how to sequence the many novel agents for crpc charles j ryan, md
DESCRIPTION
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. The Challenge of this “Abundance”. What to give ? What to give when? - PowerPoint PPT PresentationTRANSCRIPT
11
How to Sequence the many novel agents for CRPC
Charles J Ryan, MDProfessor of Clinical Medicine and Urology
Helen Diller Family Comprehensive Cancer CenterUniversity of California, San Francisco
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
Baseline PSA
ProgressionTumor/Bone Progression
Pain
Death
Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771.
Chemotherapy
ECOG PS Decline
Delay, Prevent, Preserve, Survive
ECOG PS= Eastern Cooperative Oncology Group Performance Status.
24-48 months
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”
1*Kaplan-Meier estimates with 95% confidence interval and number at risk.†(Percent Sipuleucel-T – percent control)/percent control.
Sipuleucel T
Sipul T
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
AR Amplification
(30%)
Intratumor Androgen Production/conversion/sequestration
Persistent Serum Androgens (e.g.
adrenals)
The Persistent Relevance of Androgens – The Biological Foundation of Secondary Hormonal Therapy
CRPC
Enzalutamide and Abiraterone – Different points, one Pathway
Androgen Production
AR Binding
Signaling Event Intervention
Conversion to DHT
Androgen Transport/
Circulation/Uptake
SCC Inhibitors
CYP 17 Inihibitors
Block Transport
5-Alpha Reductase inhibitors
AbirateroneOrteronelKetoconazole
Drugs
EnzalutamideARN-509Tok-001
Novel AR Inhibitors
Pre
-Rec
epto
r R
ecep
tor
Intracrine Production
Polymorphisms
Amplified 5 Alpha Reductase
Amplified ARSplice Variant AR
Aberration
Two very active agents
Abiraterone/Pred vs Prednisone Enzalutamide Vs Placebo
Beer et al, Proc GU ASCO 2014Ryan et al, NEJM 2012
Baseline Features: Prevail and 302
Ryan et al, Proc ASCO 2012, LBA4518
Beer et al, Proc GU ASCO 2014
Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone
12
• 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%
-25
Max
imal
Dec
line
From
Bas
elin
e (%
)
-50
-75
-100
0
25
50
75
100
Abiraterone + Prednisone Placebo + Prednisone
IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.
Sandhu GU ASCO 2014Noonen et al Proc ESMO 2012
Is “Sequencing” of Abiraterone and Enzalutamide Worth it?
Post Enz Abi response rate =11%PSA PFS= 15 weeks
PSA declines are common on ENZ post ABISustained declines and clinical benefit
<20%
Ryan Proc GU ASCO 2013
Combination Phase III: Alliance: A031201 - PI Michael Morris
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
Stratification factor: prior chemo
Arm A:Enzalutamide
Arm B:
EnzalutamideAbirateronePrednisone
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
Symptomatic Asymptomatic Visceral Non-VisceralDocetaxel √ √ √Sipuleucel-T √* √ √Abiraterone acetate
√ √ √ √Enzalutamide √ √ √ √Cabazitaxel √ √ √ √Mitoxantrone √ √ √Radium-223 √ √
*Mild symptoms.
Mohler JL, et al. J Natl Compr Canc Netw. 2013;11:1471-1479.
Be aware of Phenotypic Change….
CRPC
ASI or ARTTherapy
Primary Resistance(Non-
response)
Response
Acquired Resistance:
(compensatory /adaptive)
Death Non-PC Cause
Resistance with Phenotypic Change:e.g. Neuro-endocrine
ASI= Androgen Synthesis InhibitorART = AR Targeted Therapy
Ryan Proc GU ASCO 2013
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)
Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0
Radium-223 Dichloride, n = 614Median OS: 14.9 months
Placebo, n = 307Median OS: 11.3 months
HR = 0.69595% CI, 0.581, 0.832P = 0.000070
10
20
30
40
50
60
70
80
90
100
%
Parker C, et al. NEJM. 2013; 369(3):213-223.
May 2013, Radium-223 was FDA approved for patients with castrate- resistant prostate cancer who have bone metastases and no known visceral metastases
ALSYMPCA: Adverse EventsAll Grades Grades 3 or 4
Radium-223n = 600n (%)
Placebon = 301
n (%)
Radium-223n = 600
n (%)
Placebo n = 301
n (%)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)Nonhematologic 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)
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.
• 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)
http://www.onclive.com/publications/obtn/2012/december-2012/sequencing-of-novel-prostate-cancer-agents-is-a-work-in-progress/2
Summary Map of CRPC therapies