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Sergio Bracarda MD, Head, Department of Oncology
Azienda USL Toscana Sud-Est
Istituto Toscano Tumori (ITT)
Ospedale San Donato
Arezzo, Italy
Milano, 3 marzo 2017
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Prostata: Castration resistant
HIGHLIGHTS
Cinzia Ortega
Oncologia
ASLCN2
Outline Molecular Drivers in mCRPC
Genomic alterations
Genomic evolution in PC
Significantly mutated genes in mCRPC
Liquid Biopsies
AR indifferent disease
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MOLECULAR DRIVERS IN mCRPC Genomic alterations
Robinson et al, Cell 2015
Systematic and multi-institutional study of mCRPC tumors obtained from
living affected individuals to
• determine the landscape of somatic genomic alterations
• genomic differences between primary prostate cancer and mCRPC
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Genomic heterogeneity in prostate cancer
Presented By Eliezer Van Allen at 2017 Genitourinary Cancers Symposium
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Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium (modified)
Robinson et al , Cell 2015
The most frequently aberrant genes in mCRPC included AR (62.7%), ETS
family (56.7%), TP53 (53.3%) and PTEN (40.7%)
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Aberrations in the AR pathway
Robinson et al, Cell 2015
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium (modified)
Key genes altered
Point mutations
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Scher et al. JAMA Oncol. 2016 Jun 4.
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Slide 11
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
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No change in AR copy <br />number on abiraterone
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
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Plasma AR is associated with worse outcome in PREMIERE trial
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
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Robinson et al Cell 2015
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium
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PTEN loss
HR,a 0.39 (0.22-
0.70)
ALLAN MARTIN STUDY: CO-PRIMARY ENDPOINT: RPFS WITH
IPATASERTIB OR PLACEBO + ABIRATERONE BY ICR IHC
a Unstratified HR; 90% CI.
40
0 m
g I
pa
tase
rtib
2
00
mg
Ip
ata
sert
ib
PTEN non-loss
HR,a 0.84 (0.51-
1.37)
400 mg Ipat + Abi
Median 7.5 mo
Pbo + Abi
Median 5.6 mo
Courtesy de Bono et al, Ipatasertib, ESMO 2016
HR,a 1.13 (0.69-
1.85)
200 mg Ipat + Abi
Median 4.6 mo
Pbo + Abi
Median 5.6 mo
Pbo + Abi
Median 4.6 mo
400 mg Ipat + Abi
Median 11.5 mo
HR,a 0.46 (0.25-
0.83)
200 mg Ipat + Abi
Median 11.1 mo
Pbo + Abi
Median 4.6 mo
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DNA Repair & Metastatic PCa
Presented By James Catto at 2017 Genitourinary Cancers Symposium
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DNA Repair & Metastatic PCa
Presented By James Catto at 2017 Genitourinary Cancers Symposium
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Slide 11
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
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Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
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Cabazitaxel +/- Carboplatin in mCRPC
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
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Prostata Castration Resistant: Oral Presentations
UPDATES and NEWS from the Genitourinary Cancers Symposium - Milano, 03.03.17
Francesco Massari Oncologia Medica
Azienda Ospedaliero – Universitaria di Bologna
Policlinico S. Orsola-Malpighi
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Abstract #132
Silberstein J et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 132) Oral Abstract Session A: Prostate Cancer
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Azard AA et al. Clin Cancer Res 2015; 21:2315–24
AR gene aberrations in cfDNA are associated with resistance to ENZALUTAMIDE in mCRPC.
Enza: ctDNA analysis for AR amp/mut
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Romanel A et al. Sci Transl Med 2015; 7:312re10
AR gene aberrations in cfDNA are associated with resistance to ABIRATERONE in mCRPC.
Abi: ctDNA analysis for AR amp/mut
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Results
• 202 pts enrolled prior to starting Abi/Enza
• AR-FL status was considered as 3 groups:
AR-FL Negative (Undectable): 97/202 48%
AR-FL Positive (< Median): 52/202 26%
AR-FL Positive (>/= Median): 53/202 26%
Silberstein J et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 132) Oral Abstract Session A: Prostate Cancer
Overall Survival
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Summary
• CTC-based liquid biopsy allows AR-FL mRNA quantification
• Higher AR-FL levels correlate with AR-V7 posity
• Higher AR-FL correlate with inferior clinical outcomes
• AR-V7 remained independetly prognostic for all outcomes
in multivariable analyses
Silberstein J et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 132) Oral Abstract Session A: Prostate Cancer
Willthep
ractice
change
?
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Revisione Posters Prostata Castration Resistant: CTC: Fattori prognostici/predittivi, Sequenze Immunoterapia, Trattamenti combinati
Prostata: Castration Resistant Revisione Posters
• 1) CTC: Fattori prognostici/predittivi
• 2) Sequenze
• 3) Immunoterapia
• 4) Trattamenti combinati
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- CTC Count
- NGS
- CgA
1) CTC and Prognostic/Predictive Markers:
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The Sequencing Dilemma :
New HT Drug-1 followed by new HT Drug-2 ? …….
the inverse Sequencing ?
… or
Chemotherapy ?
(…. this is the problem..)
mCRPC, Stage IV Treatment Options: mCRPC, Stage IV Treatment Options: 2)
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Metastatic disease: STRIVE RCT
Presented By James Catto at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
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Phase 1b Trial of Anti-PD-1<br />17 Prostate Cancer Patients …….
Presented By Charles Drake at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
3) I-O
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4) Combo
Cryo + PD-1 Blockade
Presented By Charles Drake at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
4) Combo
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Will the Practice Change for CRPC in
2017 ?
“… surely not because of what presented at 2017
GUSY !!! ”
CONCLUSIONS