m0 castrate-resistant prostate cancer (crpc): what are our latest … · m0 castrate-resistant...
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M0 Castrate-Resistant Prostate Cancer (CRPC): What are our latest options?
A/Prof. Arun Azad MBBS PhD FRACPMedical Oncologist, Peter MacCallum Cancer CentreAssociate Professor, University of MelbourneChair, ANZUP Translational SubcommitteeCo-PI, #UpFrontPSMA Movember/Cancer Australia PCRAVictorian Cancer Agency Clinical Research Fellow
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Disclosures
Research Support/P.I. Astellas, Merck Serono
Employee N/A
Consultant Astellas, Janssen, Novartis
Major Stockholder N/A
Speakers Bureau Astellas, Janssen, Novartis, Amgen, Bayer
Honoraria Astellas, Janssen, Novartis, Tolmar, Amgen, Pfizer, Bayer
Scientific Advisory Board Astellas, Novartis, Sanofi, Astra-Zeneca, Tolmar, Pfizer, Janssen, Telix, Noxopharm
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Overview
• What is M0 CRPC?
• Review data from SPARTAN, PROSPER and ARAMIS trials
• Discuss clinical impact of these trials
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Shifting Landscape for CRPC: Positive Phase 3 Trials
Mitoxantrone
Zoledronic Acid
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Docetaxel
EnzalutamideAbiraterone acetate
Cabazitaxel
Denosumab
Radium-223
Sipuleucel-T
Symptom benefit
Skeletal Related Event (SRE) benefit
Overall survival benefit ± symptom/SRE benefit
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Disease continuum in prostate cancer
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Background/Rationale
• Until recently, no approved therapies for M0 CRPC
• M0 CRPC with PSA DT of < 8-10 months at significant risk for developing metastases + PCa-specific death1
• Development of metastases is a key cause of morbidity
1. Smith MR et a. J Clin Oncol 2013;31:3800-6
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PROSPER
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PROSPER
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PROSPER
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PROSPER
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PROSPER
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SPARTAN
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SPARTAN
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SPARTAN
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SPARTAN
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SPARTAN
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SPARTAN
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SPARTAN
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SPARTAN
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ARAMIS
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ARAMIS
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ARAMIS
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ARAMIS
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ARAMIS
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ARAMIS
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ARAMIS
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SUMMARYPROSPER SPARTAN ARAMIS
Drug Enzalutamide Apalutamide Darolutamide
Dose 160mg OD 240mg OD 600mg BD
MFS (mo) 36.6 vs. 14.7 HR 0.29; P<0.0001
40.5 vs. 16.2HR 0.28; P<0.0001
40.4 vs. 18.4HR 0.41; P<0.0001
OS (mo) NR vs. NRHR 0.80; P=0.1519
NR vs. 39.0HR 0.70; P=0.07
NR vs. NRHR 0.71; P=0.0452
Gr 3 / 4 AE (%) 31 45 25
Falls (%) – any Gr 11 16 4
Fatigue (%) - any Gr
33 30 16
Rash (%) – any Gr NR 24 3
Treatment stop due to AE (%)
9 11 9
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TAKE HOME MESSAGES • All 3 M0 CRPC trials clearly positive for primary
endpoint (MFS)
• OS benefit still emerging
• QoL preserved
• Overall safe (especially Darolutamide)
• Some concerning toxicity data
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DISCUSSION POINTS• Does improvement in MFS matter?
• Does M0 CRPC exist?
• Should M0 CRPC exist?
• Pros vs. Cons of treating M0 CRPC?
• Do these trials influence practice?
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Does improvement in MFS matter?
• Do not know for certain….but it probably does
• Localised disease• ICECaP showed MFS surrogate for OS
• M1 CRPC• rPFS associated with OS in COU-AA-302 + PREVAIL
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Does M0 CRPC exist?
• Novel imaging potentially rendering this to be a non-existent disease state • 98% detectable disease on PSMA PET• 50% M1 on PSMA PET
• Is M0 CRPC (by conventional imaging) just very low-volume N1/M1 CRPC?
• Perhaps all we are doing by treating M0 CRPC is bringing effective drugs forward in the disease spectrum
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Should M0 CRPC exist?
• Should we start ADT in men without metastases?
• Should we use primary ADT in elderly men?
• Is this a disease space we have artificially constructed?
• My sense is that we are increasingly delaying ADT until development of symptoms and/or metastases
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Pros vs. Cons of treating M0 CRPC
Pro Con
Delaying metastases is meaningful to patients
Is MFS a true surrogate for OS?
Metastases lead to symptoms and death
M1 CRPC often asymptomatic/minimally
symptomatic
Emerging OS signal No definitive OS improvement (yet)
Well tolerated Some concerning AEs
QoL preserved No improvement in QoL
Cost savings of delaying metastases (RT, surgery, hospitalisation)
$$$$
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Do these trials influence practice?
• Irrespective of the arguments…..if we have access to effective drugs we are going to use them....so in:
• The United States: Yes (reimbursed)
• Australia: No (not reimbursed)
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THANK YOU