Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017

Pla inum P io i y – P os a e Cance Edi o ial by Megan E.V. Ca am and Da id C. Mille on pp. 212–214 o his issue Managemen o Pa ien s wi h Ad anced P os a e Cance : The Repo o he Ad anced P os a e Cance Consensus Con e ence APCCC 2017 Silke Gillessen a [25_TD$DIFF] , *, Ge ha d A a d b , Tomasz M. Bee c , Himisha Bel an d , Albe o Bossi e , Rob B is ow , B e Ca e g , Daniel Cas ellano h , Byung Ha Chung i , Noel Cla ke j , Gedske Daugaa d k , Ian D. Da is l , Johann de Bono b , Rodol o Bo ges dos Reis m , Cha les G. D ake n , Ros Eeles o , Eleni E s a hiou p , Ch is ophe P. E ans q , S e ano Fan i , Felix Feng s , Ka im Fizazi , Ma k F ydenbe g u , Ma in Glea e , Susan Halabi w , Axel Heiden eich x , Celes ia S. Higano y , Nicolas James z , Philip Kan o aa , Pi kko-Liisa Kellokumpu-Leh inen bb , Raja B. Khauli cc , Ge o K ame dd , Ch is Logo he is ee , Fe nando Malu , Alicia K. Mo gans gg , Michael J. Mo is hh , Nicolas Mo e ii , Vedang Mu hy jj , William Oh kk , Pie Os ll , Anwa R. Padhani mm , Ch is Pa ke nn , Colin C. P i cha d oo , Mack Roach s , Ma k A. Rubin pp , Cha les Ryan qq , F ed Saad , Oli e Sa o ss , Howa d Sche , A ishay Sella uu , Neal Sho e , Ma hew Smi h ww , Howa d Soule xx , Co a N. S e nbe g yy , Hi oyoshi Suzuki zz , Ch is ophe Sweeney aaa , Ma hew R. Sydes bbb , Ian Tannock ccc , Be and Tombal ddd , Ricca do Valdagni eee , Thomas Wiegel , Au elius Omlin a a Depa men o Medical Oncology, Can onal Hospi al S . Gallen and Uni e si y o Be ne, Swi ze land; b Depa men o Medical Oncology, The Ins i u e o Cance Resea ch/Royal Ma sden, London, UK; c O egon Heal h & Science Uni e si y Knigh Cance Ins i u e, OR, USA; d Depa men o Medical Oncology, Weill Co nell Medicine, New Yo k, NY, USA; e Depa men o Radia ion Oncology, Geni o U ina y Oncology, P os a e B achy he apy Uni , Gous a e Roussy, Pa is, F ance; Depa men o Radia ion Oncology, P incess Ma ga e Cance Cen e and Uni e si y o To on o, To on o, ON, USA; g Depa men o U ology, Sidney Kimmel Cen e o P os a e and U ologic Cance s, New Yo k, NY, USA; h [3_TD$DIFF]Depa men o Medical Oncology, Hospi al Uni e si a io 12 de Oc ub e, Mad id, Spain; i Depa men o U ology, Gangnam Se e ance Hospi al, Yonsei Uni e si y Heal h Sys em, Seoul, Ko ea; j Depa men o U ology, The Ch is ie and Sal o d Royal Hospi als, Manches e , UK; k Depa men o Medical Oncology, Copenhagen Uni e si y Hospi al, Rigshospi ale , Copenhagen, Denma k; l Monash Uni e si y and Eas e n Heal h, Eas e n Heal h Clinical School, Box Hill, Aus alia; m Depa men o U ology, Ribei a ˜o P e o Medical School, Uni e si y o Sa ˜o Paulo, Sa ˜o Paulo, B azil; n Depa men o Medical Oncology, Di ision o Haema ology/Oncology, Columbia Uni e si y Medical Cen e , New Yo k, NY, USA; o Depa men o Clinical Oncology and Gene ics, The Ins i u e o Cance Resea ch and Royal Ma sden NHS Founda ion T us , London, UK; p Depa men o Medical Oncology, Uni e si y o Texas MD Ande son Cance Cen e , TX, USA; q Depa men o U ology, Uni e si y o Cali o nia, Da is School o Medicine, CA, USA; Depa men o Nuclea Medicine, Policlinico S. O sola, Uni e si a `di Bologna, I aly; s Depa men o Radia ion Oncology, Uni e si y o Cali o nia, San F ancisco, CA, USA; Depa men o Medical Oncology, Gus a e Roussy, Uni e si y o Pa is Sud, Pa is, F ance; u Depa men o Su ge y, Depa men o Ana omy and De elopmen al Biology, Facul y o Medicine, Nu sing and Heal h Sciences, Monash Uni e si y; Depa men o U ology, Vancou e P os a e Cen e, Uni e si y o B i ish Columbia, Vancou e , BC, Canada; w Depa men o Clinical ials and S a is ics, Duke Uni e si y, Du ham, NC, USA; x Depa men o U ology, Uni e si y Hospi al Ko ¨ln, Ko ¨ln, Ge many; y Depa men o Medicine, Di ision o Medical Oncology, Uni e si y o Washing on and F ed Hu chinson Cance Resea ch Cen e , WA, USA; z Depa men o Clinical Oncology, Clinical Oncology Queen Elizabe h Hospi al Bi mingham and[4_TD$DIFF] Uni e si y o Bi mingham, Bi mingham, UK; aa Depa men o Medical Oncology, Memo ial Sloan Ke e ing Cance Cen e and Weill Co nell Medical College, New Yo k, NY, USA; bb Depa men o Clinical Oncology, Tampe e Uni e si y Hospi al, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Finland; cc Depa men o U ology, Ame ican Uni e si y o Bei u Medical Cen e , Bei u , Lebanon; dd Depa men o U ology, Medical Uni e si y o EUROPEAN UROLOGY 73 (2018) 178–211 a ailable a www.sciencedi ec .com jou nal homepage: www.eu opeanu ology.com *Co esponding au ho . Can onal Hospi al S . Gallen, Ro schache s asse 95, 9007 S . Gallen, Swi ze land. Tel. +41 71 494 11 11; Fax: +41 71 494 63 25. E-mail add ess: [email p o ec ed] (S. Gillessen). h p://dx.doi.o g/10.1016/j.eu u o.2017.06.002 0302-2838/#2017 Eu opean Associa ion o U ology. Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Vienna, Vienna, Aus ia; ee [3_TD$DIFF]Depa men o Geni ou ina y Medical Oncology, MD Ande son Cance Cen e, Hous on, TX, USA; Depa men o Medical Oncology Hospi al Is aeli a Albe Eins ein and Depa men o Medical Oncology Bene ice ˆncia Po uguesa de Sa ˜o Paulo; gg Depa men o Medical Oncology and Epidemiology, Vande bil Uni e si y Medical Cen e , Di ision o Hema ology/Oncology, Nash ille, TN, USA; hh Depa men o Medical Oncology, Memo ial Sloan Ke e ing Cance Cen e , New Yo k, NY, USA; ii Depa men o U ology, Uni e si y Hospi al No d S . E ienne, S . E ienne, F ance; jj Depa men o Radia ion Oncology, Ta a Memo ial Cen e, Mumbai, India; kk Depa men o Medical Oncology, Di ision o Hema ology and Medical Oncology, Icahn School o Medicine a Moun Sinai, The Tisch Cance Ins i u e, New Yo k, NY, USA; ll Depa men o Radia ion Oncology, Ghen Uni e si y Hospi al, Ghen , Belgium; mm Depa men o Radiology, Moun Ve non Cance Cen e and Ins i u e o Cance Resea ch, London, UK; nn Depa men o Clinical Oncology, Royal Ma sden [26_TD$DIFF]NHS Founda ion T us , Su on, UK; oo Depa men o Pa hology, Uni e si y o Washing on, WA, USA; pp Depa men o Pa hology, Uni e si y o Be n and he Inselspi al, Be n (CH); qq Depa men o Medical Oncology, Clinical Medicine and U ology a he Helen Dille Family Comp ehensi e Cance Cen e a he Uni e si y o , Cali o nia, San F ancisco, CA, USA; Depa men o U ology, Cen e Hospi alie de l’Uni e si e ´de Mon e ´al, Mon eal, QC, Canada; ss Depa men o Medical Oncology, Tulane Cance Cen e , New O leans, LA, USA; Depa men o Medical Oncology, Geni ou ina y Oncology Se ice, Memo ial Sloan Ke e ing Cance Cen e, New Yo k, NY, USA; uu Depa men o Medical Oncology, Depa men o Oncology, Assa Ha o eh Medical Cen e, Tel-A i Uni e si y, Sackle School o Medicine, Ze i in, Is ael; Depa men o U ology, Ca olina U ologic Resea ch Cen e , My le Beach, SC, USA; ww Depa men o Medical Oncology, Massachuse s Gene al Hospi al Cance Cen e, Bos on, MA, USA; xx [7_TD$DIFF]P os a e Cance Founda ion, San a Monica, CA, USA; yy Depa men o Medical Oncology, San Camillo Fo lanini Hospi al, Rome, I aly; zz Depa men o U ology, Toho Uni e si y Saku a Medical Cen e , Japan; aaa Depa men o Medical Oncology, Dana-Fa be Cance Ins i u e and B igham and Women’s Hospi al, Ha a d Medical School, Bos on, MA, USA; bbb MRC Clinical T ials Uni a UCL, Ins i u e o Clinical T ials and Me hodology, Uni e si y College London, London, UK; ccc Depa men o Medical Oncology, P incess Ma ga e Cance Cen e and Uni e si y o To on o, To on o, ON, Canada; ddd Depa men o U ology, Cliniques Uni e si ai es Sain Luc, B ussels, Belgium; eee Depa men o Oncology and Haema o-oncology, Uni e si a `degli S udi di Milano. Radia ion Oncology 1, P os a e Cance P og am, Fondazione IRCCS Is i u o Nazionale dei Tumo i, Milan, I aly; Depa men o Radia ion Oncology, Klinik u ¨ S ahlen he apie und Radioonkologie des Uni e si a ¨ sklinikum Ulm, Albe -Eins ein-Allee, Ulm, Ge many A icle in o A icle his o y: Accep ed June 1, 2017 Associa e Edi o : James Ca o Keywo ds: Ad anced and high- isk localized p os a e cance Cas a ion-nai e and cas a ion- esis an p os a e cance The apeu ics Consensus Oligome as a ic p os a e cance Please isi www.eu-acme.o g/ eu opeanu ology o ead and answe ques ions on-line. The EU-ACME c edi s will hen be a ibu ed au oma ically. Abs ac Backg ound: In ad anced p os a e cance (APC), success ul d ug de elopmen as well as ad ances in imaging and molecula cha ac e isa ion ha e esul ed in mul iple a eas whe e he e is lack o e idence o low le el o e idence. The[9_TD$DIFF] Ad anced P os a e Cance Consensus Con e ence (APCCC) 2017 add essed some o hese opics. Objec i e: To p esen he epo o APCCC 2017. Design, se ing, and pa icipan s: Ten impo an a eas o con o e sy in APC manage- men we e iden ified: high- isk localised and locally ad anced p os a e cance ; ‘‘oligo- me as a ic’’ p os a e cance ; cas a ion-naı ¨ e and cas a ion- esis an p os a e cance ; he ole o imaging in APC; os eoclas - a ge ed he apy; molecula cha ac e isa ion o blood and issue; gene ic counselling/ es ing; side e ec s o sys emic ea men (s); global access o p os a e cance d ugs. A panel o 60 in e na ional p os a e cance expe s de eloped he p og am and he consensus ques ions. Ou come measu emen s and s a is ical analysis: The panel o ed publicly bu anony- mously on 150 p edefined ques ions, which ha e been de eloped ollowing a modified Delphi p ocess. Resul s and limi a ions: Vo ing is based on panellis opinion, and hus is no based on a s anda d li e a u e e iew o me a-analysis. The ou comes o he o ing had a ying deg ees o suppo , as eflec ed in he wo ding o his a icle, as well as in he de ailed o ing esul s eco ded in Supplemen a y da a. Conclusions: The p esen ed expe o ing esul s can be used o suppo in a eas o managemen o men wi h APC whe e he e is no high-le el e idence, bu indi idualised ea men decisions should as always be based on all o he da a a ailable, including disease ex en and loca ion, p io he apies ega dless o ype, hos ac o s including como bidi ies, as well as pa ien p e e ences, cu en and eme ging e idence, and logis ical and economic cons ain s. Inclusion o men wi h APC in clinical ials should be s ongly encou aged. Impo an ly, APCCC 2017 again iden ified impo an a eas in need o ials specifically designed o add ess hem. Pa ien summa y: The second Ad anced P os a e Cance Consensus Con e ence APCCC 2017 did p o ide a o um o discussion and deba es on cu en ea men op ions o men wi h ad anced p os a e cance . The aim o he con e ence is o b ing he expe ise o wo ld expe s o ca e gi e s a ound he wo ld who see less pa ien s wi h p os a e cance . The con e ence concluded wi h a discussion and o ing o he expe panel on p edefined consensus ques ions, a ge ing a eas o p ima y clinical ele ance. The esul s o hese expe opinion o es a e embedded in he clinical con ex o cu en ea men o men wi h ad anced p os a e cance and p o ide a p ac ical guide o clinicians o assis in he discussions wi h men wi h p os a e cance as pa o a sha ed and mul idisciplina y decision-making p ocess. #2017 Eu opean Associa ion o U ology. Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/ by-nc-nd/4.0/). EUROPEAN UROLOGY 73 (2018) 178–211 179 1. In oduc ion The panel o he 2017 Ad anced P os a e Cance Consensus Con e ence (APCCC 2017) consis ed o 61 mul idisciplina y cance physicians and scien is s om 21 coun ies selec ed based on hei academic ack eco d and in ol emen in clinical o ansla ional esea ch in he ield ad anced p os a e cance (APC; Table 1). Fo discussion, 10 con o e sial a eas ela ed o he managemen o men wi h APC ha we e judged o be mos impo an o discussion we e iden i ied: 1. Managemen o high- isk localised and locally ad- anced p os a e cance 2. ‘‘Oligome as a ic’’ p os a e cance 3. Managemen o cas a ion-sensi i e/naı ¨ e p os a e cance (CNCP) 4. Managemen o cas a ion- esis an p os a e cance (CRPC) 5. Imaging in APC 6. Use o os eoclas - a ge ed he apy o skele al ela ed e en s (SRE)/symp oma ic skele al e en s (SSE) p e- en ion o me as a ic CRPC (mCRPC; no o os eopo- osis/bone loss) 7. Molecula cha ac e isa ion 8. Gene ic counselling/ es ing 9. Side e ec s o sys emic ea men : p e en ion, man- agemen , and suppo i e ca e 10. Global access o p os a e cance d ugs and ea men in coun ies wi h limi ed esou ces The consensus de elopmen p ocess ollowed he p oce- du es p e iously desc ibed (Supplemen a y da a) [1].The con e ence was o ganised a ound s a e-o - he-a lec u es and p esen a ions and deba es by panellis s who e iewed and discussed he e idence ele an o he abo e selec ed opics. On he las day o he con e ence, 150 p e iously ag eed-upon ques ions we e p esen ed wi h op ions o answe sina mul iple-choice o ma seeSupplemen a y da a. The ques ions we e o ed on publicly bu anonymously. Fo all ques ions, unless s a ed o he wise, esponses we e based on he idealised assump ions ha all diagnos ic p ocedu es and ea men s (including expe ise in hei in e p e a ion and applica ion) men ioned we e eadily a ailable; he e we e no ea men con aindica ions and no op ion o include he pa ien in a clinical ial. In addi ion, o ing answe s apply only o i pa ien s wi hou limi ing como bidi ies and o pa ien s wi h p os a e adenoca cinoma (unless s a ed o he wise). When me as ases we e men ioned, hey we e de ec ed by bone scin ig aphy and/o c oss-sec ional imaging wi h compu ed omog aphy (CT) and/o magne ic esonance imaging (MRI), i no s a ed o he wise. Impo an ly, in an e o o add ess ques ions om an e idence-based and clinical u ili y pe spec i e, panellis s we e speci ically ins uc ed no o conside cos , eimbu semen , and access as ac o s in hei delibe a ions, unless o he wise s a ed, al hough clea ly hese a e c i ical ac o s in he decision making o he physician and indi idual pa ien . Table 1 – Panel membe s by coun y and special y Name Fi s name Speciali y A a d Ge Medical Oncology Bee Tomasz M. Medical Oncology Bel an Himisha Medical Oncology Bossi Albe o Radia ion Oncology, non o ing (absence du ing o ing) B is ow Rob Radia ion Oncology Ca e B e U ology Cas ellano Daniel Medical Oncology Chung Byung Ha U ology Cla ke Noel U ology Daugaa d Gedske Medical Oncology Da is Ian[17_TD$DIFF] D. Medical Oncology de Bono Johann Medical Oncology Bo ges dos Reis Rodol o U ology D ake Cha les G. Medical Oncology Eeles Ros Clinical Oncology and Gene ics E s a hiou Eleni Medical Oncology E ans Ch is ophe [18_TD$DIFF] P. U ology Fan i S e ano Nuclea Medicine, non o ing membe Feng Felix Radia ion Oncology Fizazi Ka im Medical Oncology F ydenbe g Ma k U ology Glea e Ma in U ology Gillessen Silke Medical Oncology Halabi Susan Clinical T ials and S a is ics, non o ing membe Heiden eich Axel U ology Higano Celes ia [19_TD$DIFF]S. Medical Oncology James Nicolas Clinical Oncology Kan o Philip Medical Oncology Kellokumpu-Leh inen Pi kko-Liisa Clinical Oncology Khauli Raja B. U ology K ame Ge o U ology Logo he is Ch is Medical Oncology Malu Fe nando Medical Oncology Mo gans Alicia K. Medical Oncology and Epidemiology Mo is Michael[20_TD$DIFF] J. Medical Oncology Mo e Nicolas U ology Mu hy Vedang Radia ion Oncology Oh William Medical Oncology Omlin Au elius Medical Oncology, non o ing membe Os Pie Radia ion Oncology Padhani Anwa [21_TD$DIFF] R. Radiology, non o ing membe Pa ke Ch is Clinical Oncology P i cha d Colin[22_TD$DIFF] C. Pa hology, non o ing membe Roach Mack Radia ion Oncology Rubin Ma k[23_TD$DIFF] A. Pa hology, non o ing membe Ryan Cha les Medical Oncology Saad F ed U ology Sa o Oli e Medical Oncology Sche Howa d Medical Oncology Sella A ishay Medical Oncology Sho e Neal U ology Smi h Ma hew Medical Oncology Soule Howa d P os a e Cance Founda ion, non o ing membe S e nbe g Co a N. Medical Oncology Suzuki Hi oyoshi U ology Sweeney Ch is ophe Medical Oncology Sydes Ma hew R[24_TD$DIFF]. Clinical T ials and S a is ics, non o ing membe Tannock Ian Medical Oncology Tombal Be and U ology Valdagni Ricca do Radia ion Oncology Wiegel Thomas Radia ion Oncology EUROPEAN UROLOGY 73 (2018) 178–211 180 The esul s a e in ended o se e only as a guide o clinicians o assis in he discussions wi h pa ien s as pa o a sha ed and mul idisciplina y decision-making p ocess. Fo he de ini ions used o APCCC 2017 please e e o Supplemen a y da a. The panel consis ed o o ing (52) and non o ing membe s (9). The non o ing membe s we e panellis s, o example, adiologis s, pa hologis s, and s a is icians who a e no in ol ed in clinical managemen decision making, and one clinical expe who was no p esen du ing he o ing. The op ion ‘‘unquali ied o answe ’’ (sho o m ‘‘unquali- ied’’) should ha e been chosen i a panellis lacked expe ience o a speci ic ques ion; he ‘‘abs ain’’ op ion should ha e been chosen i a panellis el unable o o e o a bes choice o any eason o had p ohibi o y con lic s o in e es . The con e ence also included an explici app oach o managemen o con lic s o in e es (Supplemen a y da a). De ailed o ing eco ds o each o he ques ions b ough o he panel a e p o ided in he Supplemen a y da a. The denomina o was based on he numbe o panel membe s who o ed on he pa icula ques ion, excluding hose who o ed ‘‘unquali ied o answe .’’ In case o ques ions ela ed o a opic o a p e ious ques ion whe e only a subse o he panellis s had o ed o a speci ic answe op ion he o es o panel membe s who o ed ‘‘abs ain’’ and ‘‘unquali ied o answe ’’ we e excluded. Consensus was decla ed i 75% o he panellis s who did no o e o ‘‘unquali ied’’ o ‘‘abs ain’’ chose he same op ion [2]. Th oughou , he pe cen age o o ing panellis s who ga e a pa icula esponse a e epo ed, he numbe o o e s, and he numbe o panellis s o each answe a e p o ided in he Supplemen a y da a. All panellis s ha e con ibu ed o he designing o he ques ions, edi ing he manusc ip , and ha e app o ed he inal documen . Impo an ly, his p ocess was uniquely able o highligh a eas o disag eemen and iden i ied p io i ies o u u e clinical esea ch, meaning a eas whe e addi ional da a acquisi ion is wa an ed. 2. High- isk localised and locally ad anced p os a e cance The panellis s no ed ha he e is lack o p ecision in he use o he e m ‘‘high isk’’ in localised p os a e cance ha is in pa in luenced by a discipline speci ic pe spec i e. The commonly used de ini ions o high- isk localised pa ien s by a ious socie ies plus he de ini ions used in he STAMPEDE ial a e summa ised in Supplemen a y da a. High- isk localised pa ien s ha e ela i ely good long- e m ou comes [3,4]. Fo he APCCC 2017 con e ence, he Eu opean Associa ion o U ology (EAU) guideline de ini ion was used [5]. 2.1. Pa hology in locally ad anced p os a e cance Pa hology epo ing o adical p os a ec omies (RP) should adhe e o he ecen ly published Ame ican Join Commi ee on Cance eigh h edi ion cance s aging manual [6]. The new guidelines include he adop ion o P ognos ic Gleason G oups along wi h Gleason sco es, he collapsing o pT2 o one single g oup, and he use o ele a ed p os a e-speci ic an igen (PSA) o inc ease clinical s aging. RP epo s should commen on umou Gleason sco es using he In e na ional Socie y o U ological Pa hology guidelines [7,8]. In men wi h posi i e lymph nodes, he o al numbe o nodes wi h me as ases, he umou olume wi hin he lymph node, and ex acapsula nodal ex ension a e poo p ognos ic ac o s [9]. In issue om pa ien s who ha e p e iously been ea ed wi h and ogen dep i a ion he apy (ADT) and/o o he sys emic ea men o adia ion he apy (RT) no Gleason sco e should be epo ed. The panel unanimously ag eed (100%) ha apa om mo phology and umou s age, he ollowing ac o s should be epo ed om a RP sample: (1) seminal esicle in ol emen , (2) ex ap os a ic ex ension, (3) posi i e su gical ma gins (num- be , leng h and loca ion, g ade a ma gin), (4) Gleason sco e, and (5) g ade g oup. The e was also consensus ha he ollowing ac o s should be epo ed: (1) ex en o p os a ic in ol emen (96%), (2) numbe and ana omic egion o esec ed lymph nodes and numbe and loca ion o in ol ed lymph nodes (94%), (3) e ia y Gleason g ade (94%), and (4) mic ome as ases e sus mac ome as ases in in ol ed lymph nodes (81%), ex anodal ex ension (81%), and me as a ic deposi s in pe inodal a issue (79%; Table 2). Cu en guidelines (EAU, Na ional Comp ehensi e Cance Ne wo k [NCCN]) ecommend pe o ming ex end- ed pel ic lymph node dissec ion o men wi h high- isk and locally APC ea ed by RP pa icula ly i he isk o lymph node me as ases based on a ailable nomog ams is es ima ed o be 5% despi e he ac ha he e a e no da a om andomised p ospec i e ials suppo ing an im- p o emen in ou come wi h lymph node dissec ion [10– 12]. The impac o minimal empla e e sus ex ended lymph node dissec ion is no known and he pa hological p ocessing and epo ing o he dissec ed ma e ial is no well de ined. The e was a consensus (84%) ha a lymph node dissec ion should be pe o med in he majo i y o men wi h cN0 cM0 high- isk p os a e cance unde going RP whe eas 9% o ed o a lymph node dissec ion in a mino i y o selec ed pa ien s and 5% did no o e o a lymph node dissec ion. Rega ding he minimum numbe o lymph nodes o cons i u e an adequa e dissec ion in he majo i y o men wi h cN0 cM0 high- isk p os a e cance 76% o he panellis s o ed o a minimum o 11 lymph nodes (49% o 11–19 lymph nodes and 27% o [1_TD$DIFF]20 lymph nodes); 15% o he panellis s o ed o i e o 10 lymph nodes, 9% abs ained. Rega ding he empla e o lymph node dissec ion in men wi h high- isk and locally ad anced p os a e cance , he e was a consensus ha he ob u a o egion (98%), in e nal iliac egion (90%), and ex e nal iliac egion (85%) should be dissec ed. Rega ding he p esac al lymph nodes, 51% o he panellis s o ed agains and 46% in a ou o dissec ion, simila ly o common iliac lymph nodes 52% o he panellis s o ed agains and 45% in a ou o dissec ion. The e was a consensus (95%) agains ou ine dissec ion o pa a-ao ic lymph nodes (Table 3). EUROPEAN UROLOGY 73 (2018) 178–211 181 2.2. Adju an adia ion he apy a e RP Adju an adia ion he apy (ART) is la gely conside ed as he adminis a ion o ex e nal beam RT in he pos ope a i e phase in absence o objec i e e idence ha disease has ecu ed o pe sis ed. In he case o p os a e cance his would mean deli e ing RT when he PSA is ‘‘unde ec able.’’ In e es ingly, he de ini ion o ‘‘unde ec able’’ has a ied o e he pas 25 y by nea ly 100 old om <0.3 ng/ml in o he pg/ml ange mo e ecen ly [13]. Th ee andomised con olled ials ha e demons a ed ha ART in case o un a ou able pa hological ea u es (eg, pT3b, R1) a e RP delays PSA ecu ence ee su i al; in one o hese ials me as ases- ee su i al and o e all su i al (OS) we e also imp o ed. In e p e a ion o hose esul s is gene ally biased by he inclusion o men wi h pe sis en disease e idenced by low bu de ec able PSA le els [14–16]. Thus, in ac many o hese pa ien s ea ed on he ART a m should be desc ibed as ecei ing ea ly sal age adia ion he apy (SRT) [17,18]. Because se e al e ospec i e s udies ha e shown ha SRT, o e ed a PSA ecu ence, may be e icien and since his app oach may sa e some men he applica ion o ART, many physicians de e ea men un il he e is e idence o ecu en disease. Un o una ely he e is no p ospec i e andomised ial compa ing ‘‘pu e’’ ART a unde ec able PSA le els as cu en ly de ined e sus SRT a ‘‘app op ia ely’’ low PSA le els. 2.2.1. ART o high isk localised p os a e cance pN0 The opic o ART was add essed in men pos -RP wi hou lymph node in ol emen on su gical pa hology (pN0), wi h unde ec able pos ope a i e PSA, and who ha e eco e ed u ina y con inence. The e was no consensus on ART in high- isk localised p os a e cance pa ien s. Fo y-eigh pe cen o he panellis s o ed o ART o any posi i e su gical ma gins, whils 27% o he panel o ed o ART only in case o mul i ocal o ex ensi e ma gins. Twen y-one pe cen o he panel did no o e o ART in his se ing. In he p esence o seminal esicle in ol emen alone 38% o he panel o ed o ART in he majo i y o pa ien s, 32% o he panel o ed o ART only i combined wi h posi i e su gical ma gins. Twen y-six pe cen o he panel did no o e o ART a all in his se ing. Fi y- i e pe cen o panellis s did no o e o ART in he case o Gleason 8–10 (Gleason G ade G oup 4 o 5) as he only ad e se ac o , 20% o he panel o ed o ART in case o Gleason 8–10 (Gleason G ade G oup 4 o 5) alone o he majo i y o pa ien s, and 23% in a mino i y o selec ed pa ien s. Rega ding adia ion ield, 51% o he subse o panellis s who o ed o ART o ed o ea men o he whole pel is and p os a ic bed, while 41% o ed o ea ing only he p os a ic bed. Thi y-six pe cen o he subse o panellis s who o ed o ART o ed o adding ADT in he majo i y o pa ien s, 32% in a mino i y o selec ed pa ien s, and 32% did no o e o he addi ion o ADT a all. F om he subse o panellis s who o ed o addi ion o ADT o ART, 69% o ed o his combined ea men in men wi h ei he pT s age 3b and/o Gleason sco e 8 (G ade g oup 4–5); 28% o ed o combined ea men in men wi h pT s age 3b alone independen o Gleason sco e; Table 3 – Lymph node (LN) dissec ion in localised p os a e cance (which LN egions should be sampled [minimal equi emen ] in men wi h cN0 cM0 high- isk p os a e cance ?) LN egion Yes (%) No (%) Abs ain (%) Ob u a o 98 2 0 In e nal iliac 90 10 0 Ex e nal iliac 85 15 0 P esac al 46 51 3 Common iliac 45 52 3 Pa a-ao ic 5 95 0 Table 2 – P os a ec omy pa hology epo ing (as clinicians, which ac o s do you wan o be epo ed om a p os a ec omy specimen in men wi h locally-ad anced p os a e cance apa om mo phology and umou s age?) Fac o Yes, use ul es o majo i y o pa ien s (influences you managemen decision; %) Only o mino i y o selec ed pa ien s (%) No (%) Abs ain (%) Seminal esicle in asion 100 0 0 0 Ex ap os a ic ex ension 100 0 0 0 Posi i e su gical ma gins: numbe , leng h and loca ion as well as g ade a ma gin 100 0 0 0 Gleason sco e and g ade g oup 100 0 0 0 Ex en o p os a ic in ol emen 96 2 2 0 I lymphadenec omy is pe o med: numbe and ana omic egion o esec ed lymph nodes and numbe and loca ion o in ol ed lymph nodes 94 6 0 0 Te ia y Gleason sco e 94 4 2 0 In any in ol ed lymph nodes: mic o- s mac ome as ases 81 9 10 0 In any in ol ed lymph nodes: ex anodal ex ension 81 9 10 0 In any in ol ed lymph nodes: me as a ic deposi s in pe inodal a issue 79 15 6 0 C ib i o m g ow h pa e n and in aduc al umou sp ead 73 14 13 0 Lympho ascula in asion 68 18 14 0 In aduc al ca cinoma 67 21 12 0 Ma ke s o inflamma ion (eg, inflamma ion wi hin p os a e cance issue, umou infil a ing lymphocy es) 23 24 53 0 EUROPEAN UROLOGY 73 (2018) 178–211 182 and 3% o ed o combined ea men in men wi h Gleason 8– 10 (Gleason G ade G oup 4 o 5) alone. Rega ding he o m o ADT 61% o he subse o panellis s o ed o a lu einizing ho mone- eleasing ho mone (LHRH) agonis /an agonis , 24% o combined ADT, and 15% o an and ogen ecep o an agonis mono he apy. Rega ding du a ion o ADT, 39% o he subse o panellis s o ed o 3–6 mo, 43% o 6–12 mo, and 18% o 18–36 mo o ADT. 2.2.2. ART o pN1 p os a e cance Fo men wi h p os a e cance and lymph node in ol emen , cance mo ali y ises signi ican ly when >2 posi i e lymph nodes a e p esen [19]. The ques ion o ART in men wi h pN1 disease (assuming adequa e lymph node sampling, sec ion 2.1) and no local ad e se ac o s (no pT3b, no R1) and unde ec able pos ope a i e PSA and who ha e eco e ed u ina y con i- nence was add essed by he consensus panel. The e was no consensus on ART in pN1 disease. Twen y-six pe cen o he panel o ed o ART in men wi h pN1 disease in a majo i y o pa ien s, 29% o ed o ART in a mino i y o selec ed pa ien s, while 43% o he panel did no o e o ART in his se ing. Rega ding adia ion ield, 97% o he subse o panellis s who o ed o ART o ed o he whole pel is plus p os a ic bed as adia ion ield. The subse o panellis s who o ed o ART also o ed on ac o s ha in luenced hei decision o ecommend ART: 62% o ed o aking bo h he numbe and loca ion o posi i e lymph nodes in o conside a ion when ecommending ART, 33% based hei decision only on he numbe o in ol ed lymph nodes, and 5% only on he loca ion o in ol ed lymph nodes. Fi y pe cen o his subse o panellis s o ed o ART in men wi h one o wo posi i e lymph nodes in he p esence o in e media e- o high-g ade, nono gan-con ined disease and in hose wi h h ee o ou lymph nodes i espec i e o g ade and T-s age, 17% o ed o ART in all pa ien s, 15% o ed o ART in pa ien s wi h 2 posi i e lymph nodes independen o g ade and T-s age, and 15% in pa ien s wi h 4 posi i e lymph nodes independen o g ade and T-s age. O he panellis s who o ed o ART o pN1 disease, 100% o ed o adding ADT o ART. Rega ding he du a ion o ADT in his si ua ion, 18–36 mo was o ed o by 57% o hese panellis s, 6–12 mo by 30%; 11% o ed o 3–6 mo, while 2% o ed o li e-long ADT. 2.3. Sal age adia ion he apy a e RP While RP gene ally yields excellen esul s in pa ien s wi h localised p os a e cance , he ecu ence a es a e RP o high- isk p os a e cance may ise as high as 50–80% [15].In he case o ecu ence, SRT is a ea men op ion [20]. The app op ia e PSA le el a which o ini ia e SRT is s ill unclea . Eu opean guidelines ecommend ini ia ing SRT be o e he pos -RP PSA le el exceeds 0.5 ng/ml, whils NCCN guidelines ecommend SRT in pa ien s wi h con i med inc easing PSA [21,22]. Two mul i-ins i u ional e ospec i e s udies showed an imp o ed eedom om biochemical p og ession and dis an me as ases ollowing e y ea ly SRT a a PSA <0.2 ng/ml as opposed o pa ien s in which SRT was ini ia ed a a PSA le el o 0.2–0.5 ng/ml e sus highe PSA alues [23,24]. Such analyses a e con ounded by lead- ime and leng h- ime bias and he opic emains an a ea o unce ain y. Acco ding o he cu en EAU guidelines, he SRT dose should be a leas 66 Gy bu he op imal dose may be highe ; he op imal dose and ac iona ion is unclea and is being add essed in se e al ongoing ials. Combining SRT wi h ADT may be an op ion, pa icula ly in men wi h high- isk disease. In he GETUG-AFU 16 ial, he 5-y eedom om biochemical p og ession was 80% wi h SRT plus 6 mo o ADT e sus 62% wi h SRT alone [25]. In he RTOG 9601 ial, OS was imp o ed wi h SRT plus 2 y o high-dose bicalu amide (150 mg daily) compa ed wi h SRT plus placebo bu a signi ican p opo ion o included men had PSA le els 0.7 ng/ml [26]. Rega ding he con i med PSA le el a which o ini ia e SRT, 44% o he panel o ed o 0.2 ng/ml, whils 38% o ed o 0.1ng/ml,10% o ed o 0.5ng/ml,and4% o <0.1 ng/ml. The panel eached no consensus ega ding a le el o PSA abo e which SRT would no be ecommended. Twen y- i e pe cen o he panellis s conside ed 2 ng/ml he maximum alue, 19% conside ed 1 ng/ml he maximum alue, 11% chose 0.5 ng/ml as a maximum alue, and 19% o he panel o ed ha he e should be no maximal uppe limi o PSA. The subse o panellis s who o ed o SRT also o ed on he addi ion o ADT. Six y-one pe cen o ed o ADT in he majo i y o men, 29% in a mino i y o selec ed pa ien s, o example, based on PSA le el and PSA doubling- ime, and 10% o hesepanellis sdidno o e o headdi iono ADT. Rega ding he du a ion o ADT in combina ion wi h SRT, 34% o hese panellis s who op ed o he addi ion o ADT o ed o 3–6 mo, 41% o 6–12 mo, and 25% o 18–36 mo o ADT. 2.4. Discussion o high- isk localised and locally ad anced p os a e cance The consensus ques ions ocused on men unde going RP and he opics o ART and SRT. The choice o p ima y ea men o high- isk and locally ad anced p os a e cance is also an a ea o con o e sy, bu was no add essed a his con e ence. The o es o he panel showed a consensus on he equi ed in o ma ion o pa hology epo ing in men unde going a RP. The e was a lack o consensus ega ding he ole o ART and SRT e lec ing he many unce ain ies and mul iple unanswe ed ques ions in bo h opics. One o he easons o unce ain y is ha he ART ials did no ha e an ea ly SRT a m as a compa a o and as such a e no compa able o cu en p ac ice. Ano he weakness o hese ials is he ela i ely high PSA a which ‘‘adju an ’’ RT was s a ed, again no compa able o cu en p ac ice. As wi h any adju an ea men , ART bea s he isk o o e ea men and can esul in acu e side e ec s as well as dele e ious e ec s on long- e m unc ional ou come EUROPEAN UROLOGY 73 (2018) 178–211 183 (eg, po ency, con inence) bu such po en ial isks mus be balanced agains he po en ial bene i s, namely imp o ed oncological ou comes [18,27,28]. The ques o de ine ‘‘unnecessa y’’ RT and how o selec which pa ien s eally equi e ART and o which pa ien s SRT is app op ia e is cu en ly ongoing. Se e al well- powe ed phase 3 ials (RADICALS, RAVES, and GETUG-17) will p o ide e idence on which o base upda ed discussions. In he mean ime, ega ding SRT, ecen e ospec i e s udies sugges ha ini ia ing SRT a lowe PSA alues (< 0.2 ng/ml) imp o es biochemical p og ession ee su i al as compa ed wi h using he adi ional ecommended con i med alue o 0.2 ng/ml and ising o de ini ion o biochemical elapse (BCR) [23,24]. These da a we e e lec ed by he o es o he panel whe ein a signi ican p opo ion o panellis s would ini ia e SRT below he PSA h eshold ecommended by cu en guidelines. The addi ion o ADT o RT as p ima y ea men o he p os a e is a well-es ablished concep [29–33]. Bu he addi ion, iming, and du a ion o ADT, speci ically o ART bu also o SRT, a e less well examined [26]. Acco dingly, he e was no consensus ega ding he ole o adding ADT o ART and SRT. P ospec i ely alida ed p ognos ic and p edic i e mo- lecula bioma ke s a e equi ed ha will imp o e he pe o mance o clinical and pa hological ea u es bu his can only be de e mined in he con ex o la ge phase 3 andomised ials wi h adequa e long- e m ollow-up. Addi ionally, he inc easing use o nex -gene a ion imaging me hods in combina ion wi h mo e sensi i e PSA assays may also al e ea men app oaches in he u u e. 3. Oligome as a ic p os a e cance 3.1. De ini ion o oligome as a ic p os a e cance Hellman and Weichselbaum [34] p oposed he e m ‘‘oligome as ases’’ in 1995 o de ining a disease s age wi h a limi ed numbe o clinically de ec able me as ases. The biological de ini ion o oligome as a ic p os a e cance is open o in e p e a ion as is he en i e concep ha his is a p ognos ic and he apeu ically dis inc subse o pa ien s ha alls somewhe e in-be ween localised and me as a ic disease. No o mal cu -o o ‘‘oligo’’ has been de ined in he li e a u e [35]. Some de ini ions inco po a e bo h he si e o me as ases in addi ion o he numbe o lesions o de ine he oligome as a ic s a e [35,36]. Va iables o include in he desc ip ion o men wi h oligome as a ic disease include: he dis inc ion o synch onous e sus me ach onous me as ases, he numbe and si e o lesions, and whe he he pa ien is cas a ion-naı ¨ e o cas a ion- esis an [36]. O impo ance is also he imaging me hod used o de ine oligome as a ic disease. Newe imaging echniques will de ec mo e me as ases in many pa ien s classi ied as ‘‘oligome as a ic’’ by con en ional imaging (CT and bone scin ig aphy). Many pa ien s conside ed as M0 on con en ional imaging may u n ou o ha e oligome as a ic disease especially when imaging is pe o med a lowe PSA le els han in he pas . The panel did no each consensus on wha cons i u ed he de ini ion o oligome as a ic disease. Six y-one pe cen o he panellis s o ed o a limi ed numbe o bone and/o lymph nodes as a clinically meaning ul de ini ion o oligome as a ic p os a e cance ha in luences ea men decisions (local abla i e ea men o all lesions sys emic he apy), 10% o he panellis s o ed o an oligome as a ic de ini ion which includes only pa ien s wi h a limi ed numbe o lymph node me as ases, 13% o ed o pa ien s wi h a limi ed numbe o me as ases a any loca ion (including isce al disease), and 10% o he panellis s did no belie e ha oligome as a ic p os a e cance exis s as a clinically meaning ul en i y . The subse o panellis s who belie ed in he concep o oligome as a ic p os a e cance o ed on he numbe o lesions. Rega ding he cu -o o he numbe o me as ases o conside a p os a e cance pa ien as oligome as a ic 14% o ed o 2 me as ases, 66% o 3 me as ases, and 20% o hese panellis s o ed o 5 me as ases as a cu -o . O [27_TD$DIFF] he panellis s belie ing in he oligome as a ic concep , 52% o ed o a biopsy (i easible) o an oligome as a ic lesion o diagnos ic pu poses in a mino i y o selec ed pa ien s, while 34% o ed o biopsy in he majo i y o pa ien s and 14% o hese panellis s did no o e o a biopsy. 3.2. Synch onous ‘‘oligome as a ic’’ cas a ion-nai e p os a e cance This sec ion add esses pa ien s diagnosed wi h de no o appa en oligome as a ic disease in he cas a ion-naı ¨ e s a e, ha is, hey p esen wi h synch onous oligome as- ases and an un ea ed p ima y. In such pa ien s, no p ospec i e andomised da a a e a ailable o show a bene i o abla i e ea men o all lesions including he p ima y— ei he wi h o wi hou sys emic he apy. Fo men who p esen wi h de no o oligome as a ic disease, a o al o 25% o he panellis s o ed o li elong ADT six cycles o doce axel wi hou local abla i e ea men . Eigh pe cen o panellis s o ed o local abla i e ea men o all lesions including he p ima y (su ge y o RT) wi hou any sys emic ea men , 22% o panellis s o ed o local abla i e ea men wi h a sho cou se (6–12 mo) o ADT doce axel, 31% o panellis s o ed o local abla i e ea men and an in e media e long cou se (24–36 mo) o ADT doce axel, 8% o panellis s o ed o local abla i e ea men and li e-long ADT doce axel . Among he panellis s who o ed o local abla i e ea men plus ADT in men wi h de-no o oligome as a ic p os a e cance and an un ea ed p ima y, 28% o ed o he addi ion o doce axel in he majo i y o pa ien s, 39% o ed o he addi ion o doce axel in a mino i y o selec ed pa ien s; 33% o hese panellis s did no o e o he addi ion o doce axel in his si ua ion. I hey o ed o ea men o he p ima y umou in his si ua ion, 45% o ed o RT, 22% o ed o su ge y, and 31% o ed o ei he RT o su ge y. 3.3. Me ach onous oligome as a ic cas a ion-naı ¨ e p os a e cance This sec ion add esses men who p esen wi h ecu en appa en oligome as a ic p os a e cance in he cas a ion- EUROPEAN UROLOGY 73 (2018) 178–211 184 naı ¨ e s a e; ha is, hey p esen wi h me ach onous me as ases a e local ea men o he p ima y. No p ospec i e andomised da a a e a ailable o show a bene i o adical abla i e ea men o all lesions wi h o wi hou sys emic he apy as compa ed wi h s anda d o ca e (ADT  doce axel) [37]. A me a-analysis o 20 small s udies o local lymph node only ecu ence a e p ima y ea men sug- ges ed ha , despi e a lack o high-le el e idence, abla i e node-di ec ed he apy may yield in good sho - e m oncologic ou comes and may de e he need o sys emic ea men [38]. The e was no consensus on ea men op ions. Fo ea men o men wi h asymp oma ic oligome as a ic ecu - en CNPC 32% o he panel o ed o sys emic he apy wi h li elong ADT doce axel wi hou local abla i e he apy o he me as ases. Twel e pe cen o ed o local abla i e he apy o he me as ases wi hou addi ional sys emic he apy, while 30% o ed o local abla i e he apy wi h a sho cou se (6–12 mo) o ADT  doce axel, 18% o local abla i e he apy wi h a longe cou se (24–36 mo) o ADT doce axel, and 4% o ed o local abla i e he apy and li elong ADT doce axel . Among he panellis s who o ed o local abla i e ea men in men wi h oligome as a ic ecu en CNPC limi ed o lymph node me as ases in he pel is, 23% o ed o sal age lymph node dissec ion, 19% o sal age lymph node dissec ion plus RT o he pel is (i no p io whole-pel is RT), 16% o hese panellis s o ed o ocal RT, and 42% o whole pel is RT (i no p io whole-pel is RT) a boos o he suspicious nodes . 3.4. Rising PSA on ADT (mCRPC) and oligome as a ic disease This sec ion add esses pa ien s diagnosed wi h oligome a- s a ic disease p og ession in he cas a ion esis an s a e. No p ospec i e andomised da a a e a ailable demons a - ing a bene i o local adical ea men o all lesions in addi ion o ADT, compa ed wi h s anda d o ca e, ha is, he addi ion o a new sys emic ea men o ADT. Among he panellis s who belie ed ha oligome as a ic mCRPC is a meaning ul en i y he e was no consensus on ea men op ions. Fo y- ou pe cen o hese panellis s o ed o con inua ion o ADT and adding addi ional sys emic he apy, 29% o local abla i e ea men o all lesions in combina ion wi h ongoing ADT and addi ion o sys emic ea men , 25% o local abla i e ea men o all lesions while con inuing ADT wi hou addi ion o sys emic ea men and 2% o ed o local abla i e ea men o all lesions and he cessa ion o ADT. 3.5. Discussion o oligome as a ic p os a e cance In addi ion o p os a e cance , he oligome as a ic s a e is o in e es in a g owing numbe o o he cance ypes, o example, b eas , enal cell, colo ec al, gas ic, and non-small cell lung cance . Like in p os a e cance , in hese diseases he majo i y o da a a e e ospec i e in na u e and he e o e di icul o in e p e . In some cases, ea men o local disease appea s obe associa ed wi hlong- e msu i al.P ospec i e ials a e ongoing in se e al o hese en i ies. The concep o oligome as ases implies ha a local he apy di ec ed a he p ima y cance and/o me as ases migh imp o e su i al hough he e is no s ong e idence o suppo his. The e was no consensus on ea men op ions, bu om he o ing i seems ha he en husiasm o he opic exceeds he e idence epo ed o da e. The a ailable da a a e no p ospec i e, a e subjec o selec ion bias, and hus equi e alida ion in p ospec i e andomised con olled ials. Such ials should ocus on OS as an endpoin , since ea lie endpoin s such as p og ession- ee su i al (PFS) o ime o sys emic he apy a e no well de ined and hei clinical impo ance is less clea . Dis in- guishing be ween synch onous and me ach onous lesions, and sepa a ing pel ic nodal elapse om M1 disease is also likely o be impo an . S udies o pa ien s wi h oligome a- s a ic disease a e o inc easing impo ance, since mo e sensi i e imaging echniques a e an icipa ed o inc ease he p opo ion o men wi h adiog aphically de ec ed lesions. A he e y leas , un il andomised clinical ial da a a e a ailable, la ge collabo a i e na ional and in e na ional egis ies o men ea ed o oligome as a ic p os a e cance should be ini ia ed o p ospec i ely collec da a on consecu i ely ea ed pa ien s. 4. Cas a ion-nai e p os a e cance The e was inconsis en use in discussions o he e ms cas a ion-naı ¨ e o cas a ion-sensi i e, o designa e p os- a e cance ei he no p e iously ea ed wi h ADT, o cance s demons a ing ongoing sensi i i y o ADT. The e m cas a ion-naı ¨ e is used in his manusc ip o simplici y o co e bo h clinical scena ios. 4.1. When o s a ADT (pos -RP WRT o [28_TD$DIFF]pos RT) The op imal iming o ini ia ion o ADT, du a ion, speci ic ADT modali y, and he indica ions o ini ia ing ADT a e no well de ined. Fo pa ien s p esen ing wi h me as ases wi h impending complica ions and especially i symp oma ic, an ini ial sho cou se o AR an agonis ea men o p e en he unwan ed clinical consequences o es os e one su ge is ecommended when LHRH agonis s a e ini ia ed. Fo pa ien s wi h BCR, he decision o ini ia e ADT will likely depend upon se e al pa ame e s including li e expec ancy, ime o PSA elapse a e local he apy, PSA kine ics, absolu e PSA le el, age, sexual unc ion, baseline a igue, ca dio ascula isk, and neu ologic and cogni i e s a us. Fo pa ien s wi h BCR wi hou o e me as a ic disease, he decision o p oceed wi h in e mi en ADT e sus con inuous ADT should also be conside ed. In men wi h nonme as a ic disease and con i med ising PSA (pos local he apy SRT), 65% o he panellis s o ed o he ini ia ion o ADT only in a mino i y o selec ed men, o example, in case o a PSA 4 ng/ml and ising wi h doubling ime less han 6 mo o a PSA 20 ng/ml (STAMPEDE inclusion c i e ia). Twen y- one pe cen o ed o s a ing ADT in he majo i y o men i espec i e o hese ac o s and 12% o ed o s a ing ADT only a e de ec ion o me as ases . 4.1.1. Moni o ing o es os e one Cu en da a do no p o ide cla i y ega ding he op imal le el o es os e one supp ession o be achie ed in men EUROPEAN UROLOGY 73 (2018) 178–211 185 wi h ad anced p os a e cance on ADT. The egula o y- app o ed le el o less han 50 ng/dl, pe Food and D ug Adminis a ion and Eu opean Medicines Agency, was based upon he ini ial leup olide egis a ion ial and 50 ng/dl was he lowes limi o de ec ion o he adioimmunoassay used a ha ime [39]. Ensuing ials ha e sugges ed ha eaching a es os e one le el o 20 ng/dl may achie e a delay in ime owa d he de elopmen o cas a ion esis ance; howe e , his h eshold, as well as he in e al a which o measu e se um es os e one le els emains unce ain [40]. In men wi h p os a e cance esponding o ADT, 44% o he panel o ed o egula moni o ing o es os e one le els (apa om measu ing es os e one a biochemical p og ession) and 34% o he panellis s o ed o measu ing es os e one in a mino i y o selec ed pa ien s (eg, ailu e o achie e PSA nadi < 0.2 ng/ml), 22% o he panel did no o e o egula es os e one measu emen in esponding pa ien s. Fi y- ou pe cen o he panel o ed o a es os e one le el <50 ng/dl (<1.73 nmol/l) as app op ia e o men on ADT, 36% o ed o a es os e one le el <20 ng/dl (<0.69 nmol/l), while 10% abs ained. The e was no consensus on he he apeu ic app oach o men wi h ising PSA on a LHRH agonis whose es os e one le el is con i med as being noncas a e (apa om uling ou applica ion e o s and/o poo compliance). Despi e he lack o e idence, 36% o he panel o ed o a change o a LHRH an agonis , 26% o addi ion o a i s -gene a ion AR an ago- nis , 20% o a change o an al e na i e LHRH agonis , and 14% o ed o o chiec omy. 4.2. Chemo he apy in cas a ion-naı ¨ e nonme as a ic p os a e cance The e is some e idence o suppo combina ion ea men as an up on al e na i e o single-modali y he apy o men who p esen wi h high- isk localised p os a e cance . Such app oaches gene ally combine ADT wi h RT and doce axel- based chemo he apy. A o al o h ee andomised ials in such pa ien s ha e been epo ed. The GETUG-12 ial showed an imp o emen in ailu e- ee su i al (FFS) wi h ou cycles o doce axel and es amus ine plus ADT as compa ed wi h ADT alone [41,42]. The second ial, RTOG 0521, so a only p esen ed as an abs ac , examined he combina ion o six cycles o adju an doce axel pos adical RT wi h ADT o 24 mo (NCT00288080). The STAMPEDE ial allowed inclusion o high- isk localised as well as biochem- ical ecu en and me as a ic pa ien s. The numbe o e en s o de ini i e in e p e a ion o su i al o M0 pa ien s in he doce axel a m o STAMPEDE is oo low and no conclusions ega ding he e ec o addi ion o doce axel on OS in his ial can be d awn [43]. A me a-analysis epo ed a consis en e ec on FFS o chemo-ho monal he apy in he M0 subg oup as opposed o ADT alone [44]. Da a o OS a e no ye ma u e. Fo men wi h N1 M0 CNPC, 71% o he panel did no o e o he addi ion o doce axel o ADT, 25% o ed o he addi ion in a mino i y o mino i y o selec ed pa ien s, and 4% o he majo i y o pa ien s. Fo men wi h biochemical elapse only, he e was a consensus (90%) o no adding doce axel o ADT. 4.3. Cas a ion-nai e p os a e cance M1 (me as a ic) Tes os e one supp ession alone has long been he s anda d ea men o pa ien s wi h me as a ic p os a e cance commencing sys emic ea men [45]. Al hough he majo - i y o men wi h mCNPC expe ience a PSA decline wi h ADT, he median FFS in a coho o newly diagnosed mCNPC was app oxima ely app oxima ely 1 y , wi h a wide ange [46]. Subg oup analyses om ecen clinical ials showed ha highe olume o me as ases and p esen a ion wi h de no o me as a ic disease a e isk ac o s associa ed wi h a sho e OS wi h ADT alone. O he pu po ed poo p ognos ic clinical ac o s include highe Gleason sco e, pain, and ele a ed alkaline phospha ase [45,47,48]. Doce axel gi en a he s a o ADT was he i s d ug shown o imp o e he OS o men wi h mCNPC in wo la ge ials [43,49]. The i s phase 3 s udy o doce axel in mCNPC, GETUG 15, showed an imp o emen in PFS bu no OS [47]. The e is ongoing discussion on he de ini ion o ‘‘high- olume’’ disease and whe he he e is a de ini ion ha is p ognos ically ele an o p edic i e o ea men bene i . Fo a de ini ion o high- olume disease, 74% o he panellis s o ed o he de ini ion, as used in CHAARTED ( isce al [lung o li e ] and/o 4 bone me as ases, a leas one beyond pel is and e eb al column), ei he wi h s anda d imaging (59%) o wi h any imaging (15%), 6% o ed o he high- olume de ini ion de eloped by SWOG ( isce al [lung o li e ] and/ o any appendicula skele al in ol emen ) and 6% o ed o a simpli ied e sion o high- olume o isce al and/o 4 bone lesions ega dless o dis ibu ion and imaging used. [29_TD$DIFF]Fou een pe cen o he panellis s had he opinion ha high- olume disease is no a clinically meaning ul en i y. Fo men wi h high- olume mCNPC, 68% o he panellis s o ed o con inuous ADT using a LHRH agonis (plus a sho cou se o i s -gene a ion AR an agonis o p e en es os e - one su ge) as hei p e e ed ho mone he apy, ano he 10% o s a ing wi h an LHRH an agonis (no la e-up p e en ion needed) and swi ching o an LHRH agonis in he cou se o ea men . Con inuous LHRH an agonis ea men was o ed o by 6%, o chiec omy by 2%, and con inuous combined ADT by 14% o he panellis s. None o he panellis s o ed o any o m o in e mi en ADT o AR-an agonis mono he apy in he high- olume M1 se ing. No all men a e sui able o chemo he apy wi h doce axel and he c i e ia ende ing a pa ien ‘‘unsui able’’ o doce axel a e no well de ined. The panel o ed on ac o s hey would conside ende ing a man ‘‘un i ’’ o doce axel. The e was a consensus o se e e hepa ic impai men (96%), neu opa hy g ade 2 (82%), and pla ele s <50 10 9 [2_TD$DIFF]/l and/o neu ophils <1.0 10 9 /l (81%). Fo he o he p oposed ac o s alone he e was no consensus (Table 4). In he o iginal publica ion o he CHAARTED ial, he subg oup o men wi h high- olume disease showed a clinically signi ican su i al bene i and he poin es ima e o he low olume pa ien s was he same in ha EUROPEAN UROLOGY 73 (2018) 178–211 186 5.5. Moni o ing in men wi h mCRPC ea ed wi h adium-223 The phase 3 adium-223 ial (ALSYMPCA) en olled pa ien s wi h symp oma ic mCRPC [72]. Pa ien s we e andomised o six injec ions o adium-223 adminis e ed e e y 4 wk o o bes s anda d o ca e alone. OS was imp o ed in he in en o ea analysis o pa ien s andomized o adium- 223 [72]. Subs an ial declines in PSA and/o lac a e dehyd ogenase we e uncommon in bo h a ms. Howe e , alkaline phospha ase (ALP) le els showed a decline in he adium ea ed pa ien s wi h 87% o adium ea ed pa ien s showing some decline in ALP a wk 12 [84]. In he subse o panellis s who use adium-223 in men wi h mCRPC 43% o ed o es ing o PSA e e y cycle, 43% o e e y 2–4 mo; 8% o ed o PSA es ing only i clinically indica ed, and 6% o no PSA es ing in his si ua ion. Rega ding ALP es ing hese panellis s o ed o ei he e e y cycle (49%) o e e y 2–4 mo (37%). Eigh pe cen o ed o ALP es ing only i clinically indica ed and 6% o ed o no ALP es ing. Since he ALSYMPCA ial did no manda e any imaging o esponse moni o ing, he ole o imaging in men ea ed wi h adium-223 is no well documen ed. Symp oma ic and PSA la es a e adium-223 ha e been desc ibed and can be accompanied by bone scin ig aphy la e [85]. Ea ly changes in bone scin ig aphy and CT assessmen s end o be un eliable o bone esponse assessmen and mus hus be in e p e ed wi h cau ion. In a e ospec i e se ies o 130 men ea ed wi h adium-223 ha had baseline imaging and moni o ing by imaging a e h ee and six cycles, he esul s showed a signi ican a e o p og ession ou side o he bone de ec ed by CT scanning [85]. In he subse o panellis s who use adium-223 in men wi h mCRPC he e was consensus (75%) o use CT and bone scin ig aphy o s aging and moni o ing o men on adium- 223, while 23% o he panellis s o ed o one o he nex - gene a ion imaging me hods. Rega ding imaging equency o men ea ed wi h adium-223, 41% o hese panellis s o ed o e e y 3–4 mo, 27% o ed o imaging a e 6 mo (comple ion o adium-223) and e e y 3–4 mo he ea e , 24% o ed o imaging a e 6 mo (comple ion o adium-223) and ollow-up imaging a p og ession, 4% o ed o imaging only as clinically indica ed. 5.6. ‘‘Oligo-p og essi e’’ mCRPC Wi h he in oduc ion o abi a e one and enzalu amide as i s -line ea men o asymp oma ic men wi h mCRPC, he e a e men in whom, o example, a single lymph node p og esses in size wi h adiological s abili y o he o he lesions. The e m oligo-p og essi e is no well-de ined in APC bu in lung cance pa ien s on no el a ge ed agen s such as anaplas ic lymphoma kinase (ALK) inhibi o s he e is g owing li e a u e on de ini ion and ea men s a egies o oligo-p og essi e disease [86]. The e was no consensus as o he mos meaning ul de ini ion o oligo-p og essi e p os a e cance (mCRPC). Fo y pe cen o he panel o ed ha hey did no belie e in oligo- p og essi e disease as a meaning ul clinical en i y, 33% o ed o he de ini ion o only one p og essing p e-exis ing lesion wi h o he wise s able/ esponding me as a ic disease, 23% o ed o 3 p og essing p e-exis ing lesions wi h o he wise s able/ esponding me as a ic disease. The subse o he panel who belie ed in oligo-p og essi e mCRPC o ed on biopsy o a p og essing lesion ( o diagnos ic pu poses). Twen y-nine pe cen o he panellis s o ed o a biopsy in he majo i y o pa ien s, 52% o a biopsy in a mino i y o selec ed pa ien s (eg, om isce al me as ases), while 19% did no o e o a biopsy. These panellis s also o ed on he ea men o men wi h oligo-p og essi e mCRPC: 40% o ed o a change o addi ion o sys emic he apy wi hou local ea men , 47% o local ea men o he p og essing lesion(s) while con inuing sys emic he apy unchanged, and 13% o local ea men o he p og essing lesion(s) plus adding o changing he sys emic ea men . 5.7. Discussion o CRPC We ha e wi nessed he success ul de elopmen o agen s including he no el and ogen signalling inhibi o s abi - a e one and enzalu amide o ea lie s age mCRPC. Mo e ecen ly, a signi ican su i al ad an age by in oducing doce axel ea men in he cas a ion-nai e s a e was con i med. I hus appea s ha we a e mo ing ou he apies ea lie in he disease, while he ques ion o op imal sequencing o he ea men op ions is s ill unanswe ed. We know ha a dis inc subse o pa ien s will no espond o ea men also depending on he sequence, o may expe ience unwa an ed oxici y. Mo eo e , i is possible ha wi h he app op ia e sequencing we may augmen he OS bene i o ou pa ien s. T ea men sequencing in APC is go e ned by a numbe o pa ame e s ha un o una ely do no ye se e he ul ima e goal o maximizing clinical ou come. Clinical decision- making is s ill la gely dependen on local eimbu semen policies and on a numbe o a iables ha a e no uly objec i e. The e a e no alida ed clinical o molecula p edic i e ma ke s o guiding ou choice hus p ede e - mining a mo e a ou able cos /bene i a io o ou pa ien s. Inc eased bene i is encompassing longe li e wi h im- p o ed quali y whe eas minimising cos including compo- nen s such as oxici y, inancial bu den, and unce ain y. Choices made in he clinic a e in pa based on objec i e da a such as a ailable le el I e idence and access o agen s. Ye , p o essional speciali y and expe ience a ec hese choices. The p esence o absence o symp oms clea ly in luenced ea men selec ion o he panellis s. We a e also being challenged by he as-ye unp o en hypo hesis ha combina o ial app oaches may enhance ou come by po en ial syne gis ic ac i i y o delay o esis ance o ea men . We a e an icipa ing esul s om se e al ele an phase 3 ials and should he e o e a oid implemen a ion o such app oaches as long as hey a e unp o en especially since conce ns o oxici y a ise. Rega ding he agg essi e a ian o CRPC, he majo i y o he panel ecognises i s exis ence and ha i is impo an o ecognise i since hese pa ien s may be less likely o espond o subsequen AR-di ec ed he apies; howe e , EUROPEAN UROLOGY 73 (2018) 178–211 193 he e was no consensus o he exac de ini ion. Wi h a mo e p o ound and e en ually ea lie supp ession o AR pa hways in he disease his o y, iden i ying and ea ing AR independen a ian s will become inc easingly impo an [87]. The de elopmen o obus bioma ke s is an a ea o ac i e esea ch. We may need a combina ion o clinical and molecula ea u es o iden i y agg essi e a ian s, encom- passing bu no limi ed o hose wi h neu oendoc ine ca cinoma mo phology de ec ed on biopsy, as a ge ed ea men app oaches based on a molecula subclassi ica- ion o APC a e de eloped. Unde s anding he ole o DNA epai in con ibu ing o he pheno ype, media ing esponse o PARP inhibi ion, and also pla inum sensi i i y and po en ial immuno he apy ea men sensi i i y is also impo an . 6. Imaging in APC Rep oducible and alida ed me hods o de ec ing and quan i ying me as a ic disease a e needed o manage pa ien s wi h APC. Cu en ly, ecommended me hods o me as a ic imaging assessmen , ha is, wi h bone scin ig- aphy and CT scans, ha e signi ican limi a ions in de ec ing me as ases as well as in moni o ing esponse o ea men bu emain he s anda d o ca e in mos se ings [1,21,88– 91]. Due o limi a ions in sys ema ically conduc ed p ospec i e s udies, he use o nex -gene a ion imaging has no been shown o impac on clinical ou come. 6.1. Nodal disease assessmen s in APC Mo phologic assessmen s o possible nodal disease using CT and MRI scans a e based on he e alua ion o de ec ed nodes based la gely on size c i e ia. O he mo phologic c i e ia, such as he nodal shape, loss o nodal hilum a , clus e ing, ex anodal disease, and enhancemen cha ac e - is ics can se e as addi ional aids o diagnosis. Un o u- na ely, mo phologic imaging is unable o iden i y mic ome as ases o o dis inguish la ge hype plas ic benign om malignan nodes. Thus, he gene al es pe o mance o mo phologic imaging emains limi ed when his ologic co ela ions using empla e lymphadenec omy a e used as he s anda d o e e ence. A me a-analysis showed a CT scan sensi i i y o 42% and speci ici y o 82%, while mo phologic MRI had a sensi i i y o 39% and a speci ici y o 82% [92]. While posi on emission omog aphy (PET)/CT has imp o ed sensi i i y, i is impo an o keep in mind ha he spa ial esolu ion o PET/CT is app oxima ely 4 mm. 6.2. Bone disease assessmen s in APC Fo he sensi i e de ec ion o me as a ic bone disease, he use o cu en ecommenda ion o bone scin ig aphy and CT scans has low sensi i i y and speci ici y [93]. Sys ema ic analyses, p ospec i e clinical s udies, and me a-analyses ha e shown compa a i e es pe o mance o whole-body di usion weigh ed MRI (WB-MRI) o NaF and choline PET/CT o he skele al assessmen s in APC [94,95]. A ecen me a-analysis unde lined he use ulness o WB-MRI as a me hod ha imp o es he MRI de ec ion o bone me as ases [96]. When e alua ing he esul s o he abo e me a-analyses and indeed in all s udies epo ing es pe o mance, he eade s should no e ha he e a e in insic e i ica ion biases ha a e pa icula ly p e alen a lesion le el analyses, because i is no possible o ob ain his opa hology o e e y bone lesion de ec ed. As a esul , mos s udies a e pa ien le el analyses, using combina ions o imaging me hods and/o ollow-up as he s anda ds o e e ence [93,94]. PET/CT can de ec a la ge numbe o skele al lesions han bone scin ig aphy [97]. Rega ding he PET/CT ace s compa a i e s udies be ween p os a e-speci ic memb ane an igen (PSMA) and choline ha e demons a ed supe io i y o PSMA o iden i y bone lesions [98]. The PET ace 18 F- luciclo ine has ecen ly been app o ed o use in No h Ame ica; a ailable da a indica e good de ec ion a es bo h o lymph nodes and o bone disease in biochemical ecu ence o p os a e cance [99]. The diagnos ic pe o - mance o luciclo ine PET was ound o be supe io o CT and o choline PET bu he e a e no compa a i e da a e sus WB-MRI and PSMA PET [100]. Impo an ly, all ou p ognos ic models and clinical ials in APC we e de eloped using CT scan and bone scin ig aphy and he essence o de ec ion o disease a diagnosis is one o isk de e mina ion. Nex gene a ion imaging may ha e supe io pe o mance cha ac e is ics compa ed wi h olde modali ies, bu clinical alida ion wi h ega d o he ques ion o impac on ou come has no ye been pe o med. 6.3. Imaging o locally ad anced p os a e cance In men p esen ing wi h high- isk o locally ad anced p os a e cance and wi h biochemical ecu ence a e local he apy, imaging o documen po en ial me as ases may be impo an . A his s a e o he disease me as ases a e mos commonly loca ed wi hin egional (N1) and non egional lymph nodes as well as in bone (M1). The e was no consensus ega ding he imaging modali y o ‘‘exclude’’ dis an me as ases in high- isk and locally ad anced p os a e cance : 41% o he panel o ed o a combina ion o CT and bone scin ig aphy, while 47% o he panel o ed o nex - gene a ion imaging me hods (37% o ed o a PET/CT wi h any o he ace s PSMA, choline, o luciclo ine and 10% o ed o a WB-MRI). 6.4. Imaging in he se ing o BCR (PSA) Clinical symp oms and PSA alone a e no good indica o s o absence o me as ases, wi h 32% o clinical M0 CRPC pa ien s being ound o be me as a ic when imaging was pe o med [101]. Rega ding PET/CT in BCR, a me a-analysis including bo h C-11 and F-18 choline-based echniques epo ed de ec ion a es g ea e han 50% o PSA alues abo e 2 ng/ml, wi h apid PSA kine ics and ele a ed Gleason sco e posi i ely ela ed o highe de ec ion a es [102–105]. The main limi a ion o choline PET/CT is he low sensi i i y when PSA alues a e <1 ng/ml. In BCR he e a e compa a i e s udies EUROPEAN UROLOGY 73 (2018) 178–211 194 be ween Ga-PSMA and choline demons a ing he supe i- o i y o Ga-PSMA in e ms o de ec ion a es a any PSA le el [106–108]. Guidelines (NCCN, EAU) ha e men ioned choline PET/CT in he si ua ion o BCR [21,22]. The use o nex -gene a ion imaging modali ies has led o iden i ica ion o me as a ic oci a lowe PSA le els. T ea ing physicians may eel mo e com o able o e ing abla ion o limi ed me as ases in hese cases, bu as o now he e a e no p ospec i e da a o show ha ea lie de ec ion o me as a ic disease wi h nex -gene a ion imaging esul s in a mean- ing ul long- e m clinical imp o emen . Imaging in men wi h ising PSA a e RP be o e s a ing SRT was o ed o by 44% o he panellis s in he majo i y o pa ien s independen o PSA le el, by 29% o panellis s in men wi h a PSA >0.5 ng/ml, by 12% o he panellis s in men wi h a PSA >1 ng/ml and by 13% o he panellis s in men wi h a PSA >2ng/ml. Fo imaging in men wi h oligome as a ic ecu en disease a e local ea men o p os a e cance wi h cu a i e in en ( SRT), 78% o he subse o panellis s who belie ed in he oligome as a ic ecu en s a e o ed o one o he nex - gene a ion imaging me hods o de ec me as a ic disease: namely 47% o ed o a PET/CT (PSMA, choline, o luciclo ine) alone, 2% o ed o a WB-MRI alone, 25% o he panel membe s o ed o a combina ion o a pel ic MRI and a PET/CT, 4% o he panellis s o ed o a combina ion o a pel ic MRI and a WB-MRI, and 22% o he panellis s o ed o imaging by CT and/o MRI and bone scin ig aphy . In men wi h de no o appa en oligome as a ic disease, 72% o he subse panellis s who belie ed in he oligome as a ic s a e o ed o one o he nex -gene a ion imaging me hods o suppo his diagnosis (apa om local s aging): namely 34% o ed o a PET/CT (PSMA, choline, o luciclo ine), 4% o ed o a WB-MRI, 34% o ed o ei he a PET/CT o WB-MRI, and 26% o hese panellis s o ed o imaging by CT and/o MRI and bone scin ig aphy. Asked abou he ecommended ace in case o a PET/CT in men wi h appa en oligome as a ic cas a ion-naı ¨ e disease, he e was a consensus (76%) amongs he panel membe s o PSMA as ace , 10% o ed o luciclo ine as a ace , and 6% o ed o choline; 4% o he panellis s o ed o any o he h ee ace s. In men wi h ising PSA on ADT (CRPC) and po en ially oligome as a ic disease, 74% o he subse o panellis s who belie e in oligome as a ic disease in mCRPC o ed o one o he nex -gene a ion imaging me hods o con i m his diagnosis: namely 48% o ed o a PET/CT (PSMA, choline, o luciclo ine), 6% o ed o a WB-MRI, 18% o he panel membe s o ed o a combina ion o a pel ic MRI and a PET/CT, 2% o he panellis s o ed o a combina ion o a pel ic MRI and a WB-MRI, and 26% o he panellis s o ed o imaging by CT and/o MRI and bone scin ig aphy. 6.5. S aging and moni o ing in mCNCP In mCNPC, wha is equi ed is an imaging modali y ha con i ms he p esence o me as ases and de ines hei loca ion. This is impo an o assessing p ognosis and o ea men decisions. Cu en guidelines (NCCN, EAU) do no commen on imaging me hods o men wi h mCNPC because o lack o da a. In mCNPC, 51% o he panel o ed o baseline imaging and ollow-up imaging a PSA nadi /comple ion o six cycles o doce axel as pa o chemo-ho monal he apy and again a p og ession (con i med PSA ise and/o clinical p og ession), 31% o he panel o ed o baseline imaging and egula moni o ing by imaging e e y 3–6 mo, and 18% o he panel o ed o baseline imaging only and moni o ing by PSA alone wi h u he imaging a p og ession. Rega ding he ecommended imaging modali y o s aging and moni o ing o men wi h mCNPC, 73% o he panel o ed o CT and bone scin ig aphy and 25% o he panellis s o ed o one o he nex -gene a ion imaging me hods. 6.6. S aging and moni o ing in mCRPC The ea ly iden i ica ion o ea men ailu e in men wi h mCRPC on sys emic he apy would help in spa ing some pa ien s u ile ea men and po en ial oxici y as well as in educing he cos s o ine ec i e ea men s and dec easing he ime o ini ia ion o a nex -line, po en ially e ec i e ea men [110]. Recen da a indica e ha he e a e a subs an ial numbe o pa ien s who ha e adiog aphic p og ession wi hou PSA p og ession, including some pa ien s wi h agg essi e a ian p os a e cance [111]. Im- aging be o e ea men ini ia ion and on- he apy may be impo an in p edic ing bo h bene i and mo e impo an ly nonbene i o ea men s. An ideal imaging me hod o moni o esponse o he apy should enable he e alua ion o umou cell iabili y, especially o bone disease. Techniques such as bone scin ig aphy, CT scans, and NaF PET ely on umou ma ix in e ac ions and a e only indi ec indica o s o umou cell iabili y. Imaging assessmen s should always be combined wi h clinical s a us and o he ac o s as also ecommended by he PCWG3 g oup [109]. Fo moni o ing by imaging in men wi h mCRPC on i s -line he apy, 54% o he panel o ed o baseline imaging and egula moni o ing by imaging e e y 3–6 mo, 28% o he panellis s o ed o baseline imaging and ollow-up imaging a PSA nadi and again a p og ession (con i med PSA ise and/o clinical p og ession); 16% o he panel o ed o baseline imaging only and moni o ing by PSA alone wi h u he imaging a p og ession. Rega ding imaging modali y o s aging and moni o ing in men wi h mCRPC, 74% o he panel o ed o CT and bone scin ig aphy and 24% o he panellis s o ed o one o he nex - gene a ion imaging me hods. Fo moni o ing o pa ien s wi h a diagnosis o agg essi e a ian mCRPC, 62% o he panellis s o ed o s anda d imaging by CT and bone scin ig aphy, 2% o ed o CT alone, and 36% o ed o nex -gene a ion imaging modali ies. 6.7. Discussion o imaging in APC The e a e su icien da a indica ing ha nex -gene a ion imaging echnologies ha e be e accu acy o de ec ing me as ases han CT and bone scin ig aphy. Howe e , hei EUROPEAN UROLOGY 73 (2018) 178–211 195 cu en use is dependen on cos s, local a ailabili y, and expe ise o in e p e a ion and he be e accu acy has no been shown o co ela e wi h imp o emen o clinical ou comes. The pe o mance o PET/CT wi h new ace s (PSMA and luciclo ine) as indica o s o ea men e icacy and as p edic o s o pa ien ou come has ye o be assessed. PSMA PET/CT should be in e p e ed wi h cau ion since he e a e da a sugges ing co ela ion be ween PSMA exp ession and AR signalling [112–117]. Tumou oci no exp essing PSMA (o lesions in o gans wi h high PSMA exp ession, eg, li e ) may no be assessable o esponse using PSMA PET/CT. No ably, o he umou ypes (eg, lung cance , enal cell cance ) and nonmalignan p ocesses like Page ’s disease and haemangioma can exp ess PSMA [118,119]. The use o hese nex -gene a ion imaging modali ies may be especially aluable in si ua ions whe e he umou bu den assessmen s a e needed o ea men decisions and/o when high sensi i i y is a equi emen . This may be pa icula ly applicable when mul imodali y sal age he a- py is being conside ed. Howe e , he p oo ha hei use leads o be e ea men decisions and ul ima ely leads o imp o ed ou comes is pending also in his si ua ion. Fo e alua ion o esponse in men wi h mCRPC i is e iden ha nex -gene a ion imaging (MRI and PET) may p o e o be mo e accu a e o e alua ing esponse o ea men [120]. Howe e , i should be no ed ha he ecen ly published PCWG3 do no ecommend he ou ine use o nex -gene a ion imaging me hods o men wi h APC ea ed on clinical ials mainly due o he lack o a ailabili y, ou come da a, and s anda disa ion ac oss global si es [109]. The ecen ly published guideline on epo ing WB-MRI in men wi h APC is a s ep in o he igh di ec ion bu hese ecommenda ions need o be adop ed, applied, and alida ed in clinical ials wi h p ima y endpoin o clinical ou come [88]. As an example, he sys ema ic e alua ion o FDG-PET s udies in pa ien s wi h Hodgkin’s disease has esul ed in a educ ion in ea men in ensi y leading o educ ion o oxici y [121]. Such ials wi h nex -gene a ion imaging a e la gely missing in men wi h APC [122]. The clinical in oduc ion o po en ially impac ul imag- ing echnologies has c ea ed an oppo uni y o p og ess by linking ana omy o unde lying biology bu he e is also a isk o up-s aging o many men in e e y disease s a e. The con ibu ion o he nex -gene a ion imaging echniques o he wel a e o pa ien s depends on pe o mance o he pu pose hey a e being applied (‘‘ i o use’’) and hei clinical u ili y (pa ien bene i ). The ea ly assessmen o new echnologies is he e o e encou aged bu hei gene al accep ance be o e measu es o pe o mance and e idence o bene i a e a leas es ima ed should no be suppo ed. No el imaging echniques should be clinically deployed ideally in a ial se ing bu a leas in egis ies wi h he goal o e icien ly es ima ing pe o mance and u ili y. Finally, i is impo an o ecognise ha he clinical ials ha o m he basis o he cu en ly app o ed ea men op ions a e based on e alua ions wi h CT and bone scin ig aphy. 7. Use o os eoclas - a ge ed he apy o SRE/SSE p e en ion o mCRPC (no o os eopo osis/bone loss) In p os a e cance , wo bone-di ec ed agen s, zoled onic acid and denosumab ha e been shown o p e en o delay he onse o SREs. Nei he o he d ugs in luences OS o PFS signi ican ly [123,124]. O he bisphosphona es, zoled onic acid is he only one ha has shown a p o ec i e e ec agains SRE in pa ien s wi h mCRPC [124,125]. Denosumab is a ully human monoclonal an ibody ha speci ically a ge s ecep o ac i a o o nuclea ac o kappa-B ligand hus e ec i ely inhibi ing os eoclas unc ion and bone eso p ion. In he se ing o mCRPC, denosumab (120 mg subcu aneous e e y 4 wk) compa ed wi h zoled onic acid (4 mg in a enous e e y 4 wk) signi ican ly imp o ed he ime o i s SRE [123]. A he p esen ime, hese agen s ha e p o en ele an e icacy only in pa ien s wi h bone mCRPC. The e is no e idence o suppo hei use in he nonme as a ic CRPC se ing and he e is e idence no o use i in he mCNPC se ing apa om os eopo osis p e en ion, using a di e en egimen, and dosage o bo h d ugs [43,126,127]. When looking a SSE, wo p ospec i e andomised s udies in men wi h mCRPC demons a ed an ad an age. The TRAPEZE s udy showed a signi ican delay in SSEs when doce axel was combined wi h zoled onic acid as compa ed wi h doce axel alone and ha he combina ion was sa e, bu he e was no imp o emen in OS [128]. In e es ingly, he bene i in delaying SSEs was in he same ange as wha was seen in he pi o al zoled onic acid s udy when chemo he - apy was no in use. Also, he ecen analysis o he la ge pi o al denosumab ial con i med a bene i in p e en ing SSEs [129]. Hypo hesis-gene a ing esul s ha e been p e- sen ed om he ALSYMPCA ial whe e he subg oup o pa ien s ecei ing a combina ion o adium-223 plus an os eoclas a ge ed he apy had a educ ion in SSE compa ed wi h adium-223 alone [72,130]. In an e a o li e p olonging he apies o mCRPC ha can also p e en o delay SREs, he added bene i o os eoclas [36_TD$DIFF]- a ge ed he apy is di icul o es ima e gi en he limi ed numbe o well designed, adequa ely powe ed s udies wi h long e m ollow-up. Rega ding he equency o adminis a ion o hese bone- di ec ed agen s a ecen andomised ial in di e en umou ypes also including 689 men wi h p os a e cance showed no inc eased isk o skele al e en s wi h zoled onicacid e e y 12 wk compa ed wi h e e y 4 wk [131]. Howe e , he p opo ion o pa ien s wi hCNPC e sus CRPC is no epo ed and bo h we e acc ued o he ial. No i m conclusions can be made om his ial because o his a iable. Fo educing he isk o skele al complica ions in men wi h mCRPC and bone me as ases, 86% o he panel we e in a ou o some o m o os eoclas - a ge ed he apy, 54% o he panel o ed o denosumab, 8% o ed o zoled onic acid, 24% o he panellis s o ed o ei he zoled onic acid o denosumab, and 10% did no o e o an os eoclas - a ge ed he apy a all. O hose panellis s who o ed o an os eoclas - a ge ed he apy in men wi h mCRPC, 68% o ed o a ea men EUROPEAN UROLOGY 73 (2018) 178–211 196 du a ion o abou 2 y and 32% o ed o no limi a ion o ea men du a ion. The ques ion o equency and du a ion o os eoclas - a ge ed he apy in he absence o signi ican oxici y o asymp oma ic men wi h mCRPC and bone me as ases esponding o i s -line sys emic mCRPC ea men is no esol ed. In he subse o panellis s who o ed o os eoclas - a ge ed he apy in men esponding o i s -line mCRPC he apy, 17% o he panellis s o ed o e e y 4 wk wi hou a de ined maximum du a ion, 37% o ed o e e y 4 wk o app oxi- ma ely 2 y and hen less equen ly, 15% o ed o e e y 3 mo, and 27% o he panel did no o e o an os eoclas - a ge ed he apy in his si ua ion. In he same pa ien popula ion, bu when hese men a e no longe esponding o i s -line he apy, 27% o he panellis s o ed o os eoclas - a ge ed he apy e e y 4 wk wi hou a de ined maximum du a ion and 53% o he panel o ed o e e y 4 wk o abou 2 y and hen less equen ly. Os eonec osis o he jaw (ONJ) is a possible se e e side e ec o os eoclas - a ge ed he apy ha inc eases wi h he du a ion o ea men [132,133] In men wi h mCRPC who de elop ONJ while on os eoclas - a ge ed he apy, he e was consensus (84%) o discon inue os eoclas - a ge ed he apy pe manen ly while 16% o he panellis s o ed o discon inua ion o he os eoclas - a ge ed he apy and es a ing a e comple e wound healing. 7.1. Discussion o he use o os eoclas - a ge ed he apy o SRE/SSE p e en ion o mCRPC The op imal iming, schedule, and du a ion o os eoclas - a ge ed he apy and he o e all balance o bene i and isk as well as e icacy in he e a o no el mCRPC ea men s a e s ill a ma e o deba e as he e is no Le el I e idence o guide decision making. E ec i e os eoclas inhibi o s a e commonly ecom- mended as pa o he o e all he apeu ic app oach o mCRPC also in an e a o mul iple li e p olonging agen s. Thei use in combina ion wi h app o ed li e p olonging mCRPC ea men s may enhance hei u ili y in e ms o educing he isk o o skele al complica ions and o main ain quali y o li e—bu hese da a ha e been de i ed om pos hoc and subg oup analyses and need o be add essed in p ospec i e clinical ials. In daily clinical p ac ice, he isk o side e ec s—especially ONJ—which inc eases wi h du a ion o he apy, by he ea ly use o os eoclas - a ge ed he apy o men wi h mCRPC has o be weighed up agains he po en ial bene i o educ ion in isk o SRE/SSE [133]. 8. Molecula cha ac e isa ion 8.1. Tumou biopsy in APC Since clinical he e ogenei y is common, mCRPC umou biopsies should be e iewed and in e p e ed in he app op ia e clinical con ex . This is especially impo an o uncommon ye challenging cases wi h small cell o neu oendoc ine di e en ia ion o umou s ha lack ex- p ession o classical p os a e ma ke s such as PSA o AR. Fu he mo e, no all pa ien s wi h clinical ea u es sugges- i e o and ogen independence demons a e small cell o neu oendoc ine ea u es on umou biopsy al hough hey may s ill bene i om pla inum based chemo he apy. These da a may po en ially be explained by molecula o e lap wi h neu oendoc ine p os a e cance [81,134]. Mo ing o wa d, inco po a ing molecula bioma ke s will likely imp o e he clinical diagnosis o non-AR d i en mCRPC and may help in pa ien selec ion o cu en he apies and selec ion o bioma ke s a i ied clinical ials [134–140]. Genomic al e a ions en iched in mCRPC wi h eme ging p ognos ic and/o ea men implica ions include AR gene mu a ion and ampli ica ion, phosphoinosi- ide 3-kinase/Ak /phospha ase and ensin homolog pa h- way al e a ions, DNA epai de ec s including loss o homologous ecombina ion (eg, BRCA1/2, ATM), and misma ch epai (wi h mic osa elli e ins abili y [MSI] and hype -mu a ed pheno ype), TP53 dele ion/mu a ion, and RB1 loss [134,140–144]. Al e a ions in ol ing RB1 and TP53 a e uni e sal in small cell cance s a ising elsewhe e in he body, such as[15_TD$DIFF] lung cance , and a e en iched in p os a e cance pa ien s wi h luminal o basal cell lineage swi ching and neu oendoc ine bioma ke exp ession and a e mecha- nis ically in ol ed in he de elopmen o ‘‘and ogen indi e en ’’ esis ance [136,139,140,143]. The panel o ed on molecula ac o s ha should be epo ed in a umou biopsy in men wi h mCRPC apa om epo ing umou mo phology (Table 10). The e was a consensus (78%) ha BRCA1, BRCA2, and ATM mu a ions should be epo ed because ha knowledge will likely in luence managemen decisions. Fo all o he ac o s he e was no consensus (Table 10). 8.2. And ogen ecep o splice a ian -7 and AR ampli ica ion/ mu a ion Using liquid biopsies in mCRPC pa ien s s a ing abi a e - one o enzalu amide, s a is ically signi ican associa ions wi h wo se ou come ha e been epo ed o de ec ion o AR splice a ian s including he AR-V7 ansc ip s in ci cula - ing cells o in exosomes, AR-V7 p o ein in he ci cula ing umo cell nucleus, o by analysing plasma cell- ee DNA AR gene copy numbe gain assessed ia cell- ee DNA o soma ic poin mu a ions simila ly quan i ied [145–150]. All s udies o da e we e single-a m ials, and s a is ically signi ican associa ions wi h esponse we e no ed—al- hough he co ela ion wi h esponse has ocused la gely on a es o PSA declines. Mo eo e , e idence emains ha some men wi h AR-V7 posi i e mCRPC may s ill espond o abi a e one/enzalu amide. The e was a consensus (96%) no o use AR-V7 es ing in daily ou ine clinical p ac ice o he majo i y o men wi h mCRPC. Simila ly, he e was a consensus (92%) no o use cell- ee DNA AR ampli ica ion and AR mu a ion es ing in daily ou ine clinical p ac ice o he majo i y o men wi h mCRPC. EUROPEAN UROLOGY 73 (2018) 178–211 197 8.3. Soma ic mu a ions Recen genomic s udies o me as a ic p os a e cance ha e iden i ied new molecula a ge s in he AR signalling pa hway, phosphoinosi ide 3-kinase pa hway, WNT pa h- way, cell cycle pa hways, and pe haps mos impo an ly, in DNA epai pa hways [135,141,151]. Fi y-nine pe cen o he panellis s did no o e o DNA sequencing o umou biopsies in he majo i y o men wi h mCRPC in ou ine daily clinical p ac ice, 37% o he panellis s o ed o a a ge ed/panel sequencing app oach, and 4% o ed o whole genome o exome sequencing. 8.4. DNA epai es ing in daily ou ine clinical p ac ice Recen s udies ha e shown ha men wi h APC commonly ha e soma ic abe a ions o genes ha make up a ious elemen s o he DNA epai machine y wi h 20–30% o APCs ha ing loss o unc ion o p o eins implica ed in homolo- gous ecombina ion epai , including BRCA2,BRCA1,ATM, PALB2, and o he s [141]. These abe a ions lead o homologous ecombina ion de iciency (HRD) de ec able by nex -gene a ion sequencing o hese genes o o he genomic sca s esul ing om his epai de ec es ima ed as an HRD sco e. A clinical ial (TOPARP) o he PARP inhibi o , olapa ib, has shown an i umou ac i i y agains p os a e cance s wi h HRD [142]. HRD de ec s ha e been p e iously epo ed o sensi ise umou cells o pla inum-based chemo he apy [152]. Clini- cal da a a e now eme ging ha HRD de ec s in p os a e cance s also sensi ise o pla inum-based chemo he apy [153] in keeping wi h p e ious epo s ha sa apla in has an i umou ac i i y agains his disease [76,154]. Soma ic dele e ious abe a ions o misma ch epai genes (MSH2,MSH6,MLH1,PMS2) ha e been ound in APC, and a e possibly associa ed wi h duc al pa hology, al hough hei p ecise equency emains unce ain and is in he ange o 5% o 15% [144,155,156]. 8.4.1. DNA epai de ec s in CNPC The p esence o DNA epai de ec s (ge mline o soma ic) in men wi h newly diagnosed mCNPC does no change he s anda d ea men ecommenda ion o 49% o he panel. Twen y- h ee pe cen o he panellis s we e mo e likely o gi e doce axel in addi ion o ADT and 22% o he panel we e mo e likely o include a pla inum agen in he chemo-ho monal ea men egimen. 8.4.2. DNA epai de ec s in mCRPC When es ing o DNA epai de ec s was conside ed o men wi h mCRPC, and no ecen mCRPC issue biopsy issue was a ailable, 70% o he subse o panellis s who suppo ed es ing in his si ua ion o ed o a esh mCRPC umou biopsy, 16% o he panellis s o ed o es ing in a chi al issue, and 14% o ed o es ing in ci cula ing cell- ee DNA. Six y- i e pe cen o he panel o ed o ea men wi h olapa ib, o ano he PARP inhibi o i a ailable and app o ed, in men wi h mCRPC and he p esence wi h DNA epai de ec s (ge mline o soma ic) based on he phase 2 da a wi h olapa ib, 29% o he panel o ed o such ea men in a mino i y o selec ed pa ien s and 4% did no o e o i a all. Some panel membe s o ed ha i was app op ia e o ex apola e he phase 2 da a om olapa ib o pla inum agen s o men wi h mCRPC and p esence o DNA epai de ec s (ge mline o soma ic): 45% in he majo i y o pa ien s and 14% in a mino i y o selec ed pa ien s; howe e 35% o he panellis s did no suppo his ex apola ion. Table 10 – As a clinician, which ac o s do you wan o ha e epo ed back o you in men wi h me as a ic cas a ion- esis an p os a e cance who unde go a me as a ic umou biopsy apa om umou mo phology and di e en ia ion? The ques ion is only abou managemen o a speci ic pa ien , no abou amilial implica ions, and based on knowledge in e ms o es accu acy/ alidi y and a ailable ea men s Fac o Yes, use ul es o majo i y o pa ien s (influences you managemen decision; %) Only o mino i y o selec ed pa ien s (%) No (%) Abs ain (%) BRCA1, BRCA2, and ATM mu a ions 78 20 2 0 PSA IHC 72 18 10 0 O he DNA epai genes (eg, CHEK2, PALB2, and o he s) 64 22 12 2 MMR gene al e a ions (MSI, MMR p o ein IHC, o by di ec sequencing) 54 22 20 4 Ch omog anin, synap ophysin, CD56/NSE 50 31 17 2 Loss o PTEN 44 26 26 4 AR amplifica ion and/o AR mu a ion 43 18 37 2 TP53 and RB1 34 22 40 4 Nuclea AR 34 18 46 2 AR-V7 33 26 37 4 PSMA 32 22 44 2 Ki67/MiB1 28 26 42 4 P os a e acid phospha ase 26 18 54 2 PD-1/PD-L1 22 31 45 2 NKX3.1 12 33 49 6 ERG IHC 12 30 56 2 ERG FISH 11 23 64 2 AR = and ogen ecep o ; FISH = fluo escen in si u hyb idiza ion; IHC = immunohis ochemis y; MMR = misma ch epai ; MSI = mic osa elli e ins abili y; PD- 1 = p og ammed cell dea h-1; PD-L1 = p og ammed dea h-ligand 1; PSA = p os a e-specific an igen; PSMA = p os a e-specific memb ane an igen; PTEN = phospha ase and ensin homolog. EUROPEAN UROLOGY 73 (2018) 178–211 198 Six y-se en pe cen o he panel o ed o s anda d i s -line mCRPC he apy in men wi h mCRPC and p esence o DNA epai de ec s (ge mline o soma ic) p og essing on ADT, 21% o he panellis s o ed o a pla inum-based combina ion, and 10% o a PARP inhibi o . In men wi h mCRPC and a p esence o DNA epai de ec s in he second-line se ing (a e s anda d i s -line he apy), 40% o he panellis s o ed o a pla inum-based combina ion, 33% o he panel o ed o s anda d second-line mCRPC ea men , 21% o ea men wi h a PARP-inhibi o , and 4% o a pla inum mono he apy. 8.5. Discussion o molecula cha ac e isa ion Gi en men wi h mCRPC a e su i ing longe , and wi h se e al ea men op ions a ailable, biopsies o me as a ic lesions a e mo e commonly pu sued o ule ou small cell ca cinoma, an agg essi e a ian , o a second malignancy. Bu he eal place o me as ases biopsy emains unclea in e e yday p ac ice. Wi h a mul i ude o po en ial p edic i e and p ognos ic ma ke s ha can be es ed in a mCRPC umou biopsy, i is impo an o p o ide some guidance. As o Ma ch 2017, he e was only consensus om he panel o es ing o BRCA1,BRCA2, and ATM mu a ions in mCRPC issue. Se e al egis a ion ials a e now being conduc ed wi h di e en PARP inhibi o s o men wi h APC and e idence o DNA epai de ec s (eg, NCT02952534, NCT02975934, NCT02854436, NCT03012321) and in he absence o app o ed PARP inhibi o s o mCRPC, en olmen o men in clinical ials is s ongly ecommended. Addi ionally, he e a e also p ospec i e ials o pla i- num-based he apy ongoing in men wi h ad anced molecula ly selec ed p os a e cance s, which may demon- s a e ha his is an impo an he apeu ic s a egy o his subg oup o pa ien s (eg, NCT02598895, NCT02311764, NCT02955082). Al hough ueMSIis a einp os a ecance ,i sp esence is impo an because MSI+ cance s ha e a high a e o du able esponses o immune checkpoin blockade using d ugs ha block he p og ammed cell dea h-1/p o- g ammeddea h-ligand1in e ac ion[157]. Based on 149 pa ien s wi h MSI-H o dMMR cance s en olled ac oss i e uncon olled, mul i-coho , mul i-cen e , single-a m clinical ials pemb olizumab has been app o ed by he FDA o use in MSI high and dMMR cance pa ien s ega dless o his ology. This app o al is o clea in e es o clinicians and o[16_TD$DIFF] pa ien s wi h p os a e cance and[37_TD$DIFF] e idence o hese al e a ions. Al hough a p opo ion o he panel o ed o using a PARP inhibi o o pla inum-based chemo he apy in mCRPC, e en in he i s -line se ing, he e is no e idence ha such a s a egy is o ad an age as compa ed wi h he s anda d app o ed mCRPC ea men s o da e. The e o e, in he absence o p ospec i e andomised ials showing clinical bene i o a s a egy using a PARP-inhibi o o a pla inum- based chemo he apy, he use o hese subs ances as i s - line mCRPC ea men ou side o clinical ials should no be gene ally ecommended. Fo he liquid bioma ke s, namely AR-V7 and AR mu a ion o ampli ica ion, he e was a consensus ha cu en ly none o hese ma ke s should be es ed in ou ine p ac ice o decision making. This consensus agains es ing is in pa based upon he low de ec ion le els o AR-V7 p io o i s - and second-line he apies and he high p obabili y ha pa ien s would ecei e abi a e one o enzalu amide in his si ua ion. These es s need o be alida ed and u he s udies need o be pe o med o de e mine hei impac on long- e m ou comes. 9. Ge mline gene ic counselling/ es ing The ae iology o p os a e cance is no well unde s ood, al hough epidemiological s udies demons a ing a con e - gence o incidence a es in some popula ions mig a ing be ween a eas wi h a low incidence o hose wi h high incidence sugges en i onmen al and li es yle isk ac o s play a ole [158]. Ha ing a posi i e amily his o y and/o a ce ain e hnic backg ound such as A o-Ca ibbean is a isk ac o o p os a e cance de elopmen . E idence om s udies whe e monozygo ic wins we e compa ed wi h dizygo ic wins sugges ha 57% o he isk o p os a e cance p os a e cance is due o gene ic ac o s [159]. Nu- me ous s udies o isks o ela i es o p os a e cance cases show a highe ela i e isk o de eloping p os a e cance , which inc eases as he age o he p oband dec eases, and he numbe o a ec ed ela i es inc eases. Fi s deg ee ela i es o p os a e cance pa ien s ha e wice he isk o de eloping he disease compa ed wi h he gene al popula ion [160].In men diagnosed unde he age o 60 y , he isk o hei i s deg ee ela i es is mo e han ou old ha o hose wi hou a amily his o y [161]. The a ia ion in incidence acco ding o e hnici y also sugges s a gene ic componen ; a es a e highe in A ican Ame ican men compa ed wi h Asian- Ame ican men [162]. S udies o amilial inhe i ance and seg ega ion analyses ha e p oposed a ious gene ic models (au osomal domi- nan , ecessi e, and X-linked) [163]. I is now ecognised ha gene ic p edisposi ion o p os a e cance is composed o common (>[1_TD$DIFF]5%) lowe isk a ian s single nucleo ide polymo phisms—mos o which a e no in coding egions and a e highe isk a ian s (coding mu a ions in genes). O e 100 single nucleo ide polymo phisms associa ed wi h he de elopmen o p os a e cance ha e been iden i ied hus a [164]. Ra e a ian s a e hose which ha e a mino allele equency o <5%, and occu oo in equen ly o be de ec ed on a genome-wide associa ion s udy. Nex -gene a ion sequencing o a ge ed a eas o whole genome/exome sequencing has enabled he de ec ion o hese a e a ian s. Resul s showed ha men om amilies whe e emales had de eloped b eas and o a ian cance caused by BRCA mu a ions ha e a i e- old ela i e isk o p os a e cance when hey ha bou a ge mline BRCA2 mu a ion compa ed wi h men wi hou a mu a ion. This ela i e isk inc eases o up o se en- old i he men in he amily de elop p os a e cance below he age o 65 y [165]. In a la ge s udy, 2000 men wi h p os a e cance we e sc eened. This showed EUROPEAN UROLOGY 73 (2018) 178–211 199 ha jus o e 1% o men who de eloped p os a e cance below he age o 65 y ca ied a dele e ious BRCA2 mu a ion and o en hey did no ha e a posi i e amily his o y [166]. Fo men who a e ca ie s o a BRCA1 mu a ion, s udies ha e shown ha he e is an app oxima ely ou - imes ela i e isk o de eloping p os a e cance o men aged unde 65 y compa ed wi h hose wi hou he mu a ion [167]. I has been subsequen ly shown in men wi h a amily his o y o a leas h ee cases o p os a e cance ha hey ha e a ge mline mu a ion in DNA epai genes in 7.3% and ha he disease was mo e likely o be agg essi e [168]. Se e al g oups ha e shown ha BRCA1 and BRCA2 mu a ion ca ie s ha e a mo e agg essi e o m o p os a e cance and also ha e a wo se p ognosis [169,170]. Mu a ion ca ie s a e also likely o p esen wi h a highe isk o local nodal in ol emen as well as wi h dis an me as a ic disease [171]. The op imal adical ea men op ion o hese pa ien s is ye o be de e mined, bu RP may be he mos sui able, al hough he numbe s o pa ien s s udied a e ela i ely small [172]. Rema kably, ge mline mu a ions ha e been ound in abou hal o he men wi h umou HR DNA epai gene de ec s and abou one in i e men wi h an misma ch epai DNA epai gene de ec [141,173]. In a la ge mul i- ins i u ional s udy o almos 700 men wi h me as a ic p os a e cance unselec ed o age o amily his o y, 11.8% o e all we e ound o ha e mode a e o high pene ance ge mline mu a ions in one o 16 DNA epai genes, wi h 7.8% o mu a ions in BRCA2,BRCA1, and ATM [173]. Two la ge single-ins i u ion s udies o me as a ic p os a e cance ound simila a es o ge mline BRCA2,BRCA1,andATM mu a ions, wi h much lowe a es in low isk indolen disease [174,175]. Rega ding gene ic counselling and es ing o men wi h newly diagnosed me as a ic p os a e cance , 20% o he panel o ed o do i in a majo i y o pa ien s: 62% o he panel o ed in a ou o gene ic counselling/ es ing in a mino i y o selec ed pa ien s and 18% did no o e o do i a all. The subse o panellis s who had o ed o gene ic es ing in a mino i y o selec ed pa ien s suppo ed gene ic counselling and es ing in men wi h a posi i e amily his o y o p os a e cance (95%); also, 93% o hese panellis s suppo ed counsel- ling/ es ing in men wi h a posi i e amily his o y o o he cance synd omes (eg, he edi a y b eas and o a ian cance synd ome and/o panc ea ic cance o Lynch synd ome). Fu he , 74% o hese panellis s o ed o gene ic counselling and es ing in men wi h p os a e cance diagnosed a 60 y bu 26% o hese panellis s did no o e o gene ic counselling and es ing based on an age cu -o alone. Among he subse o panellis s who ecommended gene ic es ing, 61% o ed o la ge panel es ing including homologous ecombina ion and misma ch DNA epai (eg, comp ehensi e cance isk assessmen panels), 15% o ed o BRCA1 and BRCA2 es ing only, 15% o ed o BRCA1, BRCA2, and ATM es ing, and 9% o ed o la ge panel es ing including homologous ecombina ion DNA epai (eg, panels ha a e also used o assess b eas cance isk). The e was a consensus (92%) ha in he p esence o a ge mline BRCA1, BRCA2, o ATM mu a ion a p ophylac ic RP was no ecommended. The panel was asked whe he he p esence o a ge mline BRCA1, BRCA2, o ATM mu a ion would in luence hei ea men decision in men wi h low- isk localised p os a e cance . Fo y- i e pe cen o ed agains ac i e su eillance in hese pa ien s, 35% o ed o s anda d ea men op ions (including ac i e su eillance), and 20% o ed o ano he ea men op ion. The panel was asked whe he he p esence o a ge mline BRCA1, BRCA2, o ATM mu a ion would in luence hei ea men decision in men wi h in e media e- o high- isk localised p os a e cance . Fi y- wo pe cen o he panel o ed o a RP o e RT, 44% o he panel o ed o s anda d ecommenda ions, and 4% o ed o RT o e a RP. 9.1. Discussion o ge mline gene ic counselling/ es ing The unde s anding o he ole o gene ics in p os a e cance de elopmen is e ol ing apidly, which is e lec ed by he ac ha 20% o he panellis s ecommended gene ic counselling and es ing in a majo i y o men wi h me as a ic p os a e cance i espec i e o amily his o y. Age a diagnosis i sel does no seem o be he bes selec ion ma ke , bu 74% o he panel who ecommended gene ic counselling and es ing in selec ed pa ien s would es in men aged 60 y . The impac o a BRCA2 ge mline mu a ion on he managemen in an o he wise heal hy man is no clea and in he absence o any p ospec i e da a he e was a consensus no o ecommend p ophylac ic RP in such men. Cu en ly, o p os a e cance ca e p o ide s o de ing ge mline gene ic cance panel es ing o o de ing his es ing in he nea u u e, he e a e se e al impo an poin s o conside including which genes o es o . The e a e eme ging p os a e cance p ac ice ecommenda ions only o BRCA1,BRCA2, and ATM mu a ions, ye mos nex - gene a ion sequencing cance panels include many mo e DNA epai genes o he same cos . The e a e cu en ly no gene-speci ic da a on ea men p edica ion o p os a e cance isk o mos DNA epai genes. Ge mline gene ic es ing should be o de ed wi h adequa e p e es and/o pos es gene ic counselling. In pa icula , he e is a need o counsel abou he possibili y o a a ian o unce ain signi icance (VUS) being de ec ed and/o a pa hogenic mu a ion in a gene in which he e a e no adequa e da a o al e managemen o p os a e cance . Pa ien s wi h VUS should be managed he same as pa ien s wi h a nega i e es esul , and he e is a dange ha in daily p ac ice VUS may be misin e p e ed as a posi i e esul . The ques ion o es ing o amily membe s is unanswe ed and sc eening ecommenda ions i mu a ions a e de ec ed need o be gene a ed. The e a e da a sugges ing ea lie PSA sc eening in men wi h BRCA2 and po en ially also in men wi h BRCA1 ge mline mu a ions [176]. Mo e da a a e needed o app op ia e counsel una ec ed male amily membe s abou p os a e cance isk and make sc eening ecommenda ions. La ge collabo a i e e o s a e unde way (eg, NCT00261456, PRACTICAL conso ium) o add ess some o he open ques ions. Howe e , in o de o mo e he ield o wa d mo e e o s a e needed o collabo a e—especially on p os a e cance s wi h ge mline mu a ions ha occu a a EUROPEAN UROLOGY 73 (2018) 178–211 200 low equency. The panel ecommends o be especially ca e ul (no o e in e p e ) abou ea men ecommenda- ions based on ge mline mu a ions in men wi h localised p os a e cance . 10. Side e ec s o sys emic ea men : p e en ion, managemen , and suppo i e ca e A subs an ial p opo ion o men wi h APC will die o a noncance - ela ed cause and mus li e wi h he acu e and ch onic side e ec s o ea men . Mos men wi h localised p os a e cance do no die o hei disease, bu will spend he es o hei li es managing he e ec s o he ea men hey ha e unde gone. The wishes o ou pa ien s and hei amilies a e clea : hey wish o be cu ed o hei disease o o ha e hei su i al p olonged, bu no necessa ily a he cos o in ole able side e ec s o ea men . Some imes i is easy o lose sigh o his goal in he sea ch o be e oncological ou comes. One-hund ed pe cen o he panel belie ed ha he e was a leas mode a e e idence ha ADT inc eases he isk o bone loss and/o ac u es; 87% belie ed his e idence was s ong. Baseline measu emen o i amin D o men wi h p os a e cance s a ing on ADT was o ed o in he majo i y o pa ien s by 43% o he panellis s, in a mino i y o pa ien s by 26% and 31% o he panellis s did no o e o i . Rou ine supplemen a ion o calcium and i amin D o men wi h p os a e cance s a ing on ADT was o ed o by 73% o he panel, only o i amin D by 13%, only calcium by 2%, and 12% o he panel did no o e o ou ine supplemen a ion. A baseline measu emen o bone mine al densi y in men wi h p os a e cance s a ing on ADT was o ed o by 62% o he panellis s in he majo i y o pa ien s, by 15% only in pa ien s wi h nonme as a ic disease and 21% did no o e o i a all. D ug he apy o p e en bone loss and/o ac u es wi h denosumab o a bisphosphona e in he dose and schedule o os eopo osis p ophylaxis in men wi h p os a e cance s a ing on ADT was o ed o in he majo i y o pa ien s by 16% o he panellis s, by 70% o panellis s only in pa ien s wi h documen ed os eopenia o os eopo osis, and 12% did no o e o i . Thi y- i e pe cen o he panellis s el ha he e is s ong e idence ha ADT inc eases he isk o diabe es, 46% el ha he e is mode a e, and 17% ha he e is weak e idence o his co ela ion. Two[38_TD$DIFF] pe cen belie e ha ADT does no change he isk o diabe es. Fo ca dio ascula disease, 12% o he panellis s el ha he e is s ong e idence ha ADT inc eases he isk, 39% el ha he e is mode a e, and 45% ha he e is weak e idence o his co ela ion. Fou [38_TD$DIFF] pe cen belie e ha ADT does no change he isk o ca dio ascula disease. A his o y o ecen /se e e ca dio ascula disease in luenced he choice o ADT in men wi h me as a ic p os a e cance o 29% o he panellis s in he majo i y o pa ien s, o 41% o he panellis s o a mino i y o selec ed pa ien s, and o 28% o he panellis s i did no in luence hei choice o ADT. Fo he subse o panellis s whose decisions was in luenced by a his o y o ecen /se e e ca dio ascula disease, 11% o ed o using LHRH agonis s, 52% o use o LHRH an agonis s, 6% o o chiec omy, 20% o any o m o in e mi en ADT, and 11% o ed o bicalu amide 150 mg/d in such a pa ien . Eigh [38_TD$DIFF] pe cen o he panellis s belie ed ha he e is s ong e idence ha ADT inc eases he isk o cogni i e changes and/ o demen ia, 29% el ha he e is mode a e, and 50% ha he e is weak e idence o his co ela ion. Thi een[38_TD$DIFF] pe cen belie e ha ADT does no change he isk o cogni i e changes and/o demen ia. Fo dep ession, 6% o he panellis s belie ed ha he e is s ong e idence ha ADT inc eases he isk, 46% el ha he e is mode a e, and 44% ha he e is weak e idence o his co ela ion. Fou [38_TD$DIFF] pe cen belie e ha ADT does no change he isk o dep ession. A mul idisciplina y managemen eam can include he necessa y expe ise o deal wi h hese issues [177]. Im- p o ed ou comes a e appa en wi h in ol emen o p os a e cance nu ses and ca e coo dina o s. Endoc inol- ogis s and and ologis s can p o ide ad ice on he manage- men o diabe es, me abolic synd ome, bone heal h, ca dio ascula , and sexual heal h. Psychologis s can p o ide suppo o he common p oblems o suicidal isk, dis ess, and long- e m psychological and sexual mo bidi y [178– 181]. The exe cise physiologis can p o ide p og ams o coun e ac he e ec s o ADT, imp o e psychological symp oms, and imp o e o e all and disease-speci ic su i al [182–184]. The di ec p o ide o ca e o men wi h APC can also lea n such skills. Comp ehensi e ge ia ic assessmen has been shown o be associa ed wi h a highe p obabili y o comple ing a ea men cou se, ewe modi ica ions o ea men , and lowe oxici y [185,186]. Rou ine in ol emen o a mul idisciplina y/mul ip o es- sional eam o p e en ion o managemen o ADT ela ed ad e se e ec s was o ed o by 42% o he panellis s o he majo i y o pa ien s, by 39% in a mino i y o selec ed pa ien s, and 17% did no o e o i . Six y-one pe cen o he panellis s o ed o ea ly access o an expe in symp om pallia ion o a dedica ed pallia i e ca e se ice and 39% o he panellis s did no o e o i . The e was consensus (94% o he panellis s) o access o opia e pain medica ion o men wi h me as a ic p os a e cance and se e e pain when lowe le el pain medica ion is no su icien . Thi y[38_TD$DIFF] pe cen o he panellis s o ed o a heal h s a us assessmen in men wi h APC 70 y be o e ea men decision in he majo i y o pa ien s, 42% o ed o i in a mino i y o selec ed pa ien s, and 24% did no o e o i . The subse o panellis s who o ed o a heal h s a us assessmen o ed o comp ehensi e ge ia ic assessmen in 26%, G8 and Mini-COG in 29%, G8 alone in 30%, and ano he ool in 15%. The e was consensus (98% o he panellis s) o egula physical exe cise in men wi h p os a e cance s a ing on ADT. 10.1. Discussion o side e ec s o sys emic ea men : p e en ion, managemen , and suppo i e ca e The aging popula ion o men wi h APC is now su i ing longe , allowing longe - e m complica ions o ea men o EUROPEAN UROLOGY 73 (2018) 178–211 201 become appa en and o a ec unc ion and symp oms. The e idence ha ADT nega i ely impac s bone heal h and he a endan isk o ac u es is conside ed s ong by a majo i y o he panel. ADT has also been associa ed wi h an inc eased isk o me abolic synd ome, ype 2 diabe es, and sa copenia; howe e , e idence linking ADT di ec ly as a cause o ascula disease is weak and he e is no con incing e idence ha ADT is linked causally o he de elopmen o demen ia as e lec ed in he o e o he panellis s [187– 196]. Men should be in o med abou he acu e bu also he long- e m side e ec s o ADT and impo an ly he possible p e en i e measu es. In e es ingly, he e was no consensus o he ou ine assessmen o heal h s a us in men aged 70 y , likely based on he ac ha he e a e no la ge p ospec i e clinical ials [39_TD$DIFF]which ha e shown ha using heal h s a us assessmen in men wi h me as a ic p os a e cance has a ele an impac on ou come, especially when compa ed wi h he judgemen o expe ienced physicians. This ecommenda ion could also e lec a lack o consensus on wha would cons i u e such a ‘‘heal h s a us assessmen .’’ Finally, he e is a need o clinical ials and egis a ion s udies speci ically in his pa ien popula ion. 11. Global access o p os a e cance d ugs and ea men in coun ies wi h limi ed esou ces The panel o ed on a numbe o ques ions ega ding ea men op ions in men wi h APC in lowe and middle- income coun ies (LMIC) because he opic o global access o APC ea men s was discussed a APCCC 2017. I li ing in a coun y wi h limi ed esou ces a ailable o heal h ca e, 90% o he panellis s o ed o o chiec omy as ADT in he me as a ic se ing. The emaining 10% o ed o an LHRH agonis . As second-line endoc ine manipula ions in LMIC in men wi h mCRPC p og essing on ADT, 44% o he panellis s o ed o a i s gene a ion AR an agonis , 24% o s e oid mono- he apy, 20% o ke oconazole, 8% o oes ogens, and 4% o es amus ine. Each o he ollowing d ugs is on he Wo ld Heal h O ganiza ion (WHO) essen ial medicines lis and/o hey can be sou ced a an a o dable p ice om gene ic manu ac u e . The panel o ed on app op ia e ea men op ions in he se ing o limi ed heal h ca e esou ces in men wi h mCRPC who a e p og essing on o a e doce axel: 77% o he panellis s o ed o a pla inum, 19% did no o e o i . Mi oxan one was o ed o by 69% o he panellis s. Thi y- nine pe cen o ed o he use o cyclophosphamide, 53% did no . The e was a consensus no o use pacli axel (78%) o doxo ubicin (84%) in his si ua ion. 11.1. Discussion o global access o p os a e cance d ugs and ea men in coun ies wi h limi ed esou ces P os a e cance gene ally is mo e common in highe income coun ies, bu his is changing as men in LMIC li e longe , due o be e con ol o in ec ious disease and o he causes o ea ly mo ali y. Men in LMIC end o p esen wi h mo e ad anced disease and access o he su i al p olonging agen s o mCRPC is limi ed o many men in LMIC. Al hough he panel ecommended o chiec omy as i s choice o ADT in men p esen ing wi h me as a ic p os a e cance , he socio-cul u al and psychological ba ie s o such an in e en ion mus be aken in o conside a ion in such ea men decisions. As seconda y ho monal ea men op ion o men wi h mCRPC, endoc ine manipula ions including glucoco icoids, oes ogens, i s gene a ion and ogen ecep o inhibi o s, and ke oconazole a e a ailable and he panel conside ed especially i s -gene a ion AR inhibi o s a alid ea men op ion in LMIC. Abi a e one and enzalu amide a e examples o high-cos d ugs wi h limi ed access in LMIC. Bo h d ugs we e de eloped subs an ially h ough esea ch in academic labo a o ies and cance cen es. In he USA, app o ed doses a e ma ke ed a US$ 7000/mo, while publicly unded heal h sys ems such as B i ain and Canada ha e been able o nego ia e a subs an ially lowe p ice o $3000/mo. Gene ic abi a e one (bu no enzalu amide) is a ailable in India o abou $450/mo, which is, howe e , s ill oo expensi e o many men wi h mCRPC in India. The ollowing d ugs which ha e shown some an i umou ac i i y bu no OS bene i in men wi h mCRPC and a e on he WHO essen ials medicine lis : ca bopla in, pacli axel, doxo ubicin, and cyclophosphamide. Ca bopla in was ecommended by a majo i y o he panellis s. Mi oxan one is no on he WHO essen ials medicine lis bu has shown a pain pallia ion bene i and could be sou ced a a easonable p ice. Many o hese d ugs a e subs an ially cheape han he app o ed and su i al p olonging agen s o mCRPC and hey can be used some imes as subs i u es o newe agen s in LMIC. While his is a easonable s a egy, i alls a sho o he ideal o p o iding he mos e ec i e ea men s o all men wi h APC. A majo goal o his consensus con e ence is o imp o e he managemen and ou comes o men wi h APC. Howe e , i is a subop imal clinical achie emen o show ha new ea men s can imp o e he du a ion and quali y o su i al o men wi h APC, bu o ha e such ea men s una ailable o a la ge segmen o he global popula ion o men wi h APC. The a ailabili y o RT as a e y e ec i e bone pain pallia ion he apy is no gi en in many coun ies. We canno easily change he way ha d ugs a e de eloped and ma ke ed o p o i by academic, pha maceu ical, and bio echnology companies, and we ce ainly espec and collabo a e wi hin his sys em o he de elopmen o needed new ea men s o men wi h APC. Bu men wi h APC a e s ill unable o access op imal ea men s, o en imes no because hey could no be made a ailable, bu because hey a e no made a ailable a an a o dable p ice. Hence, we encou age ongoing mul idisciplina y and s akeholde dialogue o u he add ess his global issue. 12. Conclusions In he absence o Le el I e idence and in a eas whe e he e a e con lic ing da a o con lic ing in e p e a ion o a ailable EUROPEAN UROLOGY 73 (2018) 178–211 202 [116] Miyamo o DT, Lee RJ, S o SL, e al. And ogen ecep o signaling in ci cula ing umo cells as a ma ke o ho monally esponsi e p os a e cance . Cance Disco 2012;2:995–1003. [117] Melle B, B emme F, Sahlmann CO, e al. Al e a ions in and ogen dep i a ion enhanced p os a e-specific memb ane an igen (PSMA) exp ession in p os a e cance cells as a a ge o diag- nos ics and he apy. EJNMMI Res 2015;5:66. [118] Rowe SP, De ille C, Palle C, e al. Up ake o 18F-DCFPyL in Page ’s disease o bone, an impo an po en ial pi all in clinical in e p e- a ion o PSMA PET s udies. Tomog aphy 2015;1:81–4. [119] Ho man MS, I a ani A. Gallium-68 p os a e-specific memb ane an igen PET imaging. PET Clin 2017;12:219–34. [120] De Gio gi U, Ca oli P, Sca pi E, e al. (18)F-Fluo ocholine PET/CT o ea ly esponse assessmen in pa ien s wi h me as a ic cas a ion- esis an p os a e cance ea ed wi h enzalu amide. Eu J Nucl Med Mol Imaging 2015;42:1276–83. [121] Enge A, Ha e kamp H, Kobe C, e al. Reduced-in ensi y chemo- he apy and PET-guided adio he apy in pa ien s wi h ad anced s age Hodgkin’s lymphoma (HD15 ial): a andomised, open- label, phase 3 non-in e io i y ial. Lance 2012;379:1791–9. [122] Pe ez-Lopez R, Ma eo J, Mossop H, e al. Di usion-weigh ed imaging as a ea men esponse bioma ke o e alua ing bone me as ases in p os a e cance : a pilo s udy. Radiology 2017;283:168–77. [123] Fizazi K, Ca ducci M, Smi h M, e al. Denosumab e sus zoled onic acid o ea men o bone me as ases in men wi h cas a ion- esis an p os a e cance : a andomised, double-blind s udy. Lan- ce 2011;377:813–22. [124] Saad F. Zoled onic acid significan ly educes pa hologic ac u es in pa ien s wi h ad anced-s age p os a e cance me as a ic o bone. Clin P os a e Cance 2002;1:145–52. [125] Saad F, Gleason DM, Mu ay R, e al. Long- e m e ficacy o zole- d onic acid o he p e en ion o skele al complica ions in pa ien s wi h me as a ic ho mone- e ac o y p os a e cance . J Na l Cance Ins 2004;96:879–82. [126] Smi h MR, Saad F, Coleman R, e al. Denosumab and bone-me as- asis- ee su i al in men wi h cas a ion- esis an p os a e can- ce : esul s o a phase 3, andomised, placebo-con olled ial. Lance 2012;379:39–46. [127] Smi h MR, Halabi S, Ryan CJ, e al. Randomized con olled ial o ea ly zoled onic acid in men wi h cas a ion-sensi i e p os a e cance and bone me as ases: esul s o CALGB 90202 (alliance). J Clin Oncol 2014;32:1143–50. [128] James ND, Pi ie SJ, Pope AM, e al. Clinical ou comes and su i al ollowing ea men o me as a ic cas a e- e ac o y p os a e cance wi h doce axel alone o wi h s on ium-89, zoled onic acid, o bo h: The TRAPEZE andomized clinical ial. JAMA Oncol 2016;2:493–9. [129] Smi h MR, Coleman RE, Klo z L, e al. Denosumab o he p e en- ion o skele al complica ions in me as a ic cas a ion- esis an p os a e cance : compa ison o skele al- ela ed e en s and symp- oma ic skele al e en s. Ann Oncol 2015;26:368–74. [130] Sa o O, Coleman R, Nilsson S, e al. E ec o adium-223 dichlo - ide on symp oma ic skele al e en s in pa ien s wi h cas a ion- esis an p os a e cance and bone me as ases: esul s om a phase 3, double-blind, andomised ial. Lance Oncol 2014;15: 738–46. [131] Himels ein AL, Fos e JC, Kha che essian JL, e al. E ec o longe - in e al s s anda d dosing o zoled onic acid on skele al e en s in pa ien s wi h bone me as ases: a andomized clinical ial. JAMA 2017;317:48–58. [132] Pa el V, Kellehe M, Sp oa C, Kwok J, McGu k M. New cance he apies and jaw nec osis. B Den J 2015;219:203–7. [133] Saad F, B own JE, Van Poznak C, e al. Incidence, isk ac o s, and ou comes o os eonec osis o he jaw: in eg a ed analysis om h ee blinded ac i e-con olled phase III ials in cance pa ien s wi h bone me as ases. Ann Oncol 2012;23: 1341–7. [134] Bel an H, P andi D, Mosque a JM, e al. Di e gen clonal e olu ion o cas a ion- esis an neu oendoc ine p os a e cance . Na Med 2016;22:298–305. [135] Bel an H, Eng K, Mosque a JM, e al. Whole-exome sequencing o me as a ic cance and bioma ke s o ea men esponse. JAMA Oncol 2015;1:466–74. [136] Apa icio AM, Shen L, Tapia EL, e al. Combined umo supp esso de ec s cha ac e ize clinically defined agg essi e a ian p os a e cance s. Clin Cance Res 2016;22:1520–30. [137] Da denne E, Bel an H, Benelli M, e al. N-Myc Induces an EZH2- media ed ansc ip ional p og am d i ing neu oendoc ine p os- a e cance . Cance Cell 2016;30:563–77. [138] Bishop JL, Thape D, Vahid S, e al. The mas e neu al ansc ip ion ac o BRN2 is an and ogen ecep o -supp essed d i e o neu o- endoc ine di e en ia ion in p os a e cance . Cance Disco 2017;7:54–71. [139] Li Y, Donmez N, Sahinalp C, e al. SRRM4 d i es neu oendoc ine ansdi e en ia ion o p os a e adenoca cinoma unde and ogen ecep o pa hway inhibi ion. Eu U ol 2017;71:68–78. [140] Mu P, Zhang Z, Benelli M, e al. SOX2 p omo es lineage plas ici y and an iand ogen esis ance in TP53- and RB1-deficien p os a e cance . Science 2017;355:84–8. [141] Robinson D, Van Allen EM, Wu YM, e al. In eg a i e clinical genomics o ad anced p os a e cance . Cell 2015;161:1215–28. [142] Ma eo J, Ca ei a S, Sandhu S, e al. DNA- epai de ec s and olapa ib in me as a ic p os a e cance . N Engl J Med 2015;373: 1697–708. [143] Ku SY, Rosa io S, Wang Y, e al. Rb1 and T p53 coope a e o supp ess p os a e cance lineage plas ici y, me as asis, and an i- and ogen esis ance. Science 2017;355:78–83. [144] P i cha d CC, Mo issey C, Kuma A, e al. Complex MSH2 and MSH6 mu a ions in hype mu a ed mic osa elli e uns able ad- anced p os a e cance . Na Commun 2014;25;5:4988. h p:// dx.doi.o g/10.1038/ncomms5988. [145] Wya AW, Azad AA, Volik SV, e al. Genomic Al e a ions in cell- ee dna and enzalu amide esis ance in cas a ion- esis an p os- a e cance . JAMA Oncol 2016;2:1598–606. [146] An ona akis ES, Lu C, Wang H, e al. AR-V7 and esis ance o enzalu amide and abi a e one in p os a e cance . N Engl J Med 2014;371:1028–38. [147] Qu F, Xie W, Nakabayashi M, e al. Associa ion o AR-V7 and p os a e-specific an igen RNA le els in blood wi h e ficacy o abi a e one ace a e and enzalu amide ea men in men wi h p os a e cance . Clin Cance Res 2017;23:726–34. [148] Del Re M, Biasco E, C uci a S, e al. The de ec ion o and ogen ecep o splice a ian 7 in plasma-de i ed exosomal RNA s ong- ly p edic s esis ance o ho monal he apy in me as a ic p os a e cance pa ien s. Eu U ol 2017;71:680–7. [149] Sche HI, Lu D, Sch eibe NA, e al. Associa ion o AR-V7 on ci cula ing umo cells as a ea men -specific bioma ke wi h ou comes and su i al in cas a ion- esis an p os a e cance . JAMA Oncol 2016;2:1441–9. [150] Romanel A, Gasi Tande el D, Con educa V, e al. Plasma AR and abi a e one- esis an p os a e cance . Sci T ansl Med 2015;7: 312 e10. [151] G asso CS, Wu YM, Robinson DR, e al. The mu a ional landscape o le hal cas a ion- esis an p os a e cance . Na u e 2012;487: 239–43. EUROPEAN UROLOGY 73 (2018) 178–211 209 [152] Ma eo J, Boysen G, Ba bie i CE, e al. DNA epai in p os a e cance : biology and clinical implica ions. Eu U ol 2017;71:417–25. [153] Cheng HH, P i cha d CC, Boyd T, Nelson PS, Mon gome y B. Biallelic inac i a ion o BRCA2 in pla inum-sensi i e me as a ic cas a ion- esis an p os a e cance . Eu U ol 2016;69:992–5. [154] S e nbe g CN, Pe ylak DP, Sa o O, e al. Mul ina ional, double- blind, phase III s udy o p ednisone and ei he sa apla in o placebo in pa ien s wi h cas a e- e ac o y p os a e cance p o- g essing a e p io chemo he apy: he SPARC ial. J Clin Oncol 2009;27:5431–8. [155] Nghiem B, Zhanga X, Lama H-M, e al. Misma ch epai enzyme exp ession in p ima y and cas a e esis an p os a e cance Asian. J U ol 2016;3:223–8. [156] Schweize MT, Cheng HH, T e iako a MS, e al. Misma ch epai deficiency may be common in duc al adenoca cinoma o he p os a e. Onco a ge 2016;7:82504–10. [157] Le DT, U am JN, Wang H, e al. PD-1 blockade in umo s wi h misma ch- epai deficiency. N Engl J Med 2015;372:2509–20. [158] Lee J, Demissie K, Lu SE, Rhoads GG. Cance incidence among Ko ean-Ame ican immig an s in he Uni ed S a es and na i e Ko eans in Sou h Ko ea. Cance Con ol 2007;14:78–85. [159] Mucci LA, Hjelmbo g JB, Ha is JR, e al. Familial isk and he i a- bili y o cance among wins in No dic coun ies. JAMA 2016;315:68–76. [160] Goldga DE, Eas on DF, Cannon-Alb igh LA, Skolnick MH. Sys- ema ic popula ion-based assessmen o cance isk in fi s -de- g ee ela i es o cance p obands. J Na l Cance Ins 1994;86: 1600–8. [161] Lange EM. Male Rep oduc i e Cance s: Epidemiology, Pa hology and Gene ics. New Yo k, NY: Sp inge ; 2010. [162] Zeigle -Johnson CM, Renne H, Mi al RD, e al. E alua ion o p os a e cance cha ac e is ics in ou popula ions wo ldwide. Canadian J U ol 2008;15:4056–64. [163] Cui J, S aples MP, Hoppe JL, English DR, McC edie MR, Giles GG. Seg ega ion analyses o 1,476 popula ion-based Aus alian ami- lies a ec ed by p os a e cance . Am J Hum Gene 2001;68: 1207–18. [164] Ahmed M, Eeles R. Ge mline gene ic p ofiling in p os a e cance : la es de elopmen s and po en ial clinical applica ions. Fu u e Sci OA 2016;2:FSO87. [165] Thompson D, Eas on D, B eas Cance Linkage C. Va ia ion in cance isks, by mu a ion posi ion, in BRCA2 mu a ion ca ie s. Am J Hum Gene 2001;68:410–9. [166] Ko e-Ja ai Z, Leongamo nle D, Saunde s E, e al. BRCA2 is a mode a e pene ance gene con ibu ing o young-onse p os a e cance : implica ions o gene ic es ing in p os a e cance pa ien s. B J Cance 2011;105:1230–4. [167] Leongamo nle D, Mahmud N, Tym akiewicz M, e al. Ge mline BRCA1 mu a ions inc ease p os a e cance isk. B J Cance 2012;106:1697–701. [168] Leongamo nle D, Saunde s E, Dadae T, e al. F equen ge mline dele e ious mu a ions in DNA epai genes in amilial p os a e cance cases a e associa ed wi h ad anced disease. B J Cance 2014;110:1663–72. [169] Na od SA, Neuhausen S, Vichodez G, e al. Rapid p og ession o p os a e cance in men wi h a BRCA2 mu a ion. B J Cance 2008;99:371–4. [170] T ygg ado i L, Vida sdo i L, Tho gei sson T, e al. P os a e cance p og ession and su i al in BRCA2 mu a ion ca ie s. J Na l Cance Ins 2007;99:929–35. [171] Cas o E, Goh C, Olmos D, e al. Ge mline BRCA mu a ions a e associa ed wi h highe isk o nodal in ol emen , dis an me as- asis, and poo su i al ou comes in p os a e cance . J Clin Oncol 2013;31:1748–57. [172] Cas o E, Goh C, Leongamo nle D, e al. E ec o BRCA mu a ions on me as a ic elapse and cause-specific su i al a e adical ea men o localised p os a e cance . Eu U ol 2015;68:186–93. [173] P i cha d CC, Ma eo J, Walsh MF, e al. Inhe i ed DNA- epai gene mu a ions in men wi h me as a ic p os a e cance . N Engl J Med 2016;375:443–53. [174] Annala M, S uss WJ, Wa ne EW, e al. T ea men ou comes and umo loss o he e ozygosi y in ge mline DNA epai -deficien p os a e cance . Eu U ol 2017;72:34–42. [175] Na R, Zheng SL, Han M, e al. Ge mline mu a ions in ATM and BRCA1/2 dis inguish isk o le hal and indolen p os a e cance and a e associa ed wi h ea ly age a dea h. Eu U ol 2017;71: 740–7. [176] Banc o EK, Page EC, Cas o E, e al. Ta ge ed p os a e cance sc eening in BRCA1 and BRCA2 mu a ion ca ie s: esul s om he ini ial sc eening ound o he IMPACT s udy. Eu U ol 2014;66:489–99. [177] Rao K, Manya K, Azad A, e al. U o-oncology mul idisciplina y mee ings a an Aus alian e ia y e e al cen e–impac on clinical decision-making and implica ions o pa ien inclusion. BJU In 2014;114(Suppl 1):50–4. [178] Chambe s SK, Fe guson M, Ga dine RA, Ai ken J, Occhipin i S. In e ening o imp o e psychological ou comes o men wi h p os a e cance . Psychooncology 2013;22:1025–34. [179] Chambe s SK, Occhipin i S, Foley E, e al. Mind ulness-based cogni i e he apy in ad anced p os a e cance : a andomized con olled ial. J Clin Oncol 2017;35:291–7. [180] Chambe s SK, Occhipin i S, Scho e L, e al. A andomised con- olled ial o a couples-based sexuali y in e en ion o men wi h localised p os a e cance and hei emale pa ne s. Psy- chooncology 2015;24:748–56. [181] Usshe JM, Pe z J, Kelle A, e al. Heal h- ela ed quali y o li e, psychological dis ess, and sexual changes ollowing p os a e cance : a compa ison o gay and bisexual men wi h he e osexual men. J Sex Med 2016;13:425–34. [182] F ieden eich CM, Wang Q, Neilson HK, Kopciuk KA, McG ego SE, Cou neya KS. Physical ac i i y and su i al a e p os a e cance . Eu U ol 2016;70:576–85. [183] Gal ao DA, Nosaka K, Taa e DR, e al. Resis ance aining and educ ion o ea men side e ec s in p os a e cance pa ien s. Med Sci Spo s Exe c 2006;38:2045–52. [184] Gal ao DA, Sp y N, Denham J, e al. A mul icen e yea -long andomised con olled ial o exe cise aining a ge ing physical unc ioning in men wi h p os a e cance p e iously ea ed wi h and ogen supp ession and adia ion om TROG 03.04 RADAR. Eu U ol 2014;65:856–64. [185] D oz JP, Alb and G, Gillessen S, e al. Managemen o p os a e cance in elde ly pa ien s: ecommenda ions o a Task Fo ce o he In e na ional Socie y o Ge ia ic Oncology. Eu U ol 2017;72:521–31. [186] Kalsi T, Babic-Illman G, Ross PJ, e al. The impac o comp ehensi e ge ia ic assessmen in e en ions on ole ance o chemo he apy in olde people. B J Cance 2015;112:1435–44. [187] Kea ing NL, O’Malley A, F eedland SJ, Smi h MR. Diabe es and ca dio ascula disease du ing and ogen dep i a ion he apy: ob- se a ional s udy o e e ans wi h p os a e cance . J Na l Cance Ins 2012;104:1518–23. [188] Kea ing NL, O’Malley AJ, F eedland SJ, Smi h MR. Diabe es and ca dio ascula disease du ing and ogen dep i a ion he apy: ob- se a ional s udy o e e ans wi h p os a e cance . J Na l Cance Ins 2010;102:39–46. [189] Kea ing NL, O’Malley AJ, Smi h MR. Diabe es and ca dio ascula disease du ing and ogen dep i a ion he apy o p os a e cance . J Clin Oncol 2006;24:4448–56. EUROPEAN UROLOGY 73 (2018) 178–211 210 [190] Alibhai SM, Duong-Hua M, Su adha R, e al. Impac o and ogen dep i a ion he apy on ca dio ascula disease and diabe es. J Clin Oncol 2009;27:3452–8. [191] Smi h MR, Finkels ein JS, McGo e n FJ, e al. Changes in body composi ion du ing and ogen dep i a ion he apy o p os a e cance . J Clin Endoc inol Me ab 2002;87:599–603. [192] Smi h MR, Lee H, Na han DM. Insulin sensi i i y du ing combined and ogen blockade o p os a e cance . J Clin Endoc inol Me ab 2006;91:1305–8. [193] Nead KT, Gaskin G, Ches e C, e al. And ogen dep i a ion he apy and u u e Alzheime ’s disease isk. J Clin Oncol 2016;34:566–71. [194] Nead KT, Gaskin G, Ches e C, Swishe -McClu e S, Leepe NJ, Shah NH. Associa ion be ween and ogen dep i a ion he apy and isk o demen ia. JAMA Oncol 2017;3:49–55. [195] Khos ow-Kha a F, Rej S, Yin H, Ap ikian A, Azoulay L. And ogen dep i a ion he apy and he isk o demen ia in pa ien s wi h p os a e cance . J Clin Oncol 2017;35:201–7. [196] Alibhai SM, B eunis H, Timilshina N, e al. Impac o and ogen- dep i a ion he apy on cogni i e unc ion in men wi h nonme a- s a ic p os a e cance . J Clin Oncol 2010;28:5030–7. EUROPEAN UROLOGY 73 (2018) 178–211 211