emerging role of chemotherapy and hormonal therapy in advanced prostate cancer treat crpcgpgu.org...
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Emerging Role of
Chemotherapy and Hormonal
Therapy in Advanced
Prostate Cancer to Treat CRPC
Daniel P. Petrylak , MD
Professor of Medicine and UrologyDirector, Genitourinary DART
Co-Director, Signal Transduction ProgramSmilow Cancer Center
Yale University School of medicine
Sequencing CRPC therapy – 2010
Zoledronic acid with CRPC (metastatic disease)
Metastatic,
minimally
symptomatic
CRPC
Symptomatic
or poor-
prognosis
CRPC
Progression after
docetaxel
chemotherapy
Secondary
hormonal RxDocetaxel
MitoxantroneBest supportive care
not known 3 months not knownSurvival
benefit
Sequencing CRPC therapy – 2017
Abiraterone or Cabazitaxelacetate
Metastatic,
minimally
symptomatic
CRPC
Symptomatic
or poor-
prognosis
CRPC
Progression after
docetaxel
chemotherapy
Secondary
hormonal RxDocetaxel
not known 3 months not known
Sipuleucel-T Docetaxel
4 months 3 months 4 months 2.5 months
Denosumab or Zoledronic acid with CRPC (metastatic disease)
Survival
benefit
Survival
benefit
Mitoxantrone
Best supportive care 2010
2014
MDV3100 – 4.8 months
Rad 223 – 3.1 monthsMDV3100 – 2.2 months
Abiraterone – 5.2 months
Rad223 – 4.6 months
Classes of Agents
• Immunotherapeutic
– Sipuleucel T
• Hormonal
– MDV3100, Abiraterone , ?Docetaxel
• Cytotoxic
– Docetaxel, Cabazitaxel
• DNA Damage
– Rad 223
How do we sequence these
agents?
• Clinical Characteristics
– Symptomatic vs Asymptomatic
– Visceral vs Non Visceral
– Pre vs Post Docetaxel
• Biological Markers
– Androgen Receptor
– TRPMSS2-ERG
Development of Castrate Resistant Prostate Cancer
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.
Abiraterone Acetate:Androgen Biosynthesis Inhibitor
Pregnenolone
DHEA Androstenedione Testosterone DHT
17OH-Pregnenolone
Cortisol
Aldosterone
Androgens
Cholesterol
Abiraterone
Abiraterone
COU 301: Overall Survival
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
PlaceboAbiraterone
AcetateMedian OS (months) 10.9 14.8 Hazard Ratio 0.6595% CI 0.54-0.77P value <0.001
Placebo
0 100 200 300 400 500 600 700
0
20
40
60
80
100
Ove
rall
Surv
ival
(%
)
Days from Randomization
Abiraterone Acetate
Median OS Δ: 3.9 months35.4% 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.
COU 302: Abiraterone AcetatePhase III Trial in Chemonaïve mCRPC
• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada
• Stratification by ECOG performance status 0 vs 1
1:1
N = 1088• Progressive
chemonaïve mCRPC patients
• Asymptomatic or mildly symptomatic
Abiraterone Acetate 1000 mg dailyPrednisone 5 mg bid
n = 546
Placebo dailyPrednisone 5 mg bid
n = 542
Primary Endpoints:• Radiographic progression-free
survival (rPFS) by central review• OS
Secondary:• Time to opiate use
(cancer-related pain)• Time to initiation of
chemotherapy• Time to ECOG PS deterioration• Time to PSA progression
Saad F, et al. AUA 2013. Abstract 713
Statistically Significant Improvement Over Placebo in rPFS and all Secondary Endpoints
Patient reported outcomes favored AA + prednisone vs placebo + prednisone Full data to be reported
*Pre-specified alpha level 0.0035 Note: All secondary end points remain significant after adjusting for multiplicity testing
Outcome AA + PrednisoneMedian (months)
Placebo + PrednisoneMedian (months) HR (95% CI) P Value
rPFS 16.5 8.3 0.53 (0.45, 0.62) < 0.0001
OS 35.3 30.1 0.79 (0.66, 0.96) 0.0151 *
Time to opiate use
(cancer related pain)Not reached 23.7 0.71 (0.59, 0.85) 0.0002
Time to chemotherapy initiation
26.5 16.8 0.61 (0.51, 0.72) < 0.0001
Time to ECOG PS deterioration
12.3 10.9 0.83 (0.72, 0.94) 0.0052
Time to PSA progression 11.1 5.6 0.50 (0.43, 0.58) < 0.0001
Saad F, et al. AUA 2013. Abstract 713
Ryan et al. Final Overall Survival Analysis of COU-AA-302,a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic
Castration-Resistant Prostate Cancer Patients Without Prior Chemotherapy
• Median follow-up of 49.2 mos
• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)
100
80
60
40
20
0
0
Ove
rall
Surv
ival
(%
)
9 21 30 48 6039
546542
525509
422401
296261
5942
00
AbirateronePrednisone
202148
Time to Death (Months)24123 36 45 54
538534
453438
359322
189132
1510
HR (95% CI): 0.81 (0.70-0.93)
p Value: 0.0033
Prednisone, 30.3 mos
Abiraterone, 34.7 mos
6 15 18 27 33 42 51 57
01
11884
218176
504493
483466
394363
330292
273227
235201
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
EnzalutamideInhibits Binding of Androgens to AR
Inhibits Nuclear Translocation of AR
Inhibits AssociationOf AR with DNA
Tumor Death
AR
Cytoplasm
X
X
X
Enzalutamide Prolonged Survival, Reducing Risk of Death
Scher HI, et al. N Engl J Med. 2013; 367:1187-1197
Median OS Δ: 4.8 months37% reduction in risk of death
Enzalutamide Placebo
MedianOverall Survival (months)
18.4 13.6
Hazard ratio 0.63 95% CI 0.53, 0.75P value < 0.001
1°end point: OS and PFS
Enzalutamide 160mg QD
Placebo QD
PREVAIL Phase III Trial of Enzalutamide in Asymptomatic or Mildly Symptomatic
mCRPC Pre Chemotherapy
RANDOMIZE
1:1
mCRPCasymptomatic or
mildly symptomatic patients < 4 BPI
(n=1,680)Fully Accrued
A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer (PREVAIL)(NCT01212991). Available at www.clinicaltrials.gov. Accessed August 21, 2013.
PREVAIL Phase III Trial of Enzalutamide in Asymptomatic or Mildly Symptomatic mCRPC
Pre Chemotherapy Prelimianry Results
• Overall Survival 30% reduction in the risk of death
(Hazard Ratio=0.70; 95% confidence interval,0.59-0.83)
• Progression Free Survival: 81% reduction in risk of
radiographic progression or death compared with
placebo (Hazard Ratio=0.19; 95% confidence interval,
0.15-0.23).
PREVAIL: Overall Survival
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.
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)
Surv
ival (%
)
211815129630 3633302724
Patients still alive at data cut off
Enzalutamide: 72%; Placebo: 63%
Antonarakis, et al AR-V7 and Resistance to
Enzalutamide and Abiraterone in Prostate
Cancer
Outcome AR-V7[–] → AR-V7[–]
(n=36)
AR-V7[–] → AR-V7[+]
(n=6)
AR-V7[+] → AR-V7[+]
(n=16)
PSA Response68%
(95%CI, 52 – 81%)
17%
(95%CI, 4 – 58%)
0%
(95%CI, 0 – 19%)
PSA Progression-Free Survival6.1 months
(95%CI, 5.9 mo – NR)
3.0 months
(95%CI, 2.3 mo – NR)
1.4 months
(95%CI, 0.9 – 2.6 mo)
Progression-Free Survival6.5 months
(95%CI, 6.1 mo – NR)
3.2 months
(95%CI, 3.1 mo – NR)
2.1 months
(95%CI, 1.9 – 3.1 mo)
AR-V7, the most important AR
transcriptional variant, is expressed at
detectable levels in CTCs in a significant
proportion of CRPC patients
Does the Earlier Use of
Chemotherapy or Next Generation
AR Targeting Agents Improve
Survival?
Chemohormonal therapy for CSPC
• CHAARTED Study
– High volume disease: ≥4 bony metastases, at least one outside of axial skeleton and/or visceral metastases
– 17 mo overall survival benefit only in high volume disease(pre-specified analysis)
– No overall survival benefit in low volume disease
• STAMPEDE Study
– Did not stratify by low vs high volume disease
• Conclusions
– Standard of care for high volume disease: ADT + docetaxel
– Standard of care for low volume disease:
ADT alone (CHAARTED) or
ADT + docetaxel (STAMPEDE)
Slide 31
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Setting and hypothesis
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Outcome measures
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Abiraterone comparison: patients
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Patient characteristics
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 36
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 37
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 38
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 39
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 40
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Slide 41
Presented By Charles Ryan at 2017 ASCO Annual Meeting
Overall study design of LATITUDE
Presented By Karim Fizazi at 2017 ASCO Annual Meeting
Treatment arms were well balanced
Presented By Karim Fizazi at 2017 ASCO Annual Meeting
Statistically significant 38% risk reduction of death
Presented By Karim Fizazi at 2017 ASCO Annual Meeting
Comparing Overall Survival Across Studies
Presented By Eric Small at 2017 ASCO Annual Meeting
Docetaxel vs. Abiraterone
Slide 20
Presented By Eric Small at 2017 ASCO Annual Meeting
Docetaxel vs. Abiraterone
Selection of Treatment
● Based on side effects
– Preexisting neuropathy
– CHF
– Liver function abnormalities
– Health care costs
Waterfall plot showing maximum PSA falls after docetaxel administration in patients previously treated with abiraterone acetate.
Mezynski J et al. Ann Oncol 2012;annonc.mds119
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Kaplan–Meier plot showing overall survival (A) and time to PSA progression (B).
Mezynski J et al. Ann Oncol 2012;annonc.mds119
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
4
0
TROPIC: Phase III Registration Study
146 Sites in 26 Countries
Primary endpoint: OS
Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety
Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression
cabazitaxel 25 mg/m² q 3 wk+ prednisone* for 10 cycles
(n=378)
mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles
(n=377)
*Oral prednisone/prednisolone: 10 mg daily.
Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease
mCRPC patients who progressed during and after treatment with a docetaxel-based regimen
(N=755)
4
1
Primary Endpoint: Overall Survival (ITT
Analysis)
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4Number
at risk
Proportionof OS (%)
80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
15.112.7Median OS (months)
0.59–0.8395% CI
<.0001P-value
0.70Hazard Ratio
CBZPMP
FIRSTANA: Study Design
159 centers worldwide
• CBZ 20 + PRED• Cabazitaxel 20 mg/m² Q3W
• + prednisone 10 mg/d n = 389
mCRPC and no prior chemotherapy
N = 1,168 pts
R
A
N
D
O
M
I
Z
E
• CBZ 25 + PRED• Cabazitaxel 25 mg/m² Q3W
• + prednisone 10 mg/d n = 388
• DOC + PRED• Docetaxel 75 mg/m² Q3W
• + prednisone 10 mg/d n = 391
FIRSTANA: Overall Survival
Median OS, months (95% CI)
DOC + PRED
CBZ 20 + PRED
CBZ 25 + PRED
24.3 (22.18–27.60)
24.5 (21.75–27.20)
25.2 (22.90–26.97)
CBZ 20 vs DOC
HR 1.009 (0.85–1.197)
P = 0.9967
CBZ 25 vs DOC
HR 0.97 (0.819–1.16)
P = 0.7574
0 3 6 9 12
366 336 307
356 319 296
345 325 296
15 18 21 24 27 30 33 36
Time (months)39 42 45 48 51 54
Number at risk
DOC + PRED
3
91 CBZ 20 + PRED
389
CBZ 25 + PRED 388
243
234
239
192
192
197
133
133
138
57
49
70
18
19
28
3
3
5
0
0
0
Pro
ba
bil
ity
of
overa
lls
urv
ival(%
)
0
10
20
30
40
50
60
70
80
90
100
DOC + PRED
CBZ 20 + PRED
CBZ 25 + PRED
Genomic aberrations of mCRPC
>90% of mCRPCs harbor actionable
mutations
Robinson D. Cell 2015
AR
TP53
PTEN
ETS fusion
~23% harbor mutations in DNA repair
pathway, including bi-allelic loss of
BRCA2, ATM, BRCA1, FANCA, RAD51B,
RAD51C and CDK12
50 mCRPCs 11 HG Un-tx PC
Approximately 50% (24 cases of mCRPC) with
aberration in DNA repair genes
Grosso 2012. Nature
PARP (Poly-(ADP-ribose) Polymerase)
PARP
Chromatic
modification
Cell DeathDNA repair
Transcriptiona
l regulation
DSB SSB/BER Apoptosis Necrosis
Olaparib in Prostate Cancer
• TOPARP study: n=49 patients with mCRPC, who are docetaxel-pre-treated. (Mateo et al. 2015)
– 32.7 % (16/49) response rate in “unselected” mCRPC patients.
– A post-hoc analysis of their prospectively obtained tumor tissue:
• 16 (33%) had mutations in DNA repair pathway (ATM, BRCA2 and others) (biomarker positive)
–14 of these patient responded
• 33 (67%) had no such mutations (biomarker negative)
–2 of these patients responded.
Conclusions
• The optimal sequence of agents is yet to be
determined
• Docetaxel chemotherapy for hormone
sensitive patients should be offered to high
disease volume patients
• The effect of lyase inhibitors on
chemotherapy is unknown.
Conclusions
• ArV7 is promising biomarker for sensitivity to
enzalutamide and abiraterone
• PARP inhibition is a promising therapeutic
target in patients with BRCA mutations