ESMO SUMMIT LATIN AMERICA 201915 Years of progress in Prostate CancerStandards of Care

NameRonald de Wit , ErasmusMC Cancer Institute , Rotterdam, the Netherlands

Sao Paulo, 23 March 2019

CONFLICT OF INTEREST DISCLOSURE

• Consultancy: Sanofi, Merck, Lilly, Bayer, Janssen, Roche, Clovis

• Speaker fees: Sanofi, Merck

• Institutional financial interests:Sanofi,Bayer

2004: TAX 327 Survival benefit despite confounding effects on OS

Improved median survival by 2.9 months: • as compared with alternativeeffective treatment (mitoxantrone)• despite 30% crossover• despite imperfect design

(first PSA evaluation at 6 weeks)

Tannock et al, N Engl J Med 2004; 1502-1512Berthold et al , J Clin Oncol 2008; 242-245

Randomised Phase II study in Asiatic patients ) n=229 (conducted as TAX327)

Docetaxel(75mg/m2)/pred vs M/pred; N= 229mCRPCOS benefit 8 months (21.9 versus 13.7 months, HR 0.63)

Ti Zou et al, Plos one 2015

Docetaxel standard 1st line chemotherapy in mCRPC

9 Phase 3 trials of docetaxel + agent have failed to improve OS

Phase 3 docetaxel +/- lenalidomide ( MAINSAIL) worse OS in exp arm, ascribed to fewer cycles and more frequent docetaxel dose reductions*

Posthoc analysis of MAINSAIL ; in MVA number of docetaxel cycles had independent prognostic importance for OS; 8 was better than 6, 10 was better than 6 or 8* (in TAX 327 med N of cycles achieved 9.6 )

Number of cycles of docetaxel/dose in mCRPC is important

* Petrylak et al Lancet Onc 2015, ** de Morree et al JAMA Onc 2016

Phase III clinical trials in mCRPCStudy Agents N Indication HR ∆ OS

TAX-3271 Docetaxel/P vs mito/P 1006 mCRPC 0.76 +2.9

IMPACT2 Sipuleucel-T vs pbo 512 mCRPC (pre-Doc) 0.78 +4.1

COU-AA-3023

COU-AA-3014Abiraterone/P vs PAbiraterone/P vs P

10881195 mCRPC (pre-Doc)

mCRPC (post-Doc)

0.810.74

+4.4+4.6

PREVAIL5

AFFIRM6Enzalutamide vs pboEnzalutamide vs pbo (or P)

17171199 mCRPC (pre-Doc)

mCRPC (post-Doc)

0.710.63

+4.0 +4.8

TROPIC7 Cabazitaxel/P vs mito/P 755 mCRPC (post-Doc) 0.70 +2.6

ALSYMPCA8 Radium-223 vs pbo 921 mCRPC 0.70 +3.6

6

SA

GB

.CA

B.1

4.08

.038

2c

4/04

/201

9

Optimal choice and sequence of current agents undefined

Most trials conducted in parallel pre-or post doce

Optimal sequence of drugs undefined

OS benefit likely smaller in subsequent lines of treatment;

is there any benefit to be expected in

3rd or even 4th line?

Limited efficacy of crossing over between AR targeted agents;

Do not loose the opportunity of using cabazitaxel

Need for biomarkers for response on taxanes and AR targeted agents

Primary resistance to AR-targeted agents

1. De Bono et al. N Engl J Med 2011; 364: 1995–2005; 2. Scher H et al. N Engl J Med 2012; ;367:1187-97 PFS: progression-free survival

Potential but not yet validated biomarkersof resistance to ART

Antonarakis ES et al. NEJM 2014;371:1028-38; Antonarakis ES et al. JAMA Oncol 2015;1:582-91 CTC: circulating tumor cell

PSA response rate:AR-V7 positive: 0% (95% CI: 0-26%)AR-V7 negative: 52.6% (95%CI: 29-76%)P=0.004

PSA response rate:AR-V7 positive: 0% (95% CI: 0-46%)AR-V7 negative: 68.0% (95% CI: 46-85%)P=0.004

PSA response rate:AR-V7 positive: 41% (95% CI: 18-67%)AR-V7 negative: 65% (95%CI: 41-85%)P=0.19

AR-V7 positive AR-V7 negative

Abiraterone Enzalutamide Taxane*

PSA

chan

ge, %

100

50

–50

–100

100

500

–50

–100

100

500

–50

–100

*Docetaxel, N=30Cabazitaxel, N=7

AR-V7 in Cabazitaxel treated patientsErasmus MC GroupDo AR-V7-positive patients benefit from cabazitaxel?

CTC response Decline to or stable <5 CTC

Overall 44%

N = 51

50% versus 36%, P = 0.40

7.5 mL blood in EDTA tube before cycle 1 and 3CellSearch enrichment, Lysis, RNA isolation, RT-qPCR

AR-V7 in Cabazitaxel treated patientsErasmus MC Group

Do AR-V7-positive patients benefit from cabazitaxel?

No difference in PFS and OS

Optimal choice and sequence of current agents undefined

Most trials conducted in parallel pre-or post doce

Optimal sequence of drugs undefined

OS benefit likely smaller in subsequent lines of treatment;

is there any benefit to be expected in

3rd or even 4th line?

Need for biomarkers for response on taxanes and AR targeted agents

Cross resistance between agents

Cross resistance between taxanesand AR- targeted agents

in vivo model of CRPC with acquired resistance to enzalutamide

Van Soest, de Wit et al. Eur Urol 2014

Impaired Efficacy of Docetaxel Post-Abiraterone?

[2-5] trials are retrospective studies

1. Tannock et al. Lancet Oncol 2013; 14:760-8; 2. Mezynski & De Bono Annal Oncol 2012. 23: 2943–2947; 3. Schweizer MT et al. Eur Urol 2014; 66:646-52; 4. Azad et al. The Prostate 2014; 74:1544-1550; 5. De Bono et al. Eur Urol 2017

Cabazitaxel Remains Active in Patients Progressingwith an AR-Targeted Agent

Van Soest RJ et al. Eur J Cancer. 2015; 51: 2562-9

Progression-Free Survival Overall Survival

Prospective, randomized phase 2 study of cabazitaxel ± budesonide

Prior AR-targeted agentNoYes

Prior AR-targeted agentNoYes

1st line taxane phase III study ; FIRSTANA

FIRSTANA: Overall Survival

FIRSTANA: Prior Treatment

1st line taxane in mCRPC

Cabazitaxel 20mg and 25mg show a similar OS benefit as

Docetaxel in a non resistant population

(<2% of patients treated with prior ABI or ENZA)

1 st line efficacy of Cabazitaxel as compared to Docetaxel in patients

progressing after ABI or ENZA is not known

If there is no benefit after 3 cycles of doce in post-abi/enza setting

consider to switch to cabazitaxel ( 20mg /m2)

15 years of progress in theManagement of Prostate Cancer

mCRPC; 2011 paradigm shift

novel AR targeted agents

pre-chemotherapy

mHSPC; 2014/2015 paradigm shift

docetaxel in addition to ADT

in men presenting with M1 disease

mHSPC; latest shift addition of abiraterone to ADT

GETUG 15 in metastatic HS PCaActivity of subsequent therapies

Lavaud P et al. J Clin Oncol 2016; 34 (suppl); abstract 5080

Modest PSA response and PFS in patients initially treated with ADT+DOC and rechallenged with DOC at disease progression

Short response to first ADT may predict poor response to Enzalutamide(Stephane Oudard, ESMO discussant 2017)

Retrospective cohort of 173 patients, including 57 treated with enzalutamide in AFFIRM trial

TTCRPC: time to castration resistance; PFS: progression-free survival

Loriot Y et al. Eur J Cancer 2015 sept ; 51(14): 1946-52

CABA is effective in patients progressingduring or rapidly after last DOC cycle

CABA also acts in cases of primary resistance to DOC3

Subgroup analysis of the TROPIC (Overall survival) N HR (95% CI)

Progression during treatment with DOC 219 0.71 (0.53-0.96)

Progression <3 months after the last DOC cycle 339 0.70 (0.56-0.89)

In favour of CABA In favour of mito

0.25 0.5 1.00 2.00

TROPIC trial1-2

1. De Bono J et al. Lancet 2010;376:1147-54 2. Oudard S et al. Future Oncol 2011;7:497-506 3. Di Lorenzo G et al. Eur Urol 2014;65:502-7

post CHAARTED/ STAMPEDE(doce) treatment

For pts > 12 months response duration on ADT

reasonable option AR-targeted therapy

(subsequent line would be cabazitaxel)

For pts< 12 months response duration on ADT most logical choice would appear cabazitaxel

In 2019 Multiple Choices and Sequences

mHSPC early taxane /late taxane

mHSPC early abi/late abi/enza

mCRPC abi/enza pre- or post taxane

mCRPC Radium 223 pre- or post taxane

Even after 4 lines considerable number of mCRPC patients wish to receive systemic therapies

New avenues: Immunotherapy

Molecular targeted therapies

Precision medicine in mCRPC

Molecular targeted treatment is based on pathways

Best known example in PC is DNA repair deficiency as a target for PARP inhibitors ( 10-15% of PC pts )*

Requires Biopsy material from metastatic lesion

or Liquid Biopsy ( CTCs or ctDNA)

*Mateo J et al. N Engl J Med 2015;373:1697-1708

CTCs vs cell-free tumor DNA (ctDNA)

CTCs cfDNAIntact tumor cell in the circulation cell-free in the circulation

DNA, RNA and protein DNA only

Detectable in 30-40% of mCRPC patients Detectable in 60% of mCRPC patients

More complex processing (EpCAM-based enrichment) Easy processing (plasma isolation)

CIRCUS study <ErasmusMC Group>

CPCT-02 study

Biopsy

DNA isolation

DNA sequencing

Plasma

Urine

ctDNA isolationdPCR

SV selection

Temporal measurements

Therapyresponse

+

CIRCUS studie

PSMA scan

CRPC patient

Conclusions

Docetaxel remains important taxane in mCRPC ,

efficacy likely impaired in post AR treatment setting

Cross-resistance between AR –targeted treatments,

do not loose the opportunity to use cabazixel

Benefit of docetaxel OR abiraterone in addition to ADT is robust in setting of mCNPC,evidence strongest in high-volume disease setting

Benefit of adding RTR in addition to ADT in mCNPC,

evidence in low-volume disease setting

esmo.org

ACKNOWLEDGEMENTSLaboratory of Translational Cancer Genomics andProteomics

John Foekens

Jaco Kraan

John Martens

Bianca Mostert

Anieta Sieuwerts

Stefan Sleijfer

Lab of TumorimmunologyReno Debets

Cancer Computational Biology CenterHarmen van de Werken

Job van Riet

Department of Medical Oncology / Urology,Erasmus MC

Martijn Lolkema

Astrid van der Veldt

Ron Mathijssen

Debbie Robbrecht

Anouk de Jong

Maud Rijnders

Joost Boormans

Robert van Soest

Wytske van Weerden

Guido Jenster

Ronald de Wit

All recruiting physicians and research nurses