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10/17/2014
1
Optimal Management of
Castration Resistant Prostate Cancer (CRPC) in 2014
15th Annual Advances in Oncology
October 10-11, 2014
Primo N. Lara, Jr., MD Professor of Medicine
UC Davis School of Medicine
Disclosures
Consultant: Janssen Pharmaceuticals, Clovis Oncology, US Diagnostic Services, Astex Therapeutics, Exelixis, Immunogen, Pfizer, Teva,
Medivation, Halozyme, Novartis Grant/Research Support: Millennium, Polaris, Oncogenex, GlaxoSmithKline,
Genentech, Aragon Pharmaceuticals, Janssen Biotech, Inc.
The presentation (does not include) discussion of the use of product(s) for
which they are not labeled (e.g., off label use) is still investigational.
Acknowledgement Daniel Petrylak MD (Yale University) for allowing me to
“borrow” some of his slides!
CRPC therapy by state: 2010
Zoledronic acid with CRPC (metastatic disease)
Metastatic,
minimally
symptomatic
CRPC
Symptomatic
or poor-
prognosis
CRPC
Progression after
docetaxel
chemotherapy
Secondary
hormonal Rx Docetaxel
Mitoxantrone Best supportive care
not known 3 months not known
Survival
benefit
2010
CRPC therapy by state: 2014
Abiraterone or Cabazitaxel acetate
Metastatic,
minimally
symptomatic
CRPC
Symptomatic
or poor-
prognosis
CRPC
Progression after
docetaxel
chemotherapy
Secondary
hormonal Rx Docetaxel
not known 3 months not known
Sipuleucel-T Docetaxel
4 months 3 months 4 months 2.5 months
Denosumab or Zoledronic acid (bone metastatic disease)
Survival
benefit
Survival
benefit
Mitoxantrone
Best supportive care 2010
2014
Enzalutamide – 4.8 months
Rad223 – 3.1 months
Enzalutamide – 2.2 months
Abiraterone – 5.2 months
Rad223 – 4.6 months
Development of CRPC
ALTERN.
SPLICING
ABERRANT
MODIFICATION
•GF, cytokines •Src
Sumo
AC
P
COFACTOR
PERTURBATION
•CoAct gain •CoR loss/dismissal
CoACT
INTRACRINE
ANDROGEN
SYNTHESIS
T
MUTATION •gain of function
AR
selective
pressure
Hormone Therapy
adaptation
CRPC
RESTORED AR ACTIVITY
(rising PSA)
RECURRENT TUMOR DEVELOPMENT
>30% CRPC
AR
DEREGULATION
•amplification •overexpression
Penning and Knudsen. Trends Endocrinol Metab. 2010;21(5):315-24.
Classes of Agents in CRPC
• Immunotherapeutic
– Sipuleucel T
• Androgen-receptor targeted
– Enzalutamide, Abiraterone , ?Docetaxel
• Cytotoxic
– Docetaxel, Cabazitaxel
• Radioisotope
– Radium 223
10/17/2014
2
Abiraterone Acetate: Androgen Biosynthesis Inhibitor
Pregnenolone
DHEA Androstenedione Testosterone DHT
17OH- Pregnenolone
Cortisol
Aldosterone
Androgens
Cholesterol
Abiraterone
Abiraterone
COU 301: Abiraterone vs. Placebo in post-docetaxel setting
2 prior chemo OS: 14.0 months abiraterone acetate vs 10.3 months placebo1 1 prior chemo OS: 15.4 months abiraterone acetate vs 11.5 months placebo1
Updated results: 4.6-month difference in median survival with abiraterone acetate2
Placebo Abiraterone
Acetate Median OS (months) 10.9 14.8 Hazard Ratio 0.65 95% CI 0.54-0.77 P value <0.001
Placebo
0 100 200 300 400 500 600 700
0
20
40
60
80
100
Ove
rall
Su
rviv
al
(%)
Days from Randomization
Abiraterone Acetate
Median OS Δ: 3.9 months 35.4% reduction in risk of death
1. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 2. Fizazi K, et al. European Multidisciplinary Cancer Congress; 2011. Abstract 7000.
Ryan, NEJM 2013
Enzalutamide
• Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway
• No demonstrated agonist effects in pre-clinical models
Tran C et al. Science 2009;324:787-790.
T
T
AR
Nucleus
Enzalutamide Inhibits Binding of Androgens to AR
Inhibits Nuclear Translocation of AR
Inhibits Association Of AR with DNA
Tumor Death
AR
Cytoplasm
X
X
X
Enzalutamide vs. Placebo: Post-Docetaxel
Scher HI, et al. N Engl J Med. 2013; 367:1187-1197
Median OS Δ: 4.8 months 37% reduction in risk of death
Enzalutamide Placebo
Median Overall Survival (months)
18.4 13.6
Hazard ratio 0.63 95% CI 0.53, 0.75 P value < 0.001
Enzalutamide vs. Placebo in Post-Docetaxel Setting
Beer T, et al. NEJM 2014.
Median OS: Enzalutamide, 32.4 Months; Placebo, 30.2 months
Enzalutamide
Placebo
100
90
80
70
60
50
40
30
20
10
0
Hazard Ratio: 0.706
(95% CI: 0.60, 0.84)
P < 0.0001
Duration of Overall Survival (Months)
Su
rviv
al (%
)
21 18 15 12 9 6 3 0 36 33 30 27 24
Patients still alive at data cut off
Enzalutamide: 72%; Placebo: 63%
10/17/2014
3
NCI Alliance Trial A031201: Enzalutamide +/- Abiraterone Acetate
Phase III Trial in Chemonaïve mCRPC
Phase 3 multicenter, randomized study conducted through the NCI’s National Clinical Trials Network (NCTN)
1:1
N = 1224 • Progressive
chemonaïve mCRPC patients
• Asymptomatic or mildly symptomatic
• PS 0-1
Enzalutamide 160 mg QD
Enzalutamide 160 mg QD Abiraterone Acetate 1000 mg QD
Prednisone 5 mg BID
Primary Endpoint: • Overall survival
Secondary: • PFS • Radiographic PFS • PSA response • Objective response • Toxicity
UCDCC#243: Enzalutamide + Metformin Trial (PI: CP Evans)
SCREENING
Day -28 to -1
Patients with
progressive
CRPC, prior
chemotherapy
allowed¥,
ECOG 0-2,
serum
testosterone
must be at
castrate levels
(< 50 ng/dL)
within 14 days
prior to
registration
Meta-
static
Soft
Tissue or
Bone
Biopsy¥
“3+3”
DOSE
ESCALATION
DLT with expanded
cohort of 6 patients
(Maximum of 24
patients with up to
18 of the patients at
MTD expansion)
PROGRESSION*
(measured by
PSA and
radiographic
disease
progression for
soft tissue and
bone disease)
*optional
metastatic soft
tissue or bone
biopsy
(only if consent is
obtained)
End of Treatment
Initiation of cytotoxic or
investigational therapy
Intolerable adverse event
Any seizure
Creatinine, LFTs, ANC, or
platelet values that mandate
discontinuation
Gross noncompliance or
violation
PFS endpoint reached: treatment
may continue if not starting cytotoxic or
investigational therapy
Confirmed PSA progression
Confirmed bone disease
progression on Week 13 bone scan
Bone disease progression
on Week ≥ 25 bone scan
Soft tissue disease progression
on CT scan or MRI
FOLLOW-UP
Every 4 weeks
after progression
or discontinuation
of treatment
(total 12 weeks)
* Discontinuation
due to DLT,
continue to follow
every 4 weeks
until AE is stable
or resolved.
¥ CRPC patients who have been treated with docetaxel chemotherapy (and abiraterone pre-chemotherapy is
acceptable) will have a radiographic metastatic soft tissue or bone biopsy, which is mandatory at screening and
optional at progression. Abiraterone may have only been given pre-chemotherapy.
Androgen Receptor Splice Variants
Some variants still constitutively active as transcription factor despite lack of LBD
AR Splice Variant Mediated Resistance
Nelson, NEJM 2014
Antoranakis, NEJM 2014
10/17/2014
4
6 injections at 4-week intervals
Radium-223 dichloride (50 kBq/kg) +
best standard of care†
Placebo (saline) + best standard of care†
•Total ALP: < 220 U/L vs. ≥ 220 U/L •Bisphosphonate use: Yes vs. No •Prior docetaxel: Yes vs. No
•Confirmed Symptomatic CRPC
•≥2 bone metastases
•No known visceral metastases
•Post-docetaxel or unfit for docetaxel*
Radium 223 Phase III Study Design1
Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
*Unfit for docetaxel includes patients 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, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole
PATIENTS STRATIFICATION
R
A
N
D
O
M
I
Z
E 2:1
N=921
TREATMENT PHASE
>100 centers in 19 countries Planned follow-up is 3 years
Radium-223 dichloride (n = 614)
Placebo (n = 307)
Median OS (months)
14.9 11.3
HR 0.695
95% CI 0.581–0.832
P value 0.00007
Radium 223: Overall Survival
Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-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
0
10
20
30
40
50
60
70
80
90
100
Pa
tien
ts (
%)
Treatment Radium-223 dichloride Placebo
3.6 month OS benefit
Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
Ran
do
miz
e
Mitoxantrone 12 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles N=1006
TAX 3271
SWOG 99162
Random
ize
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid
Q 21 days
Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5*
Dexamethasone 20 mg, tid d 1 & 2
N=770
*Warfarin and aspirin
Pivotal Docetaxel CRPC Trials
1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.
0%
20%
40%
60%
80%
100%
0 12 24 36 48 Months
D+E
M+P
# at
Risk
338
336
# of
Deaths
217
235
Median in Months
18
16
HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
S9916: Overall Survival
Docetaxel q 3 wk
Weekly Docetaxel
10/17/2014
5
Phase III Trials of Docetaxel Combinations in CRPC
Docetaxel/Pred vs
Docetaxel Combined
With:
Status Results
DN-101 Terminated early Negative
GVAX Terminated early Negative
Bevacizumab Completed Negative
VEGF-Trap Completed Negative
Atrasentan Completed Negative
ZD4054 Completed Negative
Dasatinib Completed Negative
Lenalidomide Completed Negative
Custersin (OGX-011) Completed Negative
To date, no combination improves on docetaxel and pred
Cabazitaxel vs. Mitoxantrone in Post-Docetaxel CRPC Setting
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4 Number
at risk
Proportion of OS (%)
80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
15.1 12.7 Median OS (months)
0.59–0.83 95% CI
<.0001 P-value
0.70 Hazard Ratio
CBZP MP
E3805 – CHAARTED
Chemotherapy in Hormone Sensitive Prostate Cancer
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
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
Sweeney, ASCO 2014
N = 790
High Extent: > 4 bone mets, visceral mets
Primary endpoint: Overall survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Arm ALIVEDEAD MEDIANTOTAL
A 397 101 296 57.6B 393 136 257 44.0
Pro
ba
bility
Presented by: Christopher J. Sweeney, MBBS
HR=0.61 (0.47-0.80) p=0.0003
Median OS:
ADT + D: 57.6 months
ADT alone: 44.0 months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Arm ALIVEDEAD MEDIANTOTAL
A 134 19 115 .B 142 26 116 .
Pro
ba
bility
OS by extent of metastatic disease at start of ADT
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Arm ALIVEDEAD MEDIANTOTAL
A 263 82 181 49.2B 251 110 141 32.2
Pro
ba
bility
Presented by: Christopher J. Sweeney, MBBS
In patients with high volume metastatic disease, there is a 17 month
improvement in median overall survival from 32.2 months to 49.2 months We projected 33 months in ADT alone arm with collaboration of SWOG9346 team
High volume Low volume
p=0.0006
HR=0.60 (0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT alone: Not reached
Conclusions
• Taxanes are active against prostate cancer – Docetaxel SOC in “high-volume” metastatic HSPC and CRPC
– Cabazitaxel improves OS in post-docetaxel CRPC setting
• AR-targeted therapies (Enzalutamide, Abiraterone) improve survival – Resistance mechanisms include selection of AR-splice variants
• Radium 223 and Sipuleucel-T improve survival in select CRPC subsets
• Optimal sequence of therapies is undefined
Recommended