results
A low PSA test does not mean that a person does not have
prostate cancer, and a high PSA does not necessarily mean a
person does have prostate cancer.
Biopsy
Pain and very rarely infection.
Distress and anxiety
Being diagnosed with prostate cancer is associated with anxiety.
Over-diagnosis and treatment
Over-diagnosis refers to the detection of cancers that would not
otherwise have become clinically apparent. This could result in
treatment of a prostate cancer that may not have been a problem
for a man in his lifetime
The risks of treatment such as radiation and surgery include
urinary problems and incontinence, sexual dysfunction, and bowel
problems.
BCCA web site: Google “BCCA PSA Screening”
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Genitourinary/Prostate/PSAScreening/Recommendations.htm
Minimum components of consent
Benefits
Early detection of prostate cancer can save lives.
Early detection and treatment of prostate cancer can
avert future prostate cancer-related problems.
BCCA web site: Google “BCCA PSA Screening”
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Genitourinary/Prostate/PSAScreening/Recommendations.htm
How to do it:
If the patient wants it
Every 4 years starting 50-55 (45 if high risk)
Any PSA that is high (age-adjusted) needs
1. Checking
2. Then referral to a Urologist
Or abnormal DRE
•
Refer to a Urologist
Stop when life expectancy <10 years
Summary
Small decrease in prostate cancer mortality
At a cost of probable overall net harm
Patients should be informed of its availability
And make their own decision
With your guidance
Watch out for “normal PSA’s” that are high
for age
>1 ng/ml in 40’s
>2 ng/ml in 50’s
Refer promptly if abnormal PSA
Those with <10 yr life expectancy should not
be screened
Localized Prostate Ca
BCCA Promotes Active Surveillance
Monitoring of low risk cancer with intervention if the
cancer progresses to intermediate risk
Low risk: PSA≤10 and Gleason score ≤6
Of BCCA patients referred to Rad Onc last year
1/3 had ‘low risk’ prostate cancer
2/3 of these had no immediate treatment
2/3 of those will avoid treatment for 5 years
LOW RISK RESULTS
Weighted
% PSA Progression Free
Treatment Success
>40 months follow-up or less than 100 patients
100
HDR
90
80
Proton
68 51 50
92
46 11314
96
110
97 66 25
22
8
13
75
48
37
2014 816 6286
11435
44
3
60
41 82
33
32
203 6985
71
6584 3172 99 29 101 39103 11228 1067
98 89
42 94 95
61 93
18 88102
38
54
36
105 24
73
1947
43 55
78
2 26
64
12 83
40
20258
1 100 7 87
76 56
107 106
77
9
70 80
41
15 45
57 74 79
20
10959
17
90
53
+
27
LDR Brachy
111
5
16
115
52
104
108
EBRT/IMRT
Surgery
63
70
7
34
← Years from Treatment →
91
60
49
11
1
2 3 4 5 6 7 8 9 10 11 12 13 14 15
• Prostate Cancer Results Study Group
Seeds &
ADT
EBRT &
ADT
EBRT &
Seeds
Robot RP
Seeds
Surgery
EBRT
CRYO
HIFU
Protons
Hypo EBRT
HDR
• Numbers within symbols refer to references
11/16/2015 Update of
BJU Int, 2012, Vol. 109(Supp 1)
Prostate Cancer Center of Seattle
24
Management Objective of Metastatic
Prostate Cancer
 Cancer incurable.
 Have patient live as well as possible, and as long
as possible in co-existance with metastatic
prostate cancer.
 Use available systemic therapy cost-effectively at
appropriate time, keeping side effects to a
minimum.
THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF
THE PROSTATE GLAND
CHARLES HUGGINS, M.D.; R. E. STEVENS, Jr., M.D.; CLARENCE V. HODGES, M.D.
Arch Surg. 1941;43(2):209-223.
In this paper evidence is presented that
significant improvement often occurs in the
clinical condition of patients with far
advanced cancer of the prostate after they
have been subjected to castration.
Conversely, the symptoms are aggravated
when androgens are injected. We believe
that this work provides a new concept of
prostatic carcinoma.
Charles B. Huggins
Nobel Prize in
Physiology or
Medicine 1966
The Predominate Sources of Androgen
~90% androgen
synthesis
Testes
~10% androgen
synthesis
Adrenal
Gland
• In healthy men, ~90% of circulating
androgens are synthesized in the testes
• ~10% of circulating androgens are secreted by the adrenals
• DHT is the primary androgen in prostatic tissue
Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123.
27
Androgens Drive
Prostatic Tumor Growth
LHRH therapy or
orchiectomy may
be used to
suppress testicular
sources
LHRH therapy
of androgen
or orchiectomy
Prostatic Tumor
Tissue
Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123.
Adrenal
Gland
Treatment with LHRH
therapy or orchiectomy
is used to induce
regression of prostate
tumor tissue and cause
cell death; however, it
is rarely curative
28
Primary Androgen Deprivation Therapy
Orchiectomy
Cheap
Permanent
Medical vs surgical side effects similar
LHRH Agonists
Injections every one to six months.
Requires biclutamide x 1 month to avoid flare.
Home Care programs.
Intermittent strategy
LHRH Antagonists
Monthly injections.
Works faster.
No flare or need for biclutamide for this purpose.
Intermittent ADT
PR.7: Non-Metastatic
PR.8: Metastatic
JM Crook et al, NEJM367:895, 2013; M. Hussain et al, NEJM, 368:1314, 2013
2nd Line Hormone Therapy
Many options currently available to inhibit extragonadal androgen
production or androgen receptors
Biclutamide, nilutamide, flutamide
Prednisone 10 mg daily
Dexamethasone 2 mg daily
Clinical Impact?
PSA response rate 20-30%
TTP/duration of response 3-6 months
Survival and clinical benefit have never been well defined
• Are we changing natural history?
But...
Well tolerated, inexpensive
Some very good PSA and symptomatic responses
Appropriate for patients with minimal symptoms, no visceral metastases
and chemotherapy-ineligible
“Big Guns” kept in reserve for when really needed.
Defining The Patient Population:
Castration Resistant Prostate Cancer
• Aka: Hormone Refractory, Androgen Independent
• Prostate Cancer Clinical Trials Working Group:
– Castrate level of testosterone (<50 ng/dL/1.7 nmol/L)
– Nodal or visceral progression
– Bone Progression: appearance of 2 or more new lesions
• Heterogenous Group
• No clinical metastases
• Clinical metastases
– Asymptomatic
– Symptomatic
PSA Rise
Biochemical
Clinical Metastases
Symptomatic Disease
36+ Months
18-24+ Months
12-18 Months
Death
Prostate Cancer Before 1996
Localized
“Treat” with curative intent
Local
Relapse
Hormone Therapy (incurable)
Failed Localized
Therapy
Biochemical
Progression
prednisone
Metastatic
HRPC
(asympt.)
Death
A whole lot of nothing
Metastatic
HRPC
(sympt)
Systemic Therapies
Cytotoxic Therapy for
Castration-Resistant Prostate
Cancer
Assessing Response to
Chemotherapy
 Most men with metastatic prostate cancer have
bone metastases.
 Soft Tissue Disease on CT Scan
 Lymph nodes, liver, lung.
 Necessary to rely on surrogate endpoints to
assess response
 decline in serum PSA, LDH.
 improvement in pain
 QOL
Timing of Chemotherapy
 Many patients who have disease progression
following androgen-deprivation therapy do not
immediately require cytotoxic chemotherapy
 Not for PSA relapse only
 Not for clinically silent metastatic disease
 Performance status reserve required
 Consider PSA doubling time in borderline case
TAX-327
Stratification:
Pain level
PPI ≥ 2 or
AS ≥ 10
vs.
PPI < 2 or
AS < 10
KPS
≤70 vs. ≥ 80
Docetaxel 75 mg/m2 q3 wks +
Prednisone 5 mg bid
R
A
N
D
O
M
I
Z
E
Docetaxel 30 mg/m2 wkly
5 of 6 wks +
Prednisone 5 mg bid
Overall
Survival
Mitoxantrone 12 mg/m2
q3 wks +
Prednisone 5 mg bid
Tannock et al., NEJM, 2004 (slide courtesy of Dr. K. Chi)
TAX-327—Overall Survival
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
0.3
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0.2
0.1
Median
survival
(mos)
Hazard
ratio
P-value
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
0.03
0.009
0.3
–
0.0
0
6
12
18
24
30
Tannock et al., NEJM, 2004 (slide courtesy of Dr. K. Chi)
STRATIFICATION
Extent of Mets
-High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
-Yes vs No
Prior Adjuvant ADT
≤12 vs > 12
months
NEJM, 373: 737, 2015
R
A
N
D
O
M
I
Z
E
•
•
•
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for maximum 6
cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate every 3
weeks while
receiving
docetaxel and at
week 24 then
every 12 weeks
Evaluate every
12 weeks
Follow for time to
progression and
overall survival
Chemotherapy at
investigator’s
discretion at
progression
ADT allowed up to 120 days prior to randomization.
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but no daily prednisone
High volume: visceral metastases and/or 4 or more bone
metastases (at least 1 beyond pelvis and vertebral column)
CHAARTED: Overall Survival
Summary
 Addition of docetaxel x 6 cycles to initial ADT
improves overall survival in patients with
metastatic disease: a new standard of care
 Recommended in patients with high volume
metastases (≥ 4 bone mets with ≥ 1 outside
spine/pelvis or visceral mets) or poor prognosis
 Consider in patients with non-high volume
disease/good prognosis but risk vs. benefit ratio needs
to be considered
 Do not consider in patients without metastatic disease
TAX-327—Overall Survival
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
0.3
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0.2
0.1
Median
survival
(mos)
Hazard
ratio
P-value
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
0.03
0.009
0.3
–
0.0
0
6
12
18
24
30
Tannock et al., NEJM, 2004 (slide courtesy of Dr. K. Chi)
2nd Line Chemotherapy
 Patients are older, and generally more
symptomatic
 The expectation is for short duration of survival,
so emphasis on QOL and symptom
management is paramount
 Consider repeat docetaxel for good responders
 Cabizitaxel in robust patients
 Mitoxantrone weak
New Pills for CRPC
 Abiratirone acetate
 Enzalutamide
Mechanism of Action:
Abiratirone Inhibits Androgen Production at
Multiple Sites

Zytiga inhibits the
CYP17 enzyme
complex that is
required for
testosterone
biosynthesis in all
three sites:



Testes
Adrenal Gland
Prostate Tumor
Tissue
Abiraterone
acetate
Testes
Adrenal
Gland
LHRH Therapy
Orchiectomy
Prostatic Tumor
Tissue
Sites of Abiratirone Acetate Action in
Steroidogenesis Pathway
Cholesterol
Pregnenolone
Aldosterone
CYP17A1
Abiraterone
17OHPregnenolone
Cortisol
CYP17A1
DHEA
Androstenedione
Testosterone
DHT
Mechanism of Action:
Effect on Adrenal Function
Blocking the CYP17 enzyme
also causes decreased
cortisol levels
This Leads to ACTH
increase
Resulting in excess
aldosterone
(Mineralocorticoids)
Can cause hypertension,
hypokalemia and fluid
retention
Prednisone
X
Co-administration
of a corticosteroid
suppresses ACTH
drive, resulting in
a reduction in the
incidence and
severity of
mineralocorticoid
adverse reactions
Abiratirone : Need for Prednisone
Low-dose steroid replacement reduces
mineralocorticoid-related toxicity
Cholesterol
No Prednisone
Pregnenolone
T
T
CYP17
C17,20-lyase
DHEA
Corticosterone
Abiraterone
17α –OHprogesterone
11-Deoxycortisol
Abiraterone
CYP17
17α-hydroxylase
17α-OHpregnenolone
DOC
T
T
Progesterone
Androstenedione
Testosterone
Aldosterone
Prednisone
SALT
Mineralocorticoids
HTN
Low K+
Cortisol
DHT
Estradiol
Source: Attard et al. J Clin Oncol. 2008;26:4563-4571; Ryan et al. J Clin Oncol. 2010;28:1481-1488.
SUGAR
Glucocorticoids
SEX
Androgens
COU-AA-301 Study Design
Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study
(147 sites in 13 countries; USA, Europe, Australia, Canada)
T
• 1195 patients with
progressive, mCRPC
• Failed 1 or 2 chemotherapy
regimens, one of which
contained docetaxel
• Randomised 2:1
• Stratification by:
• ECOG performance
status (0-1 vs. 2)
• Worst pain over previous
24 hours (BPI short form;
0-3 [absent] vs. 4-10
[present])
• Prior chemotherapy (1 vs.
2)
• Type of progression (PSA
only vs. radiographic
progression with or
without PSA progression)
Primary endpoint:
R
E
A
T
Abiraterone acetate
1000 mg daily
Prednisone 5mg twice daily
Placebo daily
Prednisone 5mg twice daily
U
N
T
I
L
P
R
O
G
R
E
S
S
I
O
N
OS (25% improvement; HR 0.8)
de Bono et al. N Engl J Med 2011; 346(21): 1995-2005
Abiraterone Acetate Improves Overall
Survival in mCRPC
Hazard ratio = 0.646 (0.54-0.77) P < 0.0001
100
Abiraterone acetate:
14.8 months (95% CI, 14.1-15.4)
Survival (%)
80
60
Placebo:
10.9 months (95% CI, 10.2-12.0)
40
20
0
AA
Placebo
V2.0
AA
Placebo
0
3
6
797
398
736
355
657
306
9
12
15
Time to Death (Months)
520
282
68
210
105
30
18
21
2
3
0
0
de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)
Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )
Novel Study Design: Co-primary End
Points
Study COU-AA-302
Patient
Population
Progressive mCRPC
without prior
chemotherapy;
Asymptomatic or
mildly symptomatic
R
A
N
D
O
M
I
Z
E
D
1:1a
aStratification
by ECOG PS 0 vs 1.
Co-primary end points:
• rPFS (central review)
• OS
Abiraterone 1000 mg daily
+
Prednisone 5 mg BID
(actual n = 546)
Placebo daily
+
Prednisone 5 mg BID
(actual n = 542)
Secondary end points:
• Time to opiate use
• Time to initiation of
chemotherapy
• Time to ECOG PS
deterioration
• Time to PSA progression
Exploratory end points:
• HR-QoL (FACT-P, BPISF)
BID, twice daily; rPFS, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of
life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG
PS, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen.
Rathkopf D, ASCO GU 2013, Oral Presentation/ Abstract 5
MDV3100: Enzalutamide




Chen et al Lancet Oncol. 2010
AR antagonist
8 fold higher affinity
than bicalutamide
NO DNA binding
NO partial agonist
activity
TOC
AFFIRM: A Phase 3 Trial of Enzalutamide vs. Placebo
in Post-Chemotherapy Treated Castration-Resistant
Prostate Cancer (CRPC)
Scher HI, et al. N Engl J Med. 2012;367:1187-97.
For Educational Purposes Only – Not For Promotional Use
TOC
AFFIRM
Overall Survival
Overall Survival, %
HR = 0.63 (95% CI: 0.53, 0.75); p < 0.001
37% Reduction in Risk of Death
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR)
Placebo: 13.6 months
(95% CI: 11.3, 15.8)
Months
No. at Risk
Enzalutamide
Placebo
NYR: not yet reached
Scher HI, et al. N Engl J Med. 2012;367:1187-97.
For Educational Purposes Only – Not For Promotional Use
TOC
AFFIRM
Adverse Events
Any Grade
Enzalutamide
(n = 800)
Grades ≥3
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
Frequent Adverse Events More Common with Enzalutamide*
Fatigue
34%
29%
6%
7%
Diarrhea
21%
18%
1%
<1%
Hot Flash
20%
10%
0%
0%
Musculoskeletal pain
14%
10%
1%
<1%
Headache
12%
6%
<1%
0%
Adverse Events of Special Interest
Any Cardiac Disorders
6%
8%
1%
2%
Myocardial Infarction
<1%
<1%
<1%
<1%
LFT Abnormalities†
1%
2%
<1%
<1%
Seizure
<1%
0%
<1%
0%
*Adverse events that occurred in >10% of patients in the enzalutamide group and that occurred in the enzalutamide group at a
rate that was at least 2% points higher than that in the placebo group. Grade 4 and 5 events were not observed.
†Abnormalities on liver-function testing (LFT) included hyperbilirubinemia and increased levels of AST or ALT
Scher HI, et al. N Engl J Med. 2012;367:1187-97.
For Educational Purposes Only – Not For Promotional Use
PREVAIL: A Safety and Efficacy Study of Oral Enzalutamide
in Chemotherapy-Naïve Patients With Progressive
Metastatic Prostate Cancer
Planned Evaluations
Enrollment Complete
• n = 1680
mCRPC
• asymptomatic
or mildly
symptomatic
Enzalutamide
160 mg qd
R
1:1
•
• progression
after ADT
Placebo qd
• PREVAIL is a phase 3, randomized,
double-blind, placebo-controlled
trial
• Co-primary endpoints: overall
survival and progression-free
survival
www.clinicaltrials.gov (NCT01212991)
 Overall survival / Radiographic PFS
 Time to first SRE
 Initiation of cytotoxic
chemotherapy
 QoL (FACT-P, EQ-5D)
 PSA progression
 Pain palliation (BPI-SF)
 Safety (AEs, vital signs, physical
exam, lab evaluations, ECG)
 Pharmacokinetics
 Long-term follow-up (radiographic
PFS, SREs, additional therapies for
prostate cancer, OS)
 Subgroups
58
Abiraterone vs. Enzalutamide Sequencing Study
A phase 2, randomized, multicenter study
Whole Blood:
cfDNA Collection
RNA Collection
1ST LINE THERAPY
ARM A
R
A
N
D
O
M
I
S
E
n = 59
ABIRATERONE +
PREDNISONE
ENZALUTAMIDE
n = 59
ARM B
ClinicalTrials.gov: NCT02125357
Whole Blood:
cfDNA Collection
RNA Collection
Whole Blood:
cfDNA Collection
RNA Collection
P
S
A
P
R
O
G
R
E
S
S
I
O
N
2ND LINE THERAPY
ARM A
CROSS-OVER TO
ENZALUTAMIDE
CONTINUE UNTIL
CLINICAL
PROGRESSION
CROSS-OVER TO
ABIRATERONE +
PREDNISONE
CONTINUE UNTIL
CLINICAL
PROGRESSION
ARM B
Radium-223
Ca
Ra
Radium-223
 α-particles cause double-strand DNA breaks in nearby tumor
cells
 Limited penetration of α-particles (~ 2-10 cell diameters) results in
localized area of effect
ALSYMPCA: Study Design
PATIENTS
• Total ALP:
<220 U/L vs ≥220
U/L
• Bisphosphonate
use: Yes vs no
• Prior docetaxel:
Yes vs no
TREATMENT
R
A
N
D
O
M
I
Z
E
2:1
• Confirmed
symptomati
c CRPC
• ≥2 Bone
metastases
• No known
visceral
metastases
• Postdocetaxel,
unfit for
docetaxel,
or refused
docetaxela
STRATIFICATION
N = 921
6 Injections
at 4-week intervals
Radium 223 dichloride
(50 kBq/kg IV) +
Best standard of careb
Placebo (saline) +
Best standard of careb
136 Centers in 19 countries
Planned follow-up is 3 years
ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castration-resistant prostate cancer; IV,
intravenous.
aUnfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable.
bBest standard of care is defined as a routine standard of care at each center, eg, local external beam radiation therapy,
corticosteroids, antiandrogens, estrogens (eg, stilbestrol), estramustine, or ketoconazole.
From supplementary appendix. Parker C, et al. N Engl J Med. 2013;369:213-223
Radium-223: ALSYMPCA Trial
C. Parker et al, NEJM, 369:213, 2013
Radium-223: ALSYMPCA Trial
C. Parker et al, NEJM, 369:213, 2013
An Evolution - Not a Revolution
Class
The Old
The New
Hormones/AR-Axis
• Keto +/- Prednisone
• Bicalutamide
• Abiraterone acetate
• Enzalutamide
Bone targeted
• Zoledronic acid
• Denosumab
Chemotherapy
• Docetaxel
• Mitoxantrone
• Docetaxel
• Cabazitaxel
Radiopharmaceuticals
• Strontium-89
• Samarium-153
• Radium-223
TOC
The Disease Continuum in Prostate Cancer
& Current Treatments
Death
1st Line
Hormonal
Therapy/
nd
Castration 2 line
Hormonal
Therapies
Bicalutamide
Flutamide
Nilutamide, etc.
Local
Therapy
Docetaxel +
Prednisone
Enzalutamide
Abiraterone
Enzalutamide
Cabazitaxel +
Prednisone
Abiraterone plus
Prednisone
Radium 223
PSA
Asymptomatic
Non-Metastatic
Castration Sensitive
Symptoms
Metastatic
Castration Resistant
Time
For Educational Purposes Only – Not For Promotional Use
65
Prostate Cancer