Re iew
Me as a ic ho mone-naï e p os a e cance : a
dis inc biological en i y
Jon Co es-Mendizabal
1,8
, F ancesca Zacchi
2,3,8
, Na alia Ma ín-Ma ín
1,4,5
, Joaquin Ma eo
3,
*, and
A kai z Ca acedo
1,4,5,6,7,
*
Me as a ic ho mone-naï e p os a e cance (mHNPC) is o en he ini ial o m o p e-
sen a ion o me as a ic p os a e cance and encompasses a he e ogeneous
pa ien popula ion wi h high in e -pa ien he e ogenei y in p ognosis and esponse
o he apy. A mo e p ecise ea men o mHNPC, guided by e idence-based bio-
ma ke s, emains an unme medical need. In addi ion, he limi ed numbe o ep e-
sen a i e labo a o y models o mHNPC hampe s he ansla ion o basic esea ch
in o clinical applica ions. We p o ide a comp ehensi e o e iew o he clinical
and biological ea u es ha cha ac e ize mHNPC, highligh molecula da a ha
could explain he unique p ognos ic cha ac e is ics o mHNPC, and iden i y key
open ques ions.
Defini ion and key clinical and molecula cha ac e is ics o mHNPC
P os a e cance (PCa) is he second mos equen cance and he fi h leading cause o cance
dea hamongmenwo ldwide[1]. Mos PCa- ela ed dea hs a e associa ed wi h me as a ic
sp ead, a condi ion ha can occu in a ho mone-naï e o a cas a ion- esis an se ing.
mHNPC e e s o PCa ha has sp ead o o he o gans beyond he p os a e and has ei he no
ye been ea ed wi h ho monal he apy ( es os e one dep i a ion) o has been exposed o ho -
monal he apy bu has g own again in he con ex o no mal (non-cas a e) es os e one le els.
In medical li e a u e, he e ms me as a ic cas a ion-sensi i e p os a e cance (mCSPC), me as-
a ic cas a ion-naï e p os a e cance (mCNPC), me as a ic ho mone-sensi i e p os a e cance
(mHSPC) and mHNPC a e used in e changeably. Depending on whe he me as a ic disease is
obse ed in pa allel o an up on diagnosis o PCa o in he o m o elapsed disease a e ha ing
ecei ed adical p os a ec omy and/o adia ion he apy, mHNPC is classified as 'de no o' o ' e-
lapsed', espec i ely. The ela i e incidence o de no o e sus elapsed mHNPC depends on mul i-
ple ac o s and a ies geog aphically. In Wes e n coun ies he p e alence o me as a ic disease is
~10% [1,2], wi h an e en dis ibu ion be ween de no o and elapsed me as a ic cases [3]. Much
highe a es o de no o mHNPC a e p esen in de eloping coun ies [4]. This highe incidence o de
no o me as ases could be explained, in pa , by di e ences in ea ly diagnosis and sc eening
p og ams, access o no el imaging es modali ies, and, in gene al, o inequali ies in access o
heal hca e [5].
Mo ali y a es o PCa ha e dec eased in mos high-income coun ies since he mid-1990s as
a esul o key ad ances in ea ly de ec ion s a egies and ea men op ions. Howe e , de no o
mHNPC con inues o exhibi a high 5 yea disease-specific mo ali y [4,6]. Mo eo e , a e a
decline in he use o p os a e-specific an igen (PSA) es ing in many coun ies, mHNPC inci-
dence has spiked, and he decline in PCa mo ali y has le eled o [4–8]. The e o e, he impac
o 'ea ly e sus delayed diagnosis' in oduces highe he e ogenei y when conside ing mHNPC
and challenges he iden ifica ion o clinically ele an disease pheno ypes based on biological
di e ences.
Highligh s
Pa ien s wi h me as a ic ho mone-
naï e p os a e cance (mHNPC) exhibi
a uniquely agg essi e clinical e olu ion.
The disease cou se and esponse o
s anda d he apies o de no o mHNPC
di e om hose o o he pa ien g oups.
Clinical managemen in mHNPC bene-
fi s om in ensifica ion s a egies ha
a e dis inc om hose o localized o
cas a ion- esis an me as a ic disease.
The e is a limi ed unde s anding o
he molecula al e a ions ha lead o
mHNPC.
The e is a need o gene a e ep esen a-
i e p eclinical models o s udy mHNPC.
1
Cen e o Coope a i e Resea ch in
Biosciences (CIC bioGUNE), Basque
Resea ch and Technology Alliance
(BRTA), Bizkaia Technology Pa k, 48160
De io, Spain
2
Sec ion o Inno a ion Biomedicine-
Oncology A ea, Depa men o
Enginee ing o Inno a ion Medicine
(DIMI), Uni e si y o Ve ona and
Uni e si y and Hospi al T us (AOUI) o
Ve ona, Ve ona, I aly
3
Vall Heb on Ins i u e o Oncology
(VHIO), Vall d'Heb on Uni e si y Hospi al
Campus, Ba celona, Spain
4
Cen o de In es igación Biomédica en
Red de Cánce (CIBERONC), 28029
Mad id, Spain
5
T ansla ional P os a e Cance Resea ch
Labo a o y, CIC bioGUNE-Basu o,
Biobizkaia Heal h Resea ch Ins i u e,
48903 Ba akaldo, Bizkaia, Spain
6
Ike basque, Basque Founda ion o
Science, Bilbao, Spain
7
Biochemis y and Molecula Biology
Depa men , Uni e si y o he Basque
Coun y (UPV/EHU), Bilbao, Spain
8
Equal con ibu ions.
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 h ps://doi.o g/10.1016/j. ecan.2024.06.005 825
© 2024 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/).
T ends in
Cance OPEN ACCESS
Recen e idence sugges s ha de no o mHNPC has a dis inc and mo e agg essi e clinical ajec o y
han hose cases whe e me as a ic disease appea s yea s a e ea men o localized disease [9,10],
such as sho e ime o he de elopmen o cas a ion esis ance. In his e iew we discuss he cu en
e idence on he clinical and molecula ea u es ha could unde lie he dis inc na u e o mHNPC.
mHNPC diagnosis
Imaging ools
Defini i e diagnosis o PCa is based on his ological findings. Biopsies ha e adi ionally been guided
by ul asound scans, al hough he ad en o mul ipa ame ic magne ic esonance imaging (MRI) in
ecen yea s has inc eased he accu acy o diagnosis and disease s a ifica ion. Compu ed omog-
aphy (CT) and bone scanning (BS) a e he s anda d echniques o comple e he diagnosis o
ad anced PCa by e alua ing he p esence and ex ension o dis an disease, and hese emain he
s anda d o assessing he e ficacy o cance he apies, as pe PCWG3 (P os a e Cance Clinical T i-
als Wo king G oup 3) and RECIST ( esponse e alua ion c i e ia in solid umo s) e sion 1.1 [11,12].
New imaging echniques, such as whole-body MRI (WB-MRI), and adiolabeled p os a e-specific
memb ane an igen (PSMA) and choline combined wi h posi on emission omog aphy (PET), ha e
significan ly enhanced ou abili y o iden i y dis an disease wi h highe sensi i i y [13–15]. Beyond
he cos and accessibili y issues ha ha e limi ed widesp ead implemen a ion o hese echniques
in ou ine clinical ca e, i should be no ed ha cu en e idence o managing pa ien s wi h di e en
s a es o PCa is mos ly based on disease-s aging defini ions de i ed om CT and BS imaging.
Inco po a ing mo e sensi i e assays esul s in mig a ion o pa ien s adi ionally conside ed o be
non-me as a ic o he me as a ic g oup. Cau ion is equi ed be o e ex apola ing clinical e idence
o hese new disease-s a e defini ions. Ne e heless, i is en isaged ha hese no el echniques
will be p og essi ely adop ed in clinical p ac ice, leading o a highe p opo ion o PCa being ecog-
nized as me as a ic. Wi h app op ia e s udies gene a ing e idence o clinical u ili y, hese assays will
likely imp o e ou accu acy o s a i y pa ien s wi h mHNPC in he nea u u e.
Taken oge he , hese imaging modali ies ha e imp o ed pe o mance and accu acy in de ec ing
and moni o ing me as ases, hus enabling mo e e ec i e ea men s a egies. Howe e , addi-
ional esea ch is necessa y o es ablish hei op imal u iliza ion in clinical ca e.
Solid umo biopsy
Al hough his ological e alua ion o umo biopsies emains he gold s anda d o PCa diagnosis,
he e is limi ed in o ma ion abou he exis ence o di e en ial his ological ea u es in mHNPC, and
he e is no es ablished his opa hological s a ifica ion o mHNPC beyond he Gleason sco e.
Only a hand ul o s udies ha e explo ed specific di e ences om o he pa hological se ings,
such as PCa ea ed wi h ho monal he apy and cas a ion- esis an PCa (CRPC). In his ega d,
dis inguishable ea u es include andomly a anged small glands, hype ch oma ic nuclei, p omi-
nen nucleoli, he absence o a basal cell laye , and an inc eased numbe o apop o ic cells [16,17].
Genomic p ofiling o issue biopsies has shown clinical alue in la e-s age mCRPC. Howe e , limi ed
accessibili y o me as ases and he lack o p ima y umo esec ion in pa ien s wi h mHNPC hinde
sample a ailabili y, and hus p esen a challenge o molecula cha ac e iza ion s udies in his clinical
se ing.
Liquid biopsy
Liquid biopsy o e s a less in asi e al e na i e o solid biopsies, and enables molecula cha ac e -
iza ion and con inuous moni o ing [18]. S udies on mHNPC indica e ha ci cula ing umo cells
(CTCs) p o ide aluable in o ma ion, complemen ing he da a ob ained om solid umo biopsies.
*Co espondence:
[email p o ec ed] (J. Ma eo) and
aca [email protected]
(A. Ca acedo).
T ends in Cance
OPEN ACCESS
826 T ends in Cance , Sep embe 2024, Vol. 10, No. 9
CTCs o e p ognos ic insigh s beyond adiog aphic disease olume owing o he possible limi a ions
in he esolu ion o s anda d adiog aphic imaging [19–21]. In addi ion, he de elopmen o gene
exp ession-based signa u es in CTCs may ha bo u he p ognos ic o p edic i e po en ial [21].
Cell- ee DNA (c DNA) and ci cula ing umo DNA (c DNA) also ep esen powe ul liquid-biopsy al e -
na i es ha can in o m clinical decision-making h ough p ognos ic and p edic i e esponse and esis-
ance bioma ke s [22–24]. The c DNA ac ion co ela es wi h p og ession- ee su i al and o e all
su i al in pa ien s wi h mHNPC, and is p opo ional o he numbe o CTCs [25]. S udies epo
ha 37–74% o hese pa ien s p esen de ec able c DNA [25–28]. Rega ding mCRPC, i is unce ain
whe he c DNA le els a e compa able o hose in mHNPC [28] o whe he hey inc ease significan ly in
pa ien s wi h mCRPC [27]. Da a suppo ing a educ ion in he c DNA ac ion a e and ogen dep i a-
ion he apy (ADT) encou ages i s use o moni o ing he esponse o ea men , al hough i implies ha
he apy could limi he acquisi ion o c DNA o genomic cha ac e iza ion [25,27,28]. In e es ingly, he
u ili y o c DNA could ex end beyond disease moni o ing because his pa ame e has been associa ed
wi h isce al me as ases [28], and a combina ion o c DNA, disease olume, and alkaline phospha ase
is be e a s a i ying pa ien s acco ding o o e all su i al han he indi idual a iables [27].
Cu en classifica ion o mHNPC and di e ences in p ognosis
The e is cu en ly no his opa hological o molecula classifica ion o mHNPC ha guides pa ien
s a ifica ion o managemen in clinical p ac ice. Howe e , di e en s a egies p e iously
alida ed in mCRPC a e being es ed in mHNPC clinical ials. Molecula s a ifica ion s a egies
include PARP inhibi ion based on homologous ecombina ion deficiency p ofile, AKT inhibi ion
in PTEN-deficien umo s, o s a ifica ion o LuPSMA ([
177
Lu]-p os a e-specific memb ane
an igen-617 adionuclide) he apy based on PSMA exp ession. Clinical and pa hological ea u es
based on disease bu den [high olume (HV) s low olume (LV)], ime o me as asis p esen a ion
(de no o s ecu en me as ases), and loca ion o me as ases ha e also been used o pa ien
s a ifica ion in clinical ials in he pas decade [10,29–33], suppo ing he alidi y o hese classi-
fica ions o guide he apeu ic decisions. Despi e he epo ed po en ial o s a ifica ion o he
a o emen ioned pa ame e s, su i al di e ences be ween de no o and elapsed me as a ic pa-
ien s a e s ill unclea because he di e en dis ibu ions o diagnos ic PSA and ime since diagno-
sis a e con ounding ac o s [34].
The e a e se e al molecula and clinical di e ences be ween de no o and ecu en mHNPC.
Pa ien s wi h de no o mHNPC ypically exhibi highe median PSA le els a diagnosis compa ed
o ecu en mHNPC [9,34]. In addi ion, hey show lowe hemoglobin and albumin alues, a
highe likelihood o lymph node me as asis, and a sho e du a ion o ho mone sensi i i y han pa-
ien s wi h elapsed mHNPC [9]. Mo eo e , age was ound as an independen p edic o o sho e
PCa-specific su i al (PCSS) in men diagnosed wi h de no o mHNPC. Men aged ≥75 yea s ex-
pe ienced a mean PCSS a 5 yea s ha was 6.7 mon hs sho e han o men aged ≤54 yea s
(95% CI 5.5–7.8 mon hs) [35]. Fu he wo k will be necessa y o de e mine he eason o poo
ou comes in olde men wi h de no o mHNPC [9,36]. Al hough i is unclea whe he his is influ-
enced by di e ences in umo bu den, hese esul s collec i ely sugges ha de no o and ecu -
en mHNPC a e biologically dis inc en i ies wi h di e en ou comes. A mo e p o ound
unde s anding o he di e ences be ween hese wo mHNPC g oups will equi e u he molecula
cha ac e iza ion s udies in issue biopsies.
Molecula de e minan s o mHNPC
Genomic ea u es
The genomic cha ac e iza ion o mHNPC has been an in ensi e esea ch ocus in he pas de-
cade and he sou ce o he majo i y o molecula da a on mHNPC. PCa exhibi s a low equency
T ends in Cance OPEN ACCESS
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 827
o poin mu a ions and is ins ead cha ac e ized by copy-numbe al e a ions and la ge-scale ea -
angemen s [37,38]. Howe e , no in o ma ion ega ding he p ofile o hese al e a ions in mHNPC
has been epo ed un il e y ecen ly, and we s ill lack a comp ehensi e pic u e. Al hough some
s udies ha e claimed ha he mu a ional bu den in mHNPC is simila o ha o loco egional u-
mo s [27,39,40], o he s ha e placed mHNPC close o mCRPC ega ding genomic ea u es
[28,41,42]. Mul i- egion p ofiling o mHNPC depic ed a genomic landscape simila o ha
obse ed in single- issue biopsies om la e-s age mCRPC [43]. These findings sugges ha
pa ien s wi h mHNPC migh ha e al eady de eloped many o he ai s associa ed wi h agg es-
si e disease be o e ea men exposu e. Beyond he ype o e en s ha a e obse ed in me as-
a ic p os a e umo s, we can specula e ha he o de in which genomic al e a ions accumula e in
p os a e cells could also play a ole in he de elopmen o his le hal a ian o PCa.
Common gene ic al e a ions in mHNPC and mCRPC include TP53 loss, Speckle- ype POZ p o-
ein (SPOP) mu a ions, al e a ions in cell-cycle o DNA damage epai (DDR) genes, and WNT o
PI3K pa hway mu a ions (summa ized in Table 1). The lack o mu a ions and amplifica ions in he
and ogen ecep o (AR) gene in mHNPC ep esen s a pi o al di e ence when compa ing hese
wo me as a ic o ms o PCa, p esumably because hese mu a ions in mCRPC can p o ide
adap i e esis ance o ADT and AR- a ge ing agen s (ARTAs) [34,39,44,45]. Based on da a
om mCRPC p ecision medicine ials, his genomic p ofile suppo s he in es iga ion o pe son-
alized o molecula ly s a ified ea men in mHNPC ials based on he unique molecula land-
scape o each pa ien [26-28]. Howe e , he acquisi ion o me as a ic p ope ies ex ends
beyond he genomic ea u es o he umo . In his sense, ansc ip ional egula ion, al e na i e
RNA splicing, and ep og amming o he umo mic oen i onmen (TME) a e also impo an con-
ibu ing ac o s, bu ou unde s anding o mHNPC in his ega d is s ill in i s in ancy.
T ansc ip omic cha ac e is ics
The a ailabili y o high- h oughpu molecula da a on mHNPC is p og essi ely inc easing, which
will likely help o gene a e a mo e comp ehensi e molecula po ai o his agg essi e disease.
A p esen , howe e , he da a on hese pa ien s o en o m pa o la ge da ase s o which pa-
ien s wi h mHNPC only cons i u e a small ac ion and clinical anno a ions a e o en subop imal
[46,47]. These pa ien s a e gene ally no s udied as an independen en i y and a e ins ead
g ouped wi h pa ien s in o he clinical s a es o PCa based on common clinical o pa hological
cha ac e is ics, al hough cas a ion esis ance is a majo d i e o PCa e olu ion. Fo ins ance,
an ex ensi e ansc ip omics analysis o spine me as ases ha ocused on he classifica ion o
me as ases wi hin hei Me A-C sub ype sys em included specimens om 15 pa ien s wi h
mHNPC [47], which we e conside ed in he analysis wi hou accoun ing o hei di e en na u e.
Indeed, he s udy epo ed ha hese cases we e en iched in he ADT- esponsi e sub ype, bu i
is unclea how he p esence o mHNPC in his g oup influenced he classifica ion [47]. Ano he
example pe ains o a single-cell RNA sequencing analysis in PCa specimens, h ee o which
we e un ea ed and p esen ed me as asis a he ime o diagnosis, indica i e o de no o ho -
mone-naï e me as a ic disease [46]. Al hough subsequen s udies analyzing his da ase [48–
57] did no accoun o he mHNPC na u e o hese specimens, eanalysis o his da ase
based on pa ien me as a ic s a us enabled he iden ifica ion o dis inc cellula p og ams in
mHNPC [58].
In 2021, ansc ip omic p ofiling o a subse o pa ien s en olled in he CHAARTED clinical ial [40]
e ealed ha mHNPC exhibi s lowe AR ac i i y han non-me as a ic PCa a diagnosis and is
en iched in basal o luminal B sub ypes acco ding o he PAM50 (p edic ion analysis o mic oa ay
50) classifie [40]. Pa ien s wi h mHNPC classified as luminal B benefi ed om ADT plus doce axel
combina ion he apy, while his combined ea men was no o benefi in cases classified as
T ends in Cance
OPEN ACCESS
828 T ends in Cance , Sep embe 2024, Vol. 10, No. 9
Table 1. Genomic al e a ions in mHNPC
a
P ocess/gene Al e a ion Ou come
Genome
s abili y
Few poin mu a ions
[37,38]
La ge-scale genomic
ea angemen s and
CNA [37,38]
Genomic al e a ions in mHNPC may align wi h hose in mCRPC,
despi e conflic ing epo s [27,28,39,41–43,125]
Al e ed genome ac ion co ela es wi h disease olume, no
me as asis ime [34]
He e ogenei y wi hin and be ween di e en umo oci and
me as ases [43]
P os a e may ha e clonally independen cance s, wi h me as ases
con aining dis inc popula ions [43]
AR Lack o AR mu a ions/
amplifica ions [42,43]
AR abe a ions commonly occu in mHNPC pa ien s du ing ADT,
likely signaling he ansi ion o a cas a ion- esis an s age
[26,34,39,44,45,126]
TP53 Loss o TP53 Mos equen gene al e a ion in mHNPC [27,34,39,43,45,125,127]
Ea ly mu a ions in me as a ic pa ien s co ela e wi h he numbe o
me as a ic lesions [39,45,127]
TP53 loss p edic s p og ession- ee su i al and cas a ion
esis ance be e han AR [43,128]
TP53 mu a ions may ou weigh disease olume in ou come
de e mina ion [34,45,127]
Migh ha e a smalle impac on lung opism [129]
SPOP Inac i a ing mu a ions in
SPOP [130]
Highe esponse a es o ho mone he apy [34,131–133]
Simila o highe al e a ion equencies han in mCRPC [39,42,43,129]
Ele a ed SPOP al e a ions in ecu en and HV pa ien s [34,42,45]
Cell cycle RB1 dele ion o loss
CDK12 mu a ions
Al e a ions o cell-cycle genes a e p esen in up o 16% o mHNPC
pa ien s [27,39,41–43,45,127]
Associa ed wi h a sho e ime o cas a ion esis ance and wo se
o e all su i al [34,45,125]
HV pa ien s a e mo e likely o ha e al e a ions in he cell cycle [34,127]
The iming o me as ases shows a ied associa ions in di e en
coho s –some link cell-cycle changes o ecu en pa ien s, o he s o
de no o pa ien s [34,45,127]
RB1 loss is he mos common mu a ion and is linked o wo se o e all
su i al, especially when combined wi h he loss o o he
umo -supp esso genes [27,39,42,45,125,134]
CDK12 mu a ions a e mo e p e alen in de no o pa ien s [34,45]
DNA damage
epai (DDR)
BRCA2 and CDK12
mu a ions a e he mos
common
DDR pa hway al e a ions co ela e wi h PARP inhibi o esponse
[44]
20–27% o mHNPC pa ien s ha e DDR pa hway mu a ions
[39,42–45]
Occu ence o DDR al e a ions is linked o disease olume
[42,45,127]
DDR pa hway al e a ions may has en cas a ion esis ance and
wo sen su i al [27,34]
The e is a consensus ha DDR pa hway al e a ions do no inc ease
wi h cas a ion esis ance, sugges ing po en ial benefi s om PARPi
ea ly in ea men [34,41,44]
Pa ien s wi h ecu ing me as ases in he abdominal nodes, bones, o
isce a, and pa ien s wi h lung me as ases, p esen highe DDR
mu a ion a es [127,129]
Misma ch epai gene al e a ions a e also en iched in lung
me as ases, making hese pa ien s candida es o immune
checkpoin blockade [39,44,129]
WNT pa hway Al e a ions in APC,
CTNNB1, and RNF43
WNT pa hway gene al e a ions occu in 10–20% o pa ien s
[27,39,42,45,135]
WNT pa hway mu a ions a e mo e common in ecu ences and HV
disease [42,45,127]
Repo s conflic on he link be ween WNT pa hway al e a ions and
cas a ion esis ance de elopmen [34,39,45]
WNT pa hway mu a ions a e associa ed wi h isce al and lung
me as ases [127,129,135]
(con inued on nex page)
T ends in Cance OPEN ACCESS
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 829
basal [40]. In e es ingly, al hough he PAM50 classifica ion was able o p edic he benefi o com-
bina ion he apy, classi ying pa ien s acco ding o hei AR ac i i y was unable o do so [40]. An-
o he s udy epo ed ha pa ien s wi h de no o mHNPC p esen lowe AR ac i i y han pa ien s
wi h ecu en me as ases [59]. The CHAARTED pa ien coho was en iched o pa ien s wi h
HV and de no o disease [40], and i emains possible ha he lowe AR signaling le els
de ec ed when compa ing o pa ien s wi h localized PCa we e influenced by he inclusion o
hese pa ien s. The e o e, al hough pa ien s wi h de no o mHNPC exhibi lowe AR ac i i y
han localized o ecu en pa ien s, mo e ailo ed coho s would need o be analyzed o in es i-
ga e he s a us o ecu en mHNPC. I should be no ed ha he a o emen ioned s udy epo ed
an imp o emen in o e all su i al o pa ien s wi h mHNPC and low AR ac i i y ( he de no o
pa ien s in he coho ) when ecei ing ADT plus doce axel, ega dless o hei PAM50 classifica-
ion [59]. A ecen p ep in p esen ed he mos comp ehensi e ansc ip ional landscape o
mHNPC side-by-side wi h localized PCa analyzed a he ime a diagnosis [58], indica ing ha
we will soon ha e a hand addi ional molecula da a ha will suppo a be e molecula decon-
s uc ion o mHNPC, wi h implica ions o he clinical managemen o he disease.
AR splice a ian s
Lowe AR signaling could eflec umo -in insic p ope ies o low and ogen equi emen s, in line
wi h ecen e idence ha poin s o he exis ence o CRPC-like cells in un ea ed localized PCa
[60,61]. Ac i a ing mu a ions o amplifica ions o AR a e ex emely a e in mHNPC. Howe e ,
o he molecula al e a ions ha ende hese umo s insensi i e o AR blockade could play a
ele an ole. Al e na i e splicing o he AR mRNA, leading o he exp ession o he AR-V7 iso o m,
is a mechanism o sus ain ligand-independen AR signaling. The absence o he ligand-binding
domain in AR-V7 ende s he nuclea ecep o ac i e in he absence o and ogens o in he p es-
ence o and ogen signaling pa hway inhibi o s, esul ing in mo e agg essi e disease [62]. Di e en
g oups ha e explo ed he exp ession o AR-V7 in mHNPC, bu wi h disc epan esul s ha high-
ligh he limi a ions in he de ec ion o his iso o m using di e en molecula me hodologies [62–
64]. Because he coho s s udied o da e a e p edominan ly ocused on localized PCa, defini i e
e idence conce ning he equency and abundance o AR-V7 in mHNPC emains o be p o ided.
The umo mic oen i onmen
P e ious esea ch e o s ha e p edominan ly ocused on he genomic aspec s o he umo cell
compa men o mHNPC, limi ing ou knowledge o he mHNPC TME. Only a hand ul o s udies
ha e epo ed a highe abundance o CD163
+
mac ophages in me as a ic umo s [65]o ha e
cha ac e ized highe numbe s o ci cula ing cance -associa ed fib oblas s (cCAFs) in mHNPC
pa ien specimens [66]. In his ega d, a ecen s udy epo ed ha (i) mHNPC me as ases had
mo e immune infil a ion han localized umo s, (ii) immune infil a ion co ela ed wi h esponse
Table 1. (con inued)
P ocess/gene Al e a ion Ou come
PI3K pa hway PTEN inac i a ing
mu a ions
PI3K pa hway gene al e a ions co ela e wi h mo e agg essi e
pheno ype [44,136]
F equencies o PI3K pa hway al e a ions a e compa able in mHNPC
and ad anced PCa [39,42,43,45,125,129]
Recu en cases o en exhibi PI3K pa hway al e a ions [45]
PI3K pa hway al e a ions a e un ela ed o olume and p ognosis [45]
PTEN is commonly mu a ed in mHNPC and has been associa ed
wi h wo se p ognosis, especially in combina ion wi h he loss o o he
umo -supp esso genes [39,41–43,45,125]
a
Abb e ia ions: ADT, and ogen dep i a ion he apy; AR, and ogen ecep o ; CNA, copy-numbe al e a ion; HV, high olume
disease; mCRPC, me as a ic cas a ion- esis an p os a e cance ; mHNPC, me as a ic ho mone naï e p os a e cance ;
PARPi, PARP inhibi o ; PCa, p os a e cance .
T ends in Cance
OPEN ACCESS
830 T ends in Cance , Sep embe 2024, Vol. 10, No. 9
o he apy, (iii) immune infil a ion a ied depending on he localiza ion o he me as ases, (i ) ADT
and an i-p og ammed cell dea h p o ein 1 (an i-PD-1) combina ion he apy caused an expansion
o CD8
+
T cells in me as asis si es, and ( ) epi helial cell subclus e abundance changed a e
ea men [67]. This s udy alone sugges s ha he mHNPC TME migh di e significan ly om
ha o localized umo s, and ha he e a e al e a ions in immune infil a ion a e ADT be ween
he wo clinical s a es [67]. In addi ion, i sugges s ha pa ien s wi h mHNPC could benefi
om an ADT plus immune checkpoin blockade he apy. Repo ed [46] and upcoming [58] sin-
gle-cell RNA sequencing da a will shed ligh on he quali a i e and quan i a i e al e a ions in he
TME o his agg essi e disease.
Loco egional PCa as a p oxy o mHNPC
In he absence o mo e ex ensi e molecula analysis o mHNPC, loco egional PCa ( umo s wi h
coloniza ion o pel ic lymph nodes) can shed ligh on he molecula p ocesses ha unde lie he
acquisi ion o me as a ic capaci y in PCa, such as DNA me hyla ion changes ha occu in pa allel
o copy-numbe al e a ions ac oss he clonal e olu ion o PCa [68]. In line wi h his no ion, an-
sc ip omic analysis highligh ed he ac i a ion o oxida i e phospho yla ion in lymph node me as-
ases [69], oge he wi h gene exp ession-based p ognos ic models in his disease [70]. Single-
cell ansc ip omic s udies o lymph node me as ases and LNCaP cells (a ho mone-sensi i e
cell line de i ed om hese lesions) concluded ha (i) MYC plays an impo an ole in me as a ic
p og ession, (ii) he TME a he me as a ic si es is mo e immunosupp essi e, and (iii) ea men
esis ance is linked o changes in ch oma in accessibili y [60,71]. Howe e , i should be no ed
ha he p ognosis o pa ien s wi h loco egional PCa is be e han o mHNPC [72], and ha
hese lymph node me as ases migh only ecapi ula e a ac ion o he p ocesses al e ed in
umo s wi h hese clinical ea u es.
Expe imen al modeling o mHNPC
Expe imen al sys ems a e essen ial o p o ide causal e idence o he al e a ions ha suppo and
d i e mHNPC pa hogenesis, and o es he e ficacy o po en ial he apeu ic s a egies. The lim-
i ed esea ch ega ding his PCa se ing and he accumula ed clinical and molecula e idence
in ecen yea s imply ha i is now a c ucial momen o define and design models o mHNPC.
Pa ien -de i ed xenog a ing (PDX) ep esen s an a ac i e s a egy o s udy umo s in an indi id-
ualized manne because hey ai h ully ecapi ula e he umo a chi ec u e and he e ogenei y o
each pa ien . Howe e , xenog a s a e di ficul o es ablish, and he lack o a compe en immune
sys em migh pose limi a ions when ansla ing he esul s o a clinical se ing.
Ho mone-sensi i e PDX umo s ha e been es ablished o e he pas decades. The LuCaP se ies
was gene a ed in he 1990s, and cu en ly comp ises >30 di e en PDX models and hei de i ed
o ganoids [73,74]. These models and se e al o he s a e de i ed om me as a ic samples and
e ain and ogen sensi i i y ega dless o whe he hey come om ea ed [74,75] o un ea ed
pa ien s [74,76]. In addi ion, in he Melbou ne U ological Resea ch Alliance (MURAL) and MD An-
de son Cance Cen e (MDA) collec ions, some o he la ges se ies o PCa PDX models, a mino
ac ion o he biopsies ha gene a ed he PDX models we e om ho mone-sensi i e me as a ic
cases [77,78]. Al hough hese models a e a good s a ing poin o mHNPC esea ch, u he e -
o s will be necessa y o es ablish new PDX models ha ecapi ula e he biology o me as a ic
disease in ho mone-naï e condi ions.
O he expe imen al PCa models e ain specific cha ac e is ics o mHNPC o labo a o y esea ch
and/o o e come some o he limi a ions o PDX models (Table 2). Cell lines a e he mos simpli-
fied model o s udying cance and a e a powe ul ool o unde s and specific aspec s o he
disease. Howe e , he in i o me as a ic capaci y o PCa cell lines is limi ed when hey e ain
T ends in Cance OPEN ACCESS
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 831
Table 2. Summa y o expe imen al models o s udying mHNPC
a
Model P os Cons Name O igin AR sensi i i y Me as a ic capaci y
Cell lines Simple model
Easy o manipula e
Replicable
Able o be
in eg a ed in o a
mo e complex
model (e.g.,
xenog a ing)
Lack he e ogenei y
Lack 3D o ganiza ion
No in eg a ed in o a
complex sys em by
de aul
Low me as a ic
po en ial ha
inc eases as AR
sensi i i y dec eases
LNCaP
[79]
Lymph node me Yes No
C4-2 [85] De i ed om
LNCaP
Yes, bu lowe han
pa en al LNCaP
LN/bones (OR) [84,86]
LAPC-4
[80]
Lymph node me Yes Mic ome as asis in
hema opoie ic issue
(SC) [80]
VCaP [81] Lumba me Yes (al hough de i ed
om a ho mone- e ac o y
pa ien ) [81]
Mic ome as asis in lung
(SC) [82]
LN (OR) [83]
Pa ien -de i ed
xenog a s
(PDX)
Recapi ula e umo
a chi ec u e
Re ain
he e ogenei y
In eg a ed in o a
complex model
whe e hey ecei e
sys emic inpu
Di ficul o es ablish
High main enance
No immune
compa men
LuCaP
se ies
(>30
PDXs)
[73,74]
Samples om
me si es
Some (mos ly come om
ea ed pa ien s)
Lungs (IT) [137]
LN/lungs (OR) [138]
O he
PDXs
(BM18,
LAPC9,
MURAL,
MDA)
[75–78]
Samples om
me si es
Yes (some come om
un ea ed pa ien s)
[76–78]
Un es ed
Gene ically
enginee ed
mouse models
(GEMMs)
Allow he s udy o
he e olu ion o
PCa ( om no mal
p os a e o
me as a ic umo )
Bes model o
s udy he ole o
he immune
compa men
High main enance
Lack he genomic
he e ogenei y seen
in pa ien s
Gene ic al e a ions
pe o med o
es ablish GEMMs
may no be p e alen
in he diseased
popula ion
Me as a ic po en ial
o en inc eases as
AR sensi i i y
dec eases [106–109]
TRAMP
[100]
In oduc ion o
p os a e-specific
SV40L
Yes LN (low pene ance;
highe me as a ic
po en ial a e NE
di e en ia ion) [101]
P en [103] Induced P en
loss (+ o he
op ional
mu a ions)
P en loss: yes [103]P en
loss + TP53 loss: no
[95,98,99]P en loss +
MAPK pa hway ac i a ion:
no [90,97]P en
loss + Lkb1 loss: yes, bu
lowe [93]P en loss +
Pgc1a loss: yes [102]
P en loss + K as
ac i a ion: no [91]
P en loss: LN (low
dissemina ion) [103]
P en loss + Tp53 loss:
isce al me s (when
p og essed o CRPC)
[99]
P en loss + MAPK
pa hway ac i a ion:
LN/bone/lungs [90,97]
P en loss + Lkb1 loss:
LN/lungs [93]P en
loss + Pgc1a loss: LN
me s/bone mic ome s
[102]P en loss + K as
ac i a ion:
lung/li e /bones
[91,92,96]
Myc Induced Myc
o e exp ession
[104]
Yes Myc o e exp ession
GEMM: no [104]
Allog a cell line de i ed
om Myc
o e exp ession GEMM:
bone (IC) [105]
Myc o e exp ession +
P en loss:
li e /lung/bone [91,106]
a
Abb e ia ions: AR, and ogen ecep o ; CRPC, cas a ion- esis an p os a e cance ; GEMM, gene ically enginee ed mouse model; IC, in aca diac injec ion; IT, in a ibial
injec ion; LN, lymph node; me , me as asis; NE, neu oendoc ine; OR, o ho opic injec ion; PDX, pa ien -de i ed xenog a ; SC, subcu aneous injec ion; TRAMP, ansgenic
adenoca cinoma mouse p os a e model.
T ends in Cance
OPEN ACCESS
832 T ends in Cance , Sep embe 2024, Vol. 10, No. 9
and ogen sensi i i y. Comme cially a ailable and ogen-sensi i e cell lines (e.g., LNCaP, LAPC-4,
and VCaP) exhibi limi ed dissemina ion capaci y, mos ly es ic ed o lymph nodes [79–83], and
gain mo e p onounced me as a ic po en ial as hey acqui e and ogen-independen p ope ies
[84–86]. Gene ically enginee ed mouse models (GEMMs) o e ad an ages and limi a ions com-
pa ed o cell lines and PDX. GEMMs enable he na u al e olu ion o PCa o be s udied om pa h-
ogenesis o dissemina ion in immunocompe en en i onmen s. Howe e , as occu s in humans,
agg essi e mu ine models wi h me as a ic capabili ies a e o en accompanied by he de elop-
men o cas a ion esis ance, e en in unchallenged condi ions [87–99]. In line wi h his no ion,
he me as a ic po en ial o ho mone-sensi i e mouse models, such as he ansgenic adenoca -
cinoma mouse p os a e (TRAMP) model, is only inc eased o clinically ele an le els a e de el-
oping cas a ion esis ance [100,101]. O he cu en ly a ailable GEMMs wi h me as a ic capaci y
ha e ain and ogen sensi i i y a e based on he loss o umo supp esso P en [102,103] o he
o e exp ession o p o o-oncogene Myc [104,105]. The combina ion o bo h al e a ions esul s in
me as asis o he li e , lungs, and bones while e aining sensi i i y o cas a ion [91,106].
In conclusion, expe imen al models con inue o be indispensable ools in ad ancing ou unde -
s anding o mHNPC, bu hey p esen significan challenges. As esea ch p og esses, efining
and e hinking expe imen al models o mHNPC will boos ou knowledge o his agg essi e
disease and enhance hei u ili y in guiding he apeu ic s a egies.
Cu en ea men s and clinical ials
ADT alone was he s anda d o ca e o mHNPC un il 2015. The he apeu ic landscape o
mHNPC has apidly e ol ed in ecen yea s, ma ked by new da a om landma k ials ha en-
do se he in ensifica ion o up on ea men . These ad ances ex end beyond sys emic agen s
and encompass inno a ions in ea ing p ima y umo s and me as ases. A summa y o he key
clinical ials in he pas decade can be ound in Table 3.
Ini ial ials wi h doce axel, such as GETUG-AFU15 [30,31], did no show clea su i al ad an ages,
bu subsequen s udies such as CHAARTED [33,36] and STAMPEDE a m C [107] demons a ed
benefi s o adding chemo he apy o ADT, pa icula ly in pa ien s wi h HV disease. Mo eo e , he im-
plemen a ion o ARTA, including abi a e one ace a e and he AR inhibi o s apalu amide,
da olu amide, and enzalu amide, has shown significan su i al ad an ages in a ious ials such
as LATITUDE [32], STAMPEDE a m G [108], ENZAMET [109], ARCHES [110,111], and TITAN
[112]. Recen ials such as ARASENS [113] and PEACE [114] highligh he po en ial benefi s o
ea men in ensifica ion by combining chemo he apy and AR pa hway inhibi o s.
The ole o adio he apy o he p ima y umo in pa ien s wi h mHNPC emains a subjec o
deba e, and ials such as HORRAD [115] and STAMPEDE A m-H [116] ha e shown a ied ou -
comes depending on disease olume. Al hough STAMPEDE A m-H da a suppo he use o a-
dio he apy in addi ion o ADT in pa ien s wi h LV mHNPC, hese da a we e gene a ed be o e he
widesp ead use o ARTA in mHNPC. Recen da a om he PEACE-1 s udy sugges ha he clin-
ical benefi o adding adio he apy o ADT combined wi h ARTA is modes a mos , and u u e e-
sea ch should elucida e which pa ien s wi h mHNPC could benefi om adio he apy when also
ecei ing ADT and ARTA [114,117].
Refining he c i e ia o ea men selec ion emains a challenge because o he lack o alida ed
bioma ke s. Al hough he use o a leas one AR- a ge ing d ug seems o be uni e sally indica ed,
ques ions a ise conce ning he indica ion o doce axel and adio he apy o pa icula pa ien s
[33,36,113–116]. Mo eo e , u he unde s anding o he biological e ec s o in ensified he apy
on cance e olu ion, subclonal selec ion, and he de elopmen o esis ance could enable he
T ends in Cance OPEN ACCESS
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 833
72. Rebello, R.J. e al. (2021) P os a e cance . Na . Re . Dis.
P ime s 7, 9
73. Ellis, W.J. e al. (1996) Cha ac e iza ion o a no el and ogen-
sensi i e, p os a e-specific an igen-p oducing p os a ic ca ci-
noma xenog a : LuCaP 23. Clin. Cance Res. 2, 1039–1048
74. Nguyen, H.M. e al. (2017) LuCaP p os a e cance pa ien -de-
i ed xenog a s eflec he molecula he e ogenei y o ad-
anced disease and se e as models o e alua ing cance
he apeu ics. P os a e 77, 654–671
75. McCulloch, D.R. e al. (2005) BM18: a no el and ogen-
dependen human p os a e cance xenog a model de i ed
om a bone me as asis. P os a e 65, 35–43
76. Ka kampouna, S. e al. (2021) Pa ien -de i ed xenog a s and
o ganoids model he apy esponse in p os a e cance . Na .
Commun. 12, 1117
77. Anselmino, N. e al. (2024) In eg a i e molecula analyses o he
MD Ande son p os a e cance pa ien -de i ed xenog a (MDA
PCa PDX) se ies. Clin. Cance Res. 30, 2272–2285
78. Risb idge , G.P. e al. (2021) The MURAL collec ion o p os a e
cance pa ien -de i ed xenog a s enables disco e y h ough
p eclinical models o u o-oncology. Na . Commun. 12, 5049
79. Ho oszewicz, J.S. e al. (1983) LNCaP model o human
p os a ic ca cinoma. Cance Res. 43, 1809–1818
80. Klein, K.A. e al. (1997) P og ession o me as a ic human p os-
a e cance o and ogen independence in immunodeficien
SCID mice. Na . Med. 3, 402–408
81. Ko enchuk, S. e al. (2001) VCaP, a cell-based model sys em o
human p os a e cance . In Vi o 15, 163–168
82. Lange, T. e al. (2020) Xenog a -de i ed mRNA/miR and p o-
ein in e ac ion ne wo ks o sys emic dissemina ion in human
p os a e cance . Eu . J. Cance 137, 93–107
83. Linxweile , J. e al. (2018) A no el mouse model o human p os-
a e cance o s udy in ap os a ic umo g ow h and he de el-
opmen o lymph node me as ases. P os a e 78, 664–675
84. McGo e n, J.A. e al. (2021) A humanized o ho opic umo
mic oen i onmen al e s he bone me as a ic opism o p os-
a e cance cells. Commun. Biol. 4, 1014
85. Thalmann, G.N. e al. (1994) And ogen-independen cance
p og ession and bone me as asis in he LNCaP model o
human p os a e cance . Cance Res. 54, 2577–2581
86. Zang, G. e al. (2019) PKCze a acili a es lympha ic me as a ic
sp ead o p os a e cance cells in a mice xenog a model.
Oncogene 38, 4215–4231
87. Ga abedian, E.M. e al. (1998) A ansgenic mouse model o
me as a ic p os a e cance o igina ing om neu oendoc ine
cells. P oc. Na l. Acad. Sci. U. S. A. 95, 15382–15387
88. Masumo i, N. e al. (2001) A p obasin-la ge T an igen ans-
genic mouse line de elops p os a e adenoca cinoma and neu-
oendoc ine ca cinoma wi h me as a ic po en ial. Cance Res.
61, 2239–2249
89. Pe ez-S able, C. e al. (1997) P os a e cance p og ession,
me as asis, and gene exp ession in ansgenic mice. Cance
Res. 57, 900–906
90. Aba e-Shen, C. e al. (2003) Nkx3.1; P en mu an mice de elop
in asi e p os a e adenoca cinoma and lymph node me as ases.
Cance Res. 63, 3886–3890
91. A iaga, J.M. e al. (2020) A MYC and RAS co-ac i a ion signa-
u e in localized p os a e cance d i es bone me as asis and
cas a ion esis ance. Na . Cance 1, 1082–1096
92. Ay es , A. e al. (2013) ETV4 p omo es me as asis in esponse
o ac i a ion o PI3-kinase and Ras signaling in a
mouse model o ad anced p os a e cance . P oc. Na l. Acad.
Sci. U. S. A. 110, E3506–E3515
93. He mano a, I. e al. (2020) Gene ic manipula ion o LKB1
elici s le hal me as a ic p os a e cance . J. Exp. Med. 217,
e20191787
94. Ku, S.Y. e al. (2017) Rb1 and T p53 coope a e o supp ess
p os a e cance lineage plas ici y, me as asis, and an iand ogen
esis ance. Science 355, 78–83
95. Luna di, A. e al. (2013) A co-clinical app oach iden ifies mech-
anisms and po en ial he apies o and ogen dep i a ion esis-
ance in p os a e cance . Na . Gene . 45, 747–755
96. Mulholland, D.J. e al. (2012) P en loss and RAS/MAPK
ac i a ion coope a e o p omo e EMT and me as asis ini ia ed
om p os a e cance s em/p ogeni o cells. Cance Res. 72,
1878–1889
97. Wang, J. e al. (2012) B-Ra ac i a ion coope a es wi h PTEN
loss o d i e c-Myc exp ession in ad anced p os a e cance .
Cance Res. 72, 4765–4776
98. Yende, A.S. e al. (2023) TRIM28 p omo es luminal cell plas ici y
in a mouse model o p os a e cance . Oncogene 42,
1347–1359
99. Zou, M. e al. (2017) T ansdi e en ia ion as a mechanism o
ea men esis ance in a mouse model o cas a ion- esis an
p os a e cance . Cance Disco . 7, 736–749
100. G eenbe g, N.M. e al. (1995) P os a e cance in a ansgenic
mouse. P oc. Na l. Acad. Sci. U. S. A. 92, 3439–3443
101. Kaplan-Le ko, P.J. e al. (2003) Pa hobiology o au och honous
p os a e cance in a p e-clinical ansgenic mouse model.
P os a e 55, 219–237
102. To ano, V. e al. (2016) The me abolic co- egula o PGC1alpha sup-
p esses p os a e cance me as asis. Na . Cell Biol. 18, 645–656
103. Wang, S. e al. (2003) P os a e-specific dele ion o he mu ine
P en umo supp esso gene leads o me as a ic p os a e
cance . Cance Cell 4, 209–221
104. Ellwood-Yen, K. e al. (2003) Myc-d i en mu ine p os a e
cance sha es molecula ea u es wi h human p os a e umo s.
Cance Cell 4, 223–238
105. Simons, B.W. e al. (2019) A mouse model o p os a e cance
bone me as asis in a syngeneic immunocompe en hos .
Onco a ge 10, 6845–6854
106. Hubba d, G.K. e al. (2016) Combined MYC ac i a ion and
P en loss a e su ficien o c ea e genomic ins abili y and le hal
me as a ic p os a e cance . Cance Res. 76, 283–292
107. Cla ke, N.W. e al. (2019) Addi ion o doce axel o ho monal
he apy in low- and high-bu den me as a ic ho mone sensi i e
p os a e cance : long- e m su i al esul s om he STAMPEDE
ial. Ann. Oncol. 30, 1992–2003
108. James, N.D. e al. (2022) Abi a e one ace a e plus p ednisolone
o me as a ic pa ien s s a ing ho mone he apy: 5-yea ollow-up
esul s om he STAMPEDE andomised ial (NCT00268476).
In . J. Cance 151, 422–434
109. Da is, I.D. e al. (2019) Enzalu amide wi h s anda d fi s -line
he apy in me as a ic p os a e cance . N.Engl.J.Med.381,
121–131
110. A ms ong, A.J. e al. (2022) Imp o ed su i al wi h enzalu a-
mide in pa ien s wi h me as a ic ho mone-sensi i e p os a e
cance . J. Clin. Oncol. 40, 1616–1622
111. A ms ong, A.J. e al. (2019) ARCHES: a andomized, phase III
s udy o and ogen dep i a ion he apy wi h enzalu amide o
placebo in men wi h me as a ic ho mone-sensi i e p os a e
cance . J. Clin. Oncol. 37, 2974–2986
112. Chi, K.N. e al. (2021) Apalu amide in pa ien s wi h me as a ic
cas a ion-sensi i e p os a e cance : final su i al analysis o
he andomized, double-blind, phase III TITAN s udy. J. Clin.
Oncol. 39, 2294–2303
113. Smi h, M.R. e al. (2022) Da olu amide and su i al in me as a-
ic, ho mone-sensi i e p os a e cance . N. Engl. J. Med. 386,
1132–1142
114. Fizazi, K. e al. (2022) Abi a e one plus p ednisone added o an-
d ogen dep i a ion he apy and doce axel in de no o me as a ic
cas a ion-sensi i e p os a e cance (PEACE-1): a mul icen e,
open-label, andomised, phase 3 s udy wi h a 2 × 2 ac o ial
design. Lance 399, 1695–1707
115. Boe e, L.M.S. e al. (2019) E ec on su i al o and o-
gen dep i a ion he apy alone compa ed o and ogen
dep i a ion he apy combined wi h concu en adia ion
he apy o he p os a e in pa ien s wi h p ima y bone
me as a ic p os a e cance in a p ospec i e andomised
clinical ial: da a om he HORRAD ial. Eu . U ol. 75,
410–418
116. Pa ke , C.C. e al. (2018) Radio he apy o he p ima y umou
o newly diagnosed, me as a ic p os a e cance (STAMPEDE):
a andomised con olled phase 3 ial. Lance 392, 2353–2366
117. Bossi, A. e al. (2023) P os a e i adia ion in men wi h de no o,
low- olume, me as a ic, cas a ion-sensi i e p os a e cance
(mCSPC): esul s o PEACE-1, a phase 3 andomized ial
wi h a 2×2 design. J. Clin. Oncol. 41, LBA5000
T ends in Cance
OPEN ACCESS
840 T ends in Cance , Sep embe 2024, Vol. 10, No. 9
118. S ul z, J. and Fong, L. (2021) How o u n up he hea on he
cold immune mic oen i onmen o me as a ic p os a e cance .
P os a e Cance P os a ic Dis. 24, 697–717
119. Bishop, J.L. e al. (2015) PD-L1 is highly exp essed in enzalu a-
mide esis an p os a e cance . Onco a ge 6, 234–242
120. G a , J.N. e al. (2020) A phase II single-a m s udy o pemb o-
lizumab wi h enzalu amide in men wi h me as a ic cas a ion-
esis an p os a e cance p og essing on enzalu amide alone.
J. Immuno he . Cance 8, e000642
121. Lin, H. e al. (2021) Pemb olizumab wi h o wi hou enzalu a-
mide in selec ed popula ions o men wi h p e iously un ea ed
me as a ic cas a ion- esis an p os a e cance ha bou ing p o-
g ammed cell dea h ligand-1 s aining: a e ospec i e s udy.
BMC Cance 21, 399
122. G a zke, C. e al. (2023) KEYNOTE-991: pemb olizumab plus
enzalu amide and and ogen dep i a ion o me as a ic ho mone-
sensi i e p os a e cance . Fu u e Oncol. 18, 4079–4087
123. G a zke, C.J. e al. (2023) 1772MO pemb olizumab
(pemb o) plus enzalu amide (enza) and and ogen dep i a-
ion he apy (ADT) o pa ien s (p s) wi h me as a ic
ho mone-sensi i e p os a e cance (mHSPC): andomized
double-blind phase III KEYNOTE-991 s udy. Ann. Oncol.
34, S957–S958
124. Gao, J. e al. (2017) VISTA is an inhibi o y immune checkpoin
ha is inc eased a e ipilimumab he apy in pa ien s wi h p os-
a e cance . Na . Med. 23, 551–555
125. Hamid, A.A. e al. (2019) Compound genomic al e a ions
o TP53, PTEN, and RB1 umo supp esso s in localized and
me as a ic p os a e cance . Eu . U ol. 76, 89–97
126. Je nbe g, E. e al. (2017) Clinical ele ance o and ogen ecep o
al e a ions in p os a e cance . Endoc . Connec . 6, R146–R161
127. Deek, M.P. e al. (2021) The mu a ional landscape o me as a ic
cas a ion-sensi i e p os a e cance : he spec um heo y
e isi ed. Eu . U ol. 80, 632–640
128. De Lae e, B. e al. (2019) TP53 ou pe o ms o he and ogen
ecep o bioma ke s o p edic abi a e one o enzalu amide
ou come in me as a ic cas a ion- esis an p os a e cance .
Clin. Cance Res. 25, 1766–1773
129. Shende o , E. e al. (2019) Genomic and clinical cha ac e iza-
ion o pulmona y-only me as a ic p os a e cance : a unique
molecula sub ype. P os a e 79, 1572–1579
130. Ba bie i, C.E. e al. (2012) Exome sequencing iden ifies ecu -
en SPOP, FOXA1 and MED12 mu a ions in p os a e cance .
Na . Gene . 44, 685–689
131. An, J. e al. (2014) Des uc ion o ull-leng h and ogen ecep o
by wild- ype SPOP, bu no p os a e-cance -associa ed
mu an s. Cell Rep. 6, 657–669
132. Boysen, G. e al. (2018) SPOP-mu a ed/CHD1-dele ed le hal
p os a e cance and abi a e one sensi i i y. Clin. Cance Res.
24, 5585–5593
133. Swami, U. e al. (2020) Associa ion o SPOP mu a ions wi h
ou comes in men wi h de no o me as a ic cas a ion-sensi i e
p os a e cance . Eu . U ol. 78, 652–656
134. Nyquis , M.D. e al. (2020) Combined TP53 and RB1 loss p o-
mo es p os a e cance esis ance o a spec um o he apeu ics
and con e s ulne abili y o eplica ion s ess. Cell Rep. 31,
107669
135. Su e a, P. e al. (2023) WNT pa hway mu a ions in
me ach onous oligome as a ic cas a ion-sensi i e p os-
a e cance . In . J. Radia . Oncol. Biol. Phys. 115,
1095–1101
136. Sho ning, B.Y. e al. (2020) The PI3K–AKT–mTOR pa hway
and p os a e cance : a he c oss oads o AR, MAPK, and
WNT signaling. In . J. Mol. Sci. 21, 4507
137. Val a, M.P. e al. (2016) Sphe oid cul u e o LuCaP 136
pa ien -de i ed xenog a enables e sa ile p eclinical
models o p os a e cance . Clin.Exp.Me as asis33,
325–337
138. Linxweile , J. e al. (2020) Cance -associa ed fib oblas s
s imula e p ima y umo g ow h and me as a ic sp ead in an
o ho opic p os a e cance xenog a model. Sci. Rep. 10,
12575
T ends in Cance OPEN ACCESS
T ends in Cance , Sep embe 2024, Vol. 10, No. 9 841
