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
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
Overview
• What is M0 CRPC?
• Review data from SPARTAN, PROSPER and ARAMIS trials
• Discuss clinical impact of these trials
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
Disease continuum in prostate cancer
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
PROSPER
PROSPER
PROSPER
PROSPER
PROSPER
SPARTAN
SPARTAN
SPARTAN
SPARTAN
SPARTAN
SPARTAN
SPARTAN
SPARTAN
ARAMIS
ARAMIS
ARAMIS
ARAMIS
ARAMIS
ARAMIS
ARAMIS
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
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
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?
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
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
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
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)
$$$$
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)
THANK YOU
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