1. No category

How to Sequence the many novel agents
for CRPC
Charles J Ryan, MD
Professor of Clinical Medicine and Urology
Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco
1
The Challenge of this “Abundance”
• What to give?
• What to give when?
• What is the impact of prior treatment?
• What can guide us?
Therapeutic Goals in mCRPC
Delay, Prevent, Preserve, Survive
Pain
Baseline
PSA
Progression
Tumor/Bone
Progression
24-48 months
Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771.
ECOG PS= Eastern Cooperative Oncology Group Performance Status.
ECOG PS Decline
Chemotherapy
Death
What Anti-Tumor Therapies are
Available?
• Immunotherapy
– Sipuleucel T
• AR directed therapies
– Abiraterone
– Enzalutamide
• Chemotherapy
– Docetaxel
– Cabazitaxel
– Mitoxantrone
• Radioisotope
– Alpharadin
Immunotherapy
• Consensus
– SOC in pre-chemotherapy indolent low volume disease.
– Uptake slower than anticipated.
– Patients enthusiastic about receiving it
• Challenge
– Patients want “remission” and they don’t get it from
Sipuleucel-T.
– Cost/Perception
• Opportunity
– Earlier metastatic detection may increase use.
– “Remission induction”
Survival “Delta” may peak b/w 2-3 years: Ideal
time to use may be “EARLY CRPC”
Sipuleucel T
Sipul T
1*Kaplan-Meier
†(Percent
estimates with 95% confidence interval and number at risk.
Sipuleucel-T – percent control)/percent control.
Targeting AR in mCRPC
• Consensus
– SOC in pre-chemotherapy
– Many patients get abi who would not have gotten
chemotherapy
– Both asymptomatic and symptomatic patients.
– No comparison data of Abi vs Enz
• Challenge
– Primary resistance –
• Opportunity
– Regulatory space created by “Abiraterone/Enzalutamide
refractory, chemotherapy naive”?
– Combination studies underway
The Persistent Relevance of Androgens – The Biological
Foundation of Secondary Hormonal Therapy
Intratumor Androgen
Production/conversion
/sequestration
AR Amplification
(30%)
CRPC
Persistent Serum
Androgens (e.g.
adrenals)
Enzalutamide and Abiraterone – Different points,
one Pathway
Signaling Event
Pre -Receptor
Androgen
Production
Androgen
Transport/
Circulation/
Uptake
Receptor
Conversion
to DHT
AR
Binding
Aberration
Intracrine
Production
Polymorphisms
Intervention
SCC
Inhibitors
CYP 17
Inihibitors
Drugs
Abiraterone
Orteronel
Ketoconazole
Block
Transport
Amplified 5
Alpha Reductase
5-Alpha
Reductase
inhibitors
Amplified AR
Splice Variant AR
Novel AR
Inhibitors
Enzalutamide
ARN-509
Tok-001
Two very active agents
Enzalutamide Vs Placebo
100
Abiraterone (median, mos):
16.5
Prednisone (median, mos):
8.3
HR (95% CI):
Subjects Without Progression
or Death (%)
80
p Value:
Radiographic Progression-Free Survival (%)
Abiraterone/Pred vs Prednisone
0.53 (0.45-0.62)
< 0.0001
60
40
20
Abiraterone
Prednisone
100
Hazard Ratio: 0.186
(95% CI: 0.15, 0.23)
P<0.0001
90
80
70
60
50
40
30
20
Enzalutamide
Placebo
10
0
0
0
3
6
9
12
15
18
21
24
27
30
33
0
36
3
100
Abiraterone (median, mos):
35.3
Prednisone (median, mos):
30.1
HR (95% CI):
0.79 (0.66-0.96)
90
0.0151
80
80
60
40
12
15
18
21
Hazard Ratio: 0.706
(95% CI: 0.60,0.84)
P<0.0001
70
60
50
40
30
20
20
Abiraterone
Prednisone
Enzalutamide
Placebo
10
0
Patients still alive at data cut off
Enzalutamide: 72%; Placebo: 63%
0
0
3
6
9
12
15
18
21
24
27
30
33
36
0
Months From Randomization
Abiraterone
Prednisone
9
100
Survival (%)
Subjects Without Death (%)
p Valuea:
6
Radiographic Progression-Free Survival (Months)
Months From Randomization
546
542
538
534
524
508
503
492
482
465
452
437
421
400
393
361
333
283
3
6
9
12
15
18
21
24
27
30
33
36
33
27
2
2
0
0
Duration of Overall Survival (Months)
175
153
68
67
Ryan et al, NEJM 2012
15
9
0
0
Patients at Risk
Enzalutamide
Placebo
872
845
863
835
850
781
824
744
797
701
745
644
566
484
395
328
244
213
128
102
Beer et al, Proc GU ASCO 2014
Baseline Features: Prevail and 302
Enzalutamide
(n=872)
Placebo
(n=845)
72 (43−93)
71 (42−93)
Race: white
76.7%
77.5%
Gleason score ≥8 at initial
diagnosis
50.6%
52.4%
ECOG performance score=0
67.0%
69.2%
Baseline pain 0–1 on BPI SF-Q3
66.2%
67.5%
Baseline use of corticosteroids
4.0%
4.3%
Disease Measure
Enzalutamide
(n=872)
Placebo
(n=845)
PSA, median, ng/mL
54.1
44.2
LDH, median, IU/L
185.0
185.0
Bone disease
85.0%
81.7%
Soft tissue disease
59.3%
59.6%
Visceral disease (liver and/or lung)
11.2%
12.5%
Characteristic
Age, median (range), years
Beer et al, Proc GU ASCO 2014
Ryan et al, Proc ASCO 2012, LBA4518
Abiraterone Doubled the Maximal Decline in PSA
(≥ 50%) Relative to Prednisone Alone
Maximal Decline From Baseline (%)
Abiraterone + Prednisone
Placebo + Prednisone
100
75
50
25
0
-25
-50
-75
-100
• 29% of patients on the prednisone control arm had a decline in PSA by ≥ 50%
• 69% of patients on the abiraterone arm had a decline in PSA by ≥ 50%
IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.
12
Ryan Proc GU ASCO 2013
Is “Sequencing” of Abiraterone and
Enzalutamide Worth it?
PSA declines are common on ENZ post ABI
Sustained declines and clinical benefit
<20%
Post Enz Abi response rate =11%
PSA PFS= 15 weeks
Sandhu GU ASCO 2014
Noonen et al Proc ESMO 2012
Combination Phase III: Alliance:
A031201 - PI Michael Morris
Arm A:
Enzalutamide
Arm B:
Enzalutamide
Abiraterone
Prednisone
Stratification factor:
prior chemo
Total of 616 deaths, log-rank statistic 90% power (one sided type I error rate of 0.025) to
detect HR of 0.77 in favor of arm B
Chemotherapy
• Consensus
– Overall use declining?
– Still very useful in aggressive disease/symptom control and
visceral metastases
– More “debulking” pre Enzalutamide or Abi?
• Challenge
– Perception
– Urology practices
– Still no viable combinations.
• Opportunity
– Cabazitaxel front line.
– combinations?
– Novel delivery?
Treatments for CRPC by Symptoms
and Presence of Visceral Disease
Docetaxel
Sipuleucel-T
Abiraterone
acetate
Enzalutamide
Cabazitaxel
Mitoxantrone
Radium-223
Symptomatic
Asymptomatic
√
√*
√
√
√
√
√
√
√
√
√
√
*Mild symptoms.
Mohler JL, et al. J Natl Compr Canc Netw. 2013;11:1471-1479.
Visceral
Non-Visceral
√
√
√
√
√
√
√
√
√
√
√
Ryan Proc GU ASCO 2013
Be aware of Phenotypic Change….
Primary
Resistance(Nonresponse)
ASI or ART
Therapy
Response
Resistance with
Phenotypic Change:
e.g. Neuro-endocrine
Acquired
Resistance:
(compensatory
/adaptive)
Death Non-PC Cause
CRPC
ASI= Androgen Synthesis Inhibitor
ART = AR Targeted Therapy
Docetaxel Probably as effective post
Abiraterone/Enza
Maximal PSA Decline on Docetaxel Following Prior Abiraterone Therapy
Aggarwal Proc ASCO 2012
Radio-Isotopes
• Consensus
– OS advantage is real
– Alsympca trial was in very ill patients – in whom docetaxel
had failed or would be too toxic.
• Challenge
– Clinical data is lacking from the phase III trial.
– How to “use” it once you have started.
– No real data on integrated/subsequent use of other active
therapies (abi and enza etc)
• Opportunity
– May be easily combine-able with Abiraterone/Enzalutamide
and chemotherapy
ALSYMPCA Overall Survival
(Updated Analysis)
100
90
80
70
60
%
Radium-223 Dichloride, n = 614
Median OS: 14.9 months
50
Placebo, n = 307
40 Median OS: 11.3 months
30
20
10
0
HR = 0.695
95% CI, 0.581, 0.832
P = 0.00007
Month
0
Radium-223 614
3
578
6
504
9
369
12
274
15
178
18
105
21
60
24
41
27
18
30
7
33
1
36
0
39
0
Placebo 307
288
228
157
103
67
39
24
14
7
4
2
1
0
May 2013, Radium-223 was FDA approved for patients with castrate- resistant
prostate cancer who have bone metastases and no known visceral metastases
Parker C, et al. NEJM. 2013; 369(3):213-223.
ALSYMPCA: Adverse Events
All Grades
Grades 3 or 4
Radium-223
n = 600
n (%)
Placebo
n = 301
n (%)
Radium-223
n = 600
n (%)
Placebo
n = 301
n (%)
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)
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)
5 (2)
Vomiting
111 (19)
41 (14)
10 (2)
7 (2)
Constipation
108 (18)
64 (21)
6 (1)
4 (1)
Hematologic
Anemia
Nonhematologic
•
•
•
At 1.5 years after the final injection, there were no reports of AML, MDS, or primary bone cancer
Aplastic anemia was reported in 1 patient in the radium-223 arm (considetered treatement-related)
Primary cancers in other organs were identified in 2 Radium-223 treated patients and 3 placebo-treated
patients (deem not study-drug related by investigators)
Parker C, et al. N Engl J Med. 2013;369(3):213-223. Nilsson S, et al. J Clin Oncol. 2014;32(suppl 4): Abstract 9.
Summary Map of CRPC therapies
http://www.onclive.com/publications/obtn/2012/december-2012/sequencing-of-novelprostate-cancer-agents-is-a-work-in-progress/2