Post on 09-Mar-2021
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