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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
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
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
Genomic heterogeneity in prostate cancer
Presented By Eliezer Van Allen at 2017 Genitourinary Cancers Symposium
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%)
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
Scher et al. JAMA Oncol. 2016 Jun 4.
Slide 11
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
No change in AR copy <br />number on abiraterone
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
Plasma AR is associated with worse outcome in PREMIERE trial
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
Robinson et al Cell 2015
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium
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
DNA Repair & Metastatic PCa
Presented By James Catto at 2017 Genitourinary Cancers Symposium
DNA Repair & Metastatic PCa
Presented By James Catto at 2017 Genitourinary Cancers Symposium
Slide 11
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Cabazitaxel +/- Carboplatin in mCRPC
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
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
Abstract #132
Silberstein J et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 132) Oral Abstract Session A: Prostate Cancer
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
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
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
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
?
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
- CTC Count
- NGS
- CgA
1) CTC and Prognostic/Predictive Markers:
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)
Metastatic disease: STRIVE RCT
Presented By James Catto at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
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
4) Combo
Cryo + PD-1 Blockade
Presented By Charles Drake at 2017 Genitourinary Cancers Symposium
Willthep
ractice
change
?
4) Combo
Will the Practice Change for CRPC in
2017 ?
“… surely not because of what presented at 2017
GUSY !!! ”
CONCLUSIONS