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