Letter
to
the
Editor
Re:JoaquinMateo,KarimFizazi,SilkeGillessen,etal.
ManagingNonmetastaticCastration-resistantProstate
Cancer.EurUrol2019;75:285–93
WereadwithgreatinterestthearticlebyMateoetal.[1]on
the management of nonmetastatic castration-resistant
prostatecancer.ThePROSPER(NCT02003924)[2]andthe
SPARTAN(NCT01946204)[3]trialsshowedthat
enzaluta-mide and apalutamide improve metastasis-free survival
(MFS)amongpatients withoutevidenceofmetastasis on
conventionalradiologicalimaging(computedtomography
and bone scans). Since February 2019, data from the
ARAMIS trial (NCT02200614) have become available [4],
with similar MFS outcomes for darolutamide as for
enzalutamide and apalutamide. It should be noted that
thesafetyprofileofdarolutamideispromisingbecauseof
itslowpenetrationacrosstheblood-brainbarrierandlow
bindingaffinityfor
g
-aminobutyricacidtypeAreceptors,asshowninpreclinicalstudies.
However,thesafetyofdarolutamideseemstobebetter
than its actual effectiveness. In the PROSPER trial of
enzalutamide [2], there was a hazard ratio of 0.29 for
metastasis or death among a series of patients with a
prostate-specificantigen(PSA)doublingtimeof3.8mo.The
ARAMIS trial [4], in which there was a hazard ratio of
0.41ratioformetastasisordeath,enrolledpatientswitha
longerPSAdoublingtime(4.4mo)[1].Couldthis
dissimilar-ityberegardedasthereasonforthediscrepancy,orwoulda
fewweeksmakesuchadifferenceinanaggressivesetting?
A6-mothresholdforPSAdoublingtimehaslongbeen
considered a landmark: a shorter PSA doubling time is
associated with a trend towards greater detection of
metastasisviaprostate-specific membraneantigen–based
positronemissiontomography(83%vs60%forPSAdoubling
timeof<6movs>6mo)[5].
Sincebiologicalaggressivenessbelowthe6-mo
thresh-oldhasrarelybeeninvestigated,whatwouldweexpectin
the case of a shorter PSA doubling time? Despite the
apparent similarity, the PROSPER trial enrolled patients
with more aggressive disease, as evidenced by data for
patients assignedto the placebo group. The time to PSA
progressionintheplaceboarmwasshorterinthePROSPER
trial(3.8mo)thanintheARAMIStrial(7.3mo),suggestinga
morepronouncedimpactofenzalutamide,evenforpatients
athigherriskofprogression.
Safety and easy handling should complement the
effectiveness of new hormonal agents; this issue should
befurtheraddressedbeforeformulatingrecommendations
basedondrugtoxicity.
Conflictsofinterest:Theauthorshavenothingtodisclose.
References
[1]MateoJ,FizaziK,GillessenS,etal.Managingnonmetastatic castra-tion-resistantprostatecancer.EurUrol2019;75:285–93.
[2]Hussain M, Fizazi K,Saad F,et al. Enzalutamide in men with nonmetastatic,castration-resistantprostatecancer.NEnglJMed 2018;378:2465–74.
[3]RachnerTD,TsourdiE,HofbauerLC.Apalutamideand metastasis-freesurvivalinprostatecancer.NEnglJMed2018;378:2541–2.
[4]FizaziK,ShoreN,TammelaTL,etal.Darolutamideinnonmetastatic, castration-resistantprostatecancer.NEnglJMed2019;380:1235–46.
[5]PereiraMestreR,TregliaG,FerrariM,etal.CorrelationbetweenPSA kineticsandPSMA-PETinprostatecancerrestaging:ameta-analysis. EurJClinInvest2019;49:e13063.
BernardoRocco MariaChiaraSighinolfi* DepartmentofUrology,UniversityofModenaandReggioEmilia, Modena,Italy *Correspondingauthor.DepartmentofUrology,UniversityofModena andReggioEmilia,viadelPozzo71,Modena41100,Italy.Tel.+39059 237170;Fax:+390594222368. E-mailaddress:sighinolfi[email protected](M.C.Sighinolfi).
May17,2019
EUROPEAN UROLOGY XXX(2019)XXX–XXX
a v ai l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n al h o m e p a g e : w w w . e u r o p e an u r o l o g y . c o m
EURURO-8423;No.ofPages1
Pleasecitethisarticleinpressas:Rocco B,Sighinolfi MC.Re:JoaquinMateo,KarimFizazi,SilkeGillessen,etal.Managing
Nonmetastatic Castration-resistant Prostate Cancer. Eur Urol 2019;75:285–93. Eur Urol (2019), https://doi.org/10.1016/j.
eururo.2019.05.030
https://doi.org/10.1016/j.eururo.2019.05.030
