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Integrating Current & Novel Treatment Strategies for the Management of CRPC
Charles J Ryan, MDThomas Perkins Distinguished Professor of Medicine and Urology
Helen Diller Family Comprehensive Cancer CenterUniversity of California, San Francisco
UCSF
Progress in Metastatic Prostate Cancer
Survival
PalliationMitoxantrone
Zoledronic acid
Docetaxel
Denosumab
Sipuleucel-T
Cabazitaxel
Abiraterone
Enzalutamide
Radium-223
Samarium-153 Strontium-89
1992 1996 2000 2004 2008 2012
FDA Approvals in Castration-Resistant Prostate Cancer
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Available Treatment Agents forAdvanced Prostate Cancer
Local therapy
Androgen deprivation therapy (ADT)
Therapies after ADT
Death
ADT
supportive care (egdenosumab/bisphosphonates)
mCRPCpost-
docetaxel
mCRPCsymptomatic
mCRPCmildly
symptomatic
mCRPCasymptomatic
(failed ADT)
Hormonesensitive
Sipuleucel-T
Enzalutamide
Abiraterone Abiraterone
Docetaxel Cabazitaxel
Radium 223
EnzalutamideADT + Docetaxelin high-volume
disease?
1. How do we define Castration Resistant Prostate Cancer?
5
Testosterone 500 ng/mL
50 ng/mL
Castration Therapy
PSA
Castration Resistance
Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL)
2. What makes prostate cancer lethal and how do we assess prognosis in patients?
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Testosterone 500 ng/mL
50 ng/mL
Castration Therapy
PSA
Castration Resistance
+ = Lethal Prostate cancer
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What’s the Prognosis?
CRPC Chemo-naïve Prognostic Nomogram
Wide Range….
Halabi et al JCO 2014
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Perisistent AR Signaling Pathway is the Pivotal Target of CRPC treatment
Anantharaman A, Friedlander TW. Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review. Urol Oncol. 2015 Dec 16.
Depiction of mechanisms of resistance to androgen deprivation therapy: • AR amplification• increased intratumoralandrogen synthesis
• hypersensitivity of AR• mutations of AR• alternative splicing of AR to constitutively active splice variants.
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Mechanism #1
UCSF
Immunotherapy
Provenge: Background
s
0
5
10
15
20
PS
A (
ng/m
L)
-10 0 10 20 30
Week
Sip-T
Small EJ et al., J Clin Oncol 18: 3894, 2000
Antigen-loaded precursor APC
Precursor APC Maturing antigen-
loaded APC
In vivo T cell activation
T cells attack tumor cells
Infuse patient
APC8015
Antigen Processing
Antigen Loading
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Provenge: (second) Pivotal Trial Results
†Control was nonactivated, autologous, peripheral blood mononuclear cells.
Kantoff PW et al. N Engl J Med. 2010;363:411-422. UCSF
†
• Primary endpoint: Overall survival1,2
• Secondary endpoint: Objective disease progression2
†
Adverse event PROVENGE (n=338)
Control (n=168)
All Grades (%)
Grades 3–5 (%)
All Grades (%)
Grades 3–5 (%)
Chills 54.1 1.2 12.5 0
Fever (pyrexia) 29.3 0.3 13.7 1.8
Headache 16.0 0.3 4.8 0
Influenza‐like illness 9.8 0 3.6 0
Myalgia 9.8 0.6 4.8 0
Hypertension 7.4 0.6 3.0 0
Hyperhidrosis 5.3 0 0.6 0
Groin pain 5.0 0 2.4 0
Adverse Events
Phase 3 design allowed for crossover from placebo to vaccine
Provenge: (second) Pivotal Trial Results: Peak effect at 3 years
Kantoff PW et al. N Engl J Med. 2010;363:411-422. UCSF
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Mechanism #2
UCSF
Targeting Persistent AR signaling
The Human Endocrine System Drives Prostate Cancer Growth
Hypothalamus (Brain)
LHRH
Pituitary Gland
FSH, LH
Testicles
Testosterone
DHT
PROSTATE CANCER CELLS
Adrenal gland
Antiandrogens: Casodex FlutamideNilutamide, Enzalutamide,Apalutamide
orchiectomy
LHRH agonists(Lupron, Zoladex)
Estrogen
Abiraterone
Abiraterone
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Model of AR Amplification as Mechanism of Resistance to Androgen Deprivation Therapy
Chen et al., 2004 Nature Medicine
3BHSD1 3BHSD2
UGT2B15 UGT2B17
SRD5A1 SRD5A2
AKR1C3 17BHSD3
CYP17A
P=0.0013 P=0.0031
P=0.0050 P=0.0004
P=0.0026 P<0.0001
P=0.0005 - 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091
BP CP METS BP CP METS
- 25 - 20 - 15 - 10 - 5 0 BP CP METS BP CP METS
5 - 20 - 15 - 10 - 5 0
BP CP METS BP CP METS
- 20 - 15 - 10 - 5 0 5 BP CP METS BP CP METS
- 25 - 20 - 15 - 10 - 5 0 BP CP METS
- 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091 BP CP METS BP CP METS
- - - - - - - 10 -
- - - -
- - - - -
1. Transcripts encoding steroidogenic enzymes are detected within tumor
2. Tumor androgens in CRPC metastases from anorchid patients exceed levels in prostate cancer tissues from eugonadal subjects
3. These may be particularly relevant for tumors with overexpressed AR
AR targeting:Abiraterone – Intracrine AndrogensEnzalutamide – AR amplification
Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447‐54
CRPC samples have robust AR expression Mohler et al
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3BHSD1 3BHSD2
UGT2B15 UGT2B17
SRD5A1 SRD5A2
AKR1C3 17BHSD3
CYP17A
P=0.0013 P=0.0031
P=0.0050 P=0.0004
P=0.0026 P<0.0001
P=0.0005 - 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091
BP CP METS BP CP METS
- 25 - 20 - 15 - 10 - 5 0 BP CP METS BP CP METS
5 - 20 - 15 - 10 - 5 0
BP CP METS BP CP METS
- 20 - 15 - 10 - 5 0 5 BP CP METS BP CP METS
- 25 - 20 - 15 - 10 - 5 0 BP CP METS
- 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091 BP CP METS BP CP METS
- - - - - - - 10 -
- - - -
- - - - -
Prostate Cancer can make its own androgens
Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447‐54
Mostaghel et al. Urol Oncol 2009; 27(3): 251‐257
DHT, dihydrotestosterone; T, testosterone
The level of androgen in the tumor tissue
Serum testosterone castration stage cannot completely eradicate androgens in PC environment
There are enough androgens within the tumor tissue to activate AR
Testosterone Levels Within Metastases From the Castrate Men Exceeded Serum Levels
tAR
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11-deoxycortisol x 5 Cortisol x 2
DHEA-S < 15 μg/dLLLQ
HypokalemiaHypertensionFluid overloadRenin suppression
ACTH x 5
Abiraterone
Pregnenolone x 20Deoxycorticosterone x 60Corticosterone x 2Aldosterone
Negative feedback
Androstenedione Testosterone 1-2 ng/dL
17α-hydroxpregnenolone
Enzalutamide (Xtandi)
• Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway.
• No demonstrated agonist effects in pre‐clinical models.
Enzalutamide1
T
AR
T
Cell nucleus
Inhibits Binding of Androgens to AR
Inhibits Nuclear Translocation of AR
Inhibits AssociationOf AR with DNA
AR
Cell cytoplasm
Tran et al. Science 2009;324:787–90.
2
3
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Hormonally Driven ResistancePre‐Receptor (Ligand) and Receptor Events
Ryan, Tindall Journal of Clinical Oncology 2011
Pre‐Receptor Events:
Adrenal Androgen ProductionAnd Polymorphisms
IntracrineAndrogen Production
Receptor events:
AR Amplification and Mutation
AR Splice Variants
Two very active agents
Radiographic Progression-Free Survival (Months) 0 3 6 9 12 15 18 21
Rad
iog
rap
hic
Pro
gre
ssio
n-F
ree
Su
rviv
al (
%)
60
50
40
30
20
10
0
90
80
70
100
Enzalutamide Placebo
Hazard Ratio: 0.186 (95% CI: 0.15, 0.23) P<0.0001
Enzalutamide 872
Placebo 845 863 835
850
781
824
744
797
701
745
644
566
484
395
328
244
213
128
102
33
27
2
2
0
0
Duration of Overall Survival (Months)
Su
rviv
al (
%)
60
50
40
30
20
10
0
90
80
70
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Enzalutamide Placebo
Hazard Ratio: 0.706 (95% CI: 0.60,0.84) P<0.0001
Patients at Risk
Patients still alive at data cut off Enzalutamide: 72%; Placebo: 63%
Abiraterone/Pred vs Prednisone Enzalutamide Vs Placebo
Ryan et al NEJM 2013, Lancet Onc 201 Beer et al NEJM 2014
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Progress for Most ( 69% of patients respond to abiraterone)
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• 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
Ma
xim
al D
ecli
ne
Fro
m B
asel
ine
(%)
-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.
Time to All Landmarks Favored Abiraterone…for the population as a whole
Baseline PSA
ProgressionTumor/Bone Progression
Pain
Death
Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.
Chemotherapy
ECOG PS Decline
Primary Endpoints: rPFS and OS
Secondary Endpoints
ECOG PS = Eastern Cooperative Oncology Group Performance Status.
24‐48 months
p = 0.001p < 0.0001 p = 0.0053p < 0.0001
p < 0.0001 p = 0.0097
Ryan et al Proc ASCO 2012
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…But not a home run for all
Ryan et al Proc ASCO 2013
A patient who does not respond to abiraterone has rPFSand OS no different from Tax 327 data of a decade ago.
• Kaplan‐Meier estimates of OS and HRs (relative to the good prognosis category) were determined
Who “Does Best” with Abiraterone/Enzalutamide?
Baseline risk factor p Value Hazard
ratio
BPI (2-3 vs 0-1) < 0.0001 1.71 (1.34-2.17)
LDH ( > ULN [234 IU/L] vs ≤ ULN) < 0.0001 2.03 (1.51-2.74)
ALP ( > ULN [131 IU/L] vs ≤ ULN) 0.0004 1.60 (1.23-2.08)
Bone metastases (≥ 10 vs < 10) < 0.0001 1.92 (1.49-2.47)
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Sequen cing: Retrospective Experience Abiraterone after enzalutamide
Very Modest response
Response to Abiraterone Therapy
Study N Sequence(order drugs administered)
PSA Response Enzalutamide
Therapy(≥50%)
PSA Response(≥50%)
Median PFS Median OS
Ileana 2012 24 DocetaxelEnzalutamideAbiraterone
‐ 13% 2.4 months ‐
Noonan 2013
30 DocetaxelEnzalutamideAbiraterone
60% 3% 15.4 weeks 50.1 weeks
Loriot 2013 38 DocetaxelEnzalutamideAbiraterone
‐ 8% 2.7 months 7.2 months
HR=0.61 (95% CI: 0.43-0.87)p=0.0055
— abiraterone + prednisone (n=124)--- + prednisone (n=140)
Treatment with AA + P significantly prolonged OS to 53.6 months
placebo+prednison41.8m
COU-AA-302�randomized,�double-blind,�placebo-controlled�phase�III�clinical�study.�The�median�treatment�periodabiraterone�+�prednisone20.4m,placebo+prednisone11.2m(HR�0.41,95%CI�0.31-0.54,p<�0.0001)。
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Earlier Intervention for More Survival Benefits with 11.8 mo of OS Extended
Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11‐15 March 2016, Munich, Germany
2016 EAU COU-AA-302stratified analysis
Earlier Stage of Chemotherapy-naïve mCRPCsubjects:
[BPI] Short Form score 0-1
[PSA] < 80 ng/ml
[GS] Gleason score < 8
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Primary Resistance
CRPC
EnzalutamideOr Abiraterone
30% = Primary Resistance
Response
60+% = Acquired
Resistance:
Death Non-PC Cause
(?%) Resistance with Phenotypic Change:e.g. Neuro-endocrine
ASI= Androgen Synthesis InhibitorART = AR Targeted Therapy
Ryan Proc GU ASCO 2013
AR‐V7: AR SPLICE VARIANT “half AR” – Activated without Binding Androgen
Antonarakis ES. 2014 ASCO Annual Meeting. Abstract 5001.
NTD LBDHinge
CBP
DBD
CRPC contains variants which lack
LBD
No current therapies can inhibit because they work
through LBD
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AR Splice Variants (AR‐Vs)
AR-V13
AR-V1
AR-V2
AR-V3
AR-V4
AR-V5
AR-V6
AR-V7
AR-V8
AR-V9
AR-V12
AR-V14
AR-V10
AR-V11
31 7 82 4
66948516
6691451566905968
6694180566863249
66941675
5 6 9
6694352866944119
66931244
66931531
66942669
6694282666905852
66937320
66937464
CE4
6690084566900562
CE1
66909400
CE2
66912029
CE5
6691341266863098
1b
66915918
4155 nts
8753 nts
CE3
66763874
66766604
66788683
66788864
MTLGDNLPEQAAFWRHLHIFWDHVVKK stop
Transcripts Proteins
KALPDCERAASVHF stop
LFSINHT stop
SVQPITPDAMYL stop
1 2 3 CE1
1 2 3 CE13
1 2 CE13CE4
1 2 CE13CE43
1 2 CE23
1 2 CE23
1 2 CE33
1 2 3
1 2 CE53
1 2 93 4 8
1 2 93 4 5 6
1 2 93 4 5 6
MTLGAVVVSERILRVFGVSEWOP stop
MTLGAVVVSERILRVFGVSEWOP stop
RAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop
MTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop
MTLGD stop
MTLGAGSRVS stop
MTLGEKFRVGNCKHLKMTRP stop
MTLGGFDNLCELSS stop
1 2 3 MTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL stop
1 2 3 MTLGGKILFFLFLLLPLSPFSLIF stop
AR4
AR1/2/2b
AR1/2/3/2b
AR3
ARv567es
Alternative names AR-Vs
Transcriptional activity
Inactive
Conditional
Unknown
Constitutive
Constitutive
Unknown
Unknown
Constitutive
Unknown
Conditional
Constitutive
Unknown
Unknown
Unknown
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AR: Xq11-12
69 nts
Liu LL et al, Oncogene 2013
ARV7More abundant than others:
Compatible with detection in clinical samples
Constitutively active:
Cannot be inhibited by LBD‐targeting drugs
Produces translated protein product:
Not affected by nonsense‐mediated mRNA decay
Expression increased (~20 fold) in CRPC
Prevalence of AR‐V7 in CRPC (n=62)
• Pre‐Enza, Pre‐Abi : 11.6%
• Post‐Enza only : 25.0%
• Post‐Abi only : 51.2%
• Post‐Enza and Post‐Abi : 66.7%
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AR‐V7 and Resistance to Enzalutamide and Abiraterone in CRPC
PSA Responses According to AR‐V7 Status
Antonarakis ES, et al. N Engl J Med. 2014;371:1028‐38.
AR‐V7 positiveAR‐V7 negative
Enzalutamide‐Treated Patients
‐100
Best PSA
Response, %
chan
ge
100
50
‐50
†
*†
*†
* †
† †
†
†
† † †
†
†
††
† † †
† †
0
Abiraterone‐Treated Patients
‐100Best PSA
Response, %
chan
ge
100
50
‐50
* * **
†
†
†
†
0
AR‐V7 positiveAR‐V7 negative
The dotted line shows the threshold for defining a PSA response (≥50% reduction in PSA level from baseline).*Increase seen of > 100% in best PSA response. †Pa ents in the enzalutamide cohort who previously receivedabiraterone and patients in the abiraterone cohort who previously received enzalutamide.
Conversions of ARV-7
Nakazawa et al Ann Oncol 2015
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ARV7 ratio to flAR:ARV7 is a function of AR amplfication
Antonarakis NEJM 2014
Combination Phase III: Alliance: A031201 ‐ PI Michael Morris (accrued)
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
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Mechanism #3
UCSF
Targeting Bone Metastasis
Radium-223 Targets Bone Metastases
• Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1
– Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue
Range of alpha-particle
Radium-223
Bone surface
1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.
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TREATMENT
6 injections at 4-week intervals
Radium-223 (50 kBq/kg) + Best standard of care
Placebo (saline) + Best standard of care
RANDOMISED
2:1
N = 922
PATIENTS
• Confirmed symptomatic CRPC
• ≥ 2 bone metastases
• No known visceral metastases
• Post‐docetaxel or unfit for docetaxel
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer)
Phase III Study Design
Clinicaltrials.gov identifier: NCT00699751.
• Total ALP: < 220 U/L vs ≥ 220 U/L
• Bisphosphonate use: Yes vs No
• Prior docetaxel: Yes vs No
STRATIFICATION
Planned follow-up is 3 years
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
ALSYMPCA Overall Survival
0
10
20
30
40
50
60
70
80
90
100
%Radium‐223, n = 541Median OS: 14.0 months
Placebo, n = 268Median OS: 11.2 months
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
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How to use radium?
• Chemo refusers?
• Frailer patients?
• Post chemo
• In combination
Mechanism #4
UCSF
Targeting Variant Histologies
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Treatment Mediated Selection Pressure: Neuro‐Endocrine Prostate Cancer as an example of phenotypic change
AR Driven Adenocarcinoma
AR directed therapy
“eliminates” Adenocarcinoma
Neuro‐endocrine/small cell predominant
mCRPC Tissue Collection: West Coast Dream Team Approach
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Histology of 124 Evaluable Biopsies<br />74 % were “pure” with a single histologic subtype (**isolated by LCM)<br />Remainder (26%) were comprised of mixed populations
Presented By Eric Small at 2015 ASCO Annual Meeting
Overall survival as function of biopsy pathology<br />Grouping IAC and SCNC
Presented By Eric Small at 2015 ASCO Annual Meeting
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Clinically “Anaplastic” Histologically“Small Cell “
Need to Reconcile clinical vs histological vs genomic
Genomic Target Present?
But the holy grail is the liquid biopsy
Scher et al Proc ASCO GU 2016
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Harnessing Multi‐platform informatics to discover
Harnessing Multi‐platform informatics to discover
NEXT Ideal: A marker that melds Predictive and prognostic
Prognostic“how sick is patient?”
LDHAlkPhosOpiates y/n?Visceral Disease
Predictive“Will drug work?”
– Does Prognostic trump Predictive?‐If a predictive pattern is identified in a patient will they still be able to receive the intervention?
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Mechanism #5
UCSF
Targeting DNA repair
BRCA and prostate cancer
• Germline BRCA 1,2 are rare in prostate cancer– present in 0.33‐5%
• HOWEVER– Homologous DNA repair defects (HR) are common in prostate cancer
• Germline and somatic inactivating mutations in HR DNA repair genes collectively occur in up to 20%–25% of prostate cancers – CHEK2, BRIP1/FANCJ, SBS1, BRCA1 and ATM
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Mateo J et al. N Engl J Med 2015;373:1697‐1708.
Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration‐Resistant Prostate Cancer.
Mateo J et al. N Engl J Med 2015;373:1697‐1708.
Antitumor Activity of Olaparib and Association with Defects in DNA‐Repair Genes, According to Biomarker Status.
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PARP inhibitors in development
Source: NIH Clinical Trials registry. www.ClinicalTrials.gov. ‐ See more at: http://www.onclive.com/publications/Oncology‐live/2015/June‐2015/parp‐inhibitors‐move‐into‐the‐limelight#sthash.X2Kqz6Ic.dpuf
Carboplatin also targets defective DNA repair
• Platinum based chemotherapy active
• Underutilized.
• May ‘double cover’ neuroendocrine and HRD tumors
• Generic, well tolerated
• Need trials!
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Hagel S et al, Ann Oncol 2016
Prior studies of platinum‐based therapy
Do we know how to select patients??
Mateo et al, NEJM 2015Lord and Ashworth, Nat Rev Cancer 2016
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Integrating Biology into CRPC Management
• AR signaling is the key to most CRPC
• Variant histologies also may be implicated.
• DNA Repair defects are a ‘new’
• Tumor interrogation imperative to future therapy development
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