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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