Castrate-resistantprostatecancer:Bone-targetedagents

PrKarimFizazi,MD,PhDInstitutGustaveRoussy

Villejuif,France

Disclosure

Participationinadvisory boards orasaspeakerfor:Amgen,Astellas,Bayer,BMS,Dendreon,Ipsen,Janssen,Novartis,Orion,Sanofi-Aventis

1. Roodman GD. N Engl J Med 2004;350:1655–16642. Amgen, data on file

Osteoblastosis

Osteolysis

PC

Osteolytic andosteoblastic bonemetastases:presenceofosteoclastsirrespectiveofradiology

Osteolysis1 Osteoblastosis2

Black arrows = osteoclasts

Theprognostic importanceofbone-related factors inmCRPC

Alkaline Phosphatase Urinary N-telopeptide

Bone pain Previous SRE

Fizazi K, Eur Urol 2015

Skeletal-RelatedEvents(SRE)inmenwithbonemetastasesfromprostatecancer

PathologicFracture

25%

PainrequiringRadiationto

Bone

33%

SurgerytoBone

4%

SpinalCordCompression

8%

Saad,etal.JUrol2003;169(Suppl).

Median,days P valueZOMETA® 4mg 488 .009Placebo 321

0

20

40

60

80

100

0 120 240 360 480 600 720Days§

Perc

ent w

ithou

t eve

nt

Zoledronate:TimetoSkeletal-RelatedEventinmCRPC

Zol 4 mg 214 149 97 70 47 35 3Placebo 298 128 78 44 32 20 3

Intervalover5Months

Saad etal.JNCI2004;96:879

488321

ZoledronatePlacebo

0.009

Proportion(%) ofPatientsWithEachSRE

26

17

46

20

33

25

8 74

10

5

10

15

20

25

30

35

Radiation tobone

Fractures Spinal cordcompression

Antineoplastictherapy

Surgery tobone

Hypercalcemia

Perc

ent o

f pat

ient

s

Zoled acid 4 mg (N = 214) Placebo (N = 208)

Saad et al. JNCI 2004; 96:879

TrapezePhaseIIItrialinmCRPC:Symptomatic SkeletalEvents(SSE)

JamesN,ASCO2013

ZoledronicAcidforCRPC:Overallsurvival

• MedianOS:18.2vs15.6months• 1-yearsurvival85.2%vs.78.3%(P=0.21)2

1Saad F: Cancer Treatment Reviews (2008) 34, 183– 1922Weinfurt KP, et al. Annals of Oncology. 2006;17: 986-989.

ClodronateinHormone-SensitiveProstateCancer

Metastaticdisease (PR05trial,n=278)HR:0.77(0.60-0.98),P =.032

Nonmetastaticdisease (PR04trial,n=471)HR:1.12(0.89-1.42),P=.94

DearnaleyDP,etal.LancetOncol 2009;10:872-876.

Overallsurvival

The“viciouscycle”ofbonemetastases

BoneRANK

RANKL

BoneResorption

Osteoclast

Prostatecancercells

Ca2+

GrowthFactors(TGF-β, IGFs,FGFs, PDGFs,

BMPs)

CytokinesandGrowthFactors(ET-1,IL-6,IL-8,TNF-a,PTHrP,etc)

AdaptedfromRoodmanGD.NEnglJMed. 2004;350:1655-64.

RANKL

Directeffectsontumor?

TargetingRANK-L:Proofofconcept

OPG

RANKL

CTR CTROSB+2b

OSB+2a

OSB+LNCaP

OSB+PC3

Fizazi et al., Clin Cancer Res 2003;9:2587–2597Fizazi et al., J Clin Oncol 2009; 27: 1564-71

RANK-L overexpressed by osteoblasts

in bone metastases

Positive randomized Phase II: Denosumab decreases uNTx (biomarker for osteolysis)

Denosumab:TimetoFirstSREinpatientswithestablishedbonemetastases

0

1.00

Prop

ortio

nofSub

jectsW

ithou

tSRE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KMEstimateofMedianMonths

DenosumabZoledronicacid

20.717.1

HR0.82(95%CI:0.71,0.95)P =0.0002(Non-inferiority)P =0.008(Superiority)

StudyMonth

18% RiskReduction

Fizazi et al. Lancet 2011; 377: 811-822

Denosumab:timetofirstsymptomatic event (SSE)

SmithMetal.,AnnOncol 2015

0

1

2

3

4

5

6

7

8

9

%

Spinal cord compression

Preventingtheonsetoftheworstenemy:

Placebo Zoledronicacid

Dmab

103trialZApivotaltrial

8% 4% 2.7%

Zoledronicacid

Saad, et al. J Natl Cancer Inst 2004;96:879–82; Fizazi et al. Lancet 2011; 377: 811-822

Bone-targetedagents:Aretheyworthusing?

• Morbidityreduced• Preventionvs treatment• Overallgoodtolerance• Cheaperthanmostnewcancerdrugs

• Nodemonstratedroleinsurvival

• ONJ(1-2%),hypocalcemia

Osteonecrosis ofthejaw• Datafrom 3randomized trials(n=5723)• ONJin89(1.6%)pts

– 37(1.3%)zoledronic acid– 52(1.8%)denosumab (p=0.13)

• Toothextractionin62%ofpts withONJ– Disruptionofdenosumab recommended– Antibioticsrecommended

• ONJconservativetreatmentin>95%• ONJresolutionin36%

Saad F,AnnOncol 2012;23:1341-7

Nobenefit ofzoledronic acid inptswithcastrate-sensitive metastatic CaP

n= 645 pts with HSPC and bone mets

RImmediate Zoledronic Acid

Zoledronic Acid when CRPC

Median time to SRE:32 mo vs 30 mo (HR=0.97)

Smith MR, J Clin Oncol 2014; 32: 1143-50

Zoledronic acid in hormone-sensitive CaP: Survival (Stampede)

SOC 405deathsSOC+ZA 197deaths

HR(95%CI) 0.93(0.79,1.11)P-value 0.44

Non-PHp-value 0.83

MedianOS(95%CI)SOC 67m(60,91m)SOC+ZA 80m(70,NR)

RestrictedmeanOStimeSOC 58.5mSOC+Doc 59.5mDiff(95%CI) 1.0m(-1.4,3.4m)

JamesN,ASCO2015

Zoledronicacid4mgQ3monthsNo zoledronic acid*

1433 patientsProstate cancer, M0

+/- local treatment, +/- ADTHigh-risk PCa with at least one of the following criteria:• Gleason Score 8-10• pN+• PSA ³20 at diagnosis Treatmentduration4years

R

DoesZoledronicAcidpreventtheonsetofbonemetastases?TheZEUS trial

Wirth M, EAU 2013

Primary endpoint: Bone metastases

Zoledronate 13.7%Control 13%

p=0.72

Median follow-up: 4.8 years Overall survival

Should Denosumab be used topreventtheonset ofbonemetastases inCRPC?

The« 147 »trial

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

HR=0.77(95%CI,0.64-0.93)P=0.0064

Proportionofpatientswith

bonem

etastasis-freesurvival

Studymonth

PlaceboDenosumab

18.725.9

7.2

Medianmonths

Delay(months)

23%

Riskreduction

Studymonth

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Median:25.2months

29.5months

Events:370

335

HR=0.85(95%CI,0.73-0.98)P=0.028

Proportionofpatients

Placebo(n=716)Denosumab(n=716)

Pts with PSA DT ≤ 6 monthsOverall population

Smith MR, et al. Lancet 2012;379:39–46Smith MR, et al. J Clin Oncol 2013

Conclusion:Bone-targeted agentsinadvanced prostatecancer

• Inmetastatic CRPC:– Zoledronic acid:SREimproved– Denosumab:SREimproved (>ZA)– SSEalso improved

• Nocurrent role inhormone-sensitivemetastaticprostatecancer(except forprevention ofboneloss)

• Notapproved innon-metastatic CRPC(unfavorablerisk/benefit balance)

TowardteamtreatmentforBonemetastases