Safety and antitumour activity of ODM-201 (BAY-1841788) in chemotherapy-naïve and CYP17 inhibitor-naïve patients : follow-up from the ARADES and ARAFOR Trials

P os a e Cance Sa e y and An i umou Ac i i y o ODM-201 (BAY-1841788) in Chemo he apy-naï e and CYP17 Inhibi o -naï e Pa ien s: Follow-up om he ARADES and ARAFOR T ials Neal D. Sho e a, *, Teu o L. Tammela b , Ch is ophe Massa d c , Pe i Bono d , John Aspeg en e , Mika Mus onen e , Ka im Fizazi c a Ca olina U ologic Resea ch Cen e , My le Beach, SC, USA; b Tampe e Uni e si y Hospi al, Depa men o U ology, Tampe e, Finland; c Ins i u Gus a e Roussy, Uni e si y o Pa is Sud, Villejui , F ance; d Comp ehensi e Cance Cen e , Helsinki Uni e si y Hospi al and Uni e si y o Helsinki, Helsinki, Finland; e O ion Co po a ion, O ion Pha ma, Espoo, Finland E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 18 ) 5 4 7 – 5 5 3 a a ilable a www.sciencedi ec .com jou na l homepage: www.eu opea nu ology.com/eu ocus A icle in o A icle his o y: Accep ed Janua y 24, 2017 Associa e Edi o : James Ca o Keywo ds: And ogen ecep o And ogen ecep o an agonis Me as a ic cas a ion- esis an p os a e cance ODM-201 Abs ac Backg ound: ODM-201, a new and ogen ecep o an agonis o ea men o me as a ic cas a ion- esis an p os a e cance (mCRPC), demons a ed an i umou ac i i y and accep - able ole abili y in phase 1/2 ials. Objec i e: To de e mine he an i umou ac i i y and sa e y p ofile o ex ended ea men wi h ODM-201 in men wi h mCRPC. Design, se ing, and pa icipan s: ARADES and ARAFOR ials wi h ODM-201 en olled chemo- he apy-naï e and CYP17 inhibi o (CYP17i)-naï e mCRPC pa ien s. Bo h ials had ex ended ollow-up. He e we epo esul s o chemo he apy-naï e and CYP17i-naï e pa ien s om bo h ials (da a cu o Oc obe 2014 o ARADES and Ap il 2015 o ARAFOR) a e ex ended ollow-up. In e en ion: A o al o 41 chemo he apy-naï e and CYP17i-naï e pa ien s ecei ed o al ODM- 201 wice daily ( o al daily dose o 1200, 1400 o 1800 mg). Ou come measu emen s and s a is ical analysis: An i umou ac i i y was assessed in e ms o p os a e-specific an igen (PSA) declines and PSA/ adiog aphic p og ession. Sa e y was assessed un il disease p og ession and/o d ug discon inua ion due o any in ole able ad e se e en (AE). Resul s and limi a ions: ODM-201 sa e y da a a e a median ea men ime o 13.5 mo (95% confidence in e al [CI] 9.7–15.6, in e qua ile ange [IQR] 7.5–22.0) we e simila o hose epo ed in he main ARADES and ARAFOR ials. The o e all AE incidence was 80.5% (n = 33/41), wi h 58.5% (n = 24/41) o pa ien s expe iencing only g ade 1–2 AEs. The mos common AEs we e a igue, back pain, dia hoea, nausea, and pain in ex emi y. The median imes o PSA and adiological p og ession we e 12.4 mo (95% CI 6.3–18.2, IQR 5.5–22.0) and 15.3 mo (95% CI 9.5–no eached [NR], IQR 6.3–NR), espec i ely. Conclusions: Ex ended ea men wi h ODM-201 (1200–1800 mg/d) was well ole a ed, wi h no new sa e y conce ns, and p o ided e idence o sus ained an i umou ac i i y in chemo he apy- naï e and CYP17i-naï e pa ien s wi h mCRPC. Pa ien summa y: P olonged ea men wi h high doses o ODM-201 was well ole a ed and p o ided long-las ing disease con ol in pa ien s wi h mCRPC. ODM-201 ep esen s a he a- peu ic ea men op ion o mCRPC. The ARAFOR ial (including he ollow-up s age) and he ollow-up componen o he ARADES ial a e egis e ed wi h ClinicalT ials.go as ial numbe s NCT01784757 and NCT01429064. © 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/). * Co esponding au ho . Ca olina U ologic Resea ch Cen e , A lan ic U ology Clinics, My le Beach, SC, USA. Tel: +1 843 449 1010, Fax: +1 843 286 0119. E-mail add ess: [email p o ec ed] (N.D. Sho e). h p://dx.doi.o g/10.1016/j.eu .2017.01.015 2405-4569/© 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/). 1. In oduc ion P os a e cance (PCa) is he hi d mos common cause o cance - ela ed dea h in men in he EU, wi h an es ima ed 92 000 dea hs in 2012 [1]. And ogen dep i a ion he apy (ADT), ia ei he o chiec omy o ea men wi h a lu einis- ing ho mone– eleasing ho mone agonis /an agonis , is he s anda d o ca e o pa ien s wi h ho mone-sensi i e ad anced PCa [2,3]. Despi e an ini ial esponse o ea men , mos pa ien s p og ess o me as a ic cas a ion- esis an PCa (mCRPC), which has a poo p ognosis [2,4,5] and equi es subsequen he apeu ic in e en ion [6,7]. Al e a ions in he and ogen ecep o (AR) signalling pa hway a e he main unde lying molecula mechanism d i ing mCRPC [8–10]. As umou g ow h o PCa cells in he cas a ion- esis an disease s age is dependen on pe - sis en AR signalling, he AR axis is conside ed an e ec i e he apeu ic a ge in mCRPC [11,12]. Speci ic and ogen axis- and AR- a ge ing agen s—abi a e one and enzalu amide— ha e been app o ed in he EU and he USA o mCRPC ea men . Bo h compounds imp o ed o e all su i al and adiog aphic p og ession- ee su i al and had a bene- icial impac on quali y o li e (QoL) in phase 3 ials includ- ing pos -chemo he apy [13–15] and p e-chemo he apy [16,17] mCRPC pa ien s. New AR inhibi o s a e being de el- oped o ea men o mCRPC, including ODM-201, an in es- iga ional nons e oidal o al AR an agonis ha is s uc u - ally di e en om any o he an iand ogen compound, including enzalu amide and apalu amide [18]. A p eclinical s udy showed ha ODM-201 has an i umou ac i i y in i o, as i inhibi ed umou g ow h in a mu ine VCap CRPC xenog a model, wi h highe ac i i y han enzalu amide [18]. In wo phase 1/2 ials, ODM-201 exhibi ed an i umou ac i i y and was well ole a ed in men wi h mCRPC. In he open-label mul icen e ARADES ial (NCT01429064), a non- andomised, i s -in-man, dose escala ion phase 1 (n = 24) showed ha an i umou ac i i y was achie ed a all doses es ed (200–1800 mg/d) and no dose-limi ing oxici y was obse ed [19]. In he phase 2 ex ension (n = 110), a p os a e-speci ic an igen (PSA) decline was obse ed wi h all ODM-201 doses es ed (200–1400 mg/d), and he 1400-mg/d dose led o he g ea es PSA esponse in chemo he apy-naï e and CYP17 inhibi o (CYP17i)-naï e pa ien s. Fu he mo e, ODM-201 was well ole a ed, wi h >99% o ad e se e en s (AEs) being g ade 1–2 [19]. ARAFOR (NCT01784757) was an open-label mul icen e ial ha included a pha macokine ic componen (n = 30) and an open-label ex ension s udy (n = 30) [20]. ODM-201 demons a ed an i umou ac i i y and was well ole a ed in chemo he apy-naï e pa ien s: a PSA esponse (50% dec ease in PSA le els om baseline a week 12) was obse ed in 25/30 pa ien s (83%), and 91% o ea men - eme gen AEs we e o g ade 1–2 [20]. Wi h he p e ious indings om he ARADES and ARAFOR ials, he sa e y and umou -supp ession ac i i y o ex ended ODM-201 dosing in men wi h mCRPC a e o clinical in e es , as hese pa ien s usually bene i om p olonged ea men . He e we epo da a om he ollow-up o he ARADES and ARAFOR ials on he sa e y and an i umou ac i i y o ODM-201 in pa ien s wi h mCRPC, who did no ecei e p io chemo he apy o CYP17i. 2. Pa ien s and me hods 2.1. S udy design and pa ien s The da a p esen ed he e om he ARADES (cu o da e Oc obe 31, 2014) [19] and ARAFOR (cu o da e Ap il 30, 2015) ials [20] include hose pa ien s who we e chemo he apy- and CYP17i-naï e and ecei ed 1200, 1400 o 1800 mg/d o ODM-201. The comple e s udy design was published p e iously [19,20]. In b ie , male pa ien s we e aged 18 y , had p og essi e mCRPC, an Eas e n Coope a i e Oncology G oup pe o - mance s a us (ECOG-PS) sco e o 0–1, and se um es os e one le els <1.7 nmol/l. Pa ien s we e included i hey we e mildly symp oma ic o asymp oma ic and hose wi h a his o y o isk o seizu es could be included. Pa ien s wi hou bila e al o chidec omy had o con inue app o ed ADT du ing he ial. In he ARADES and ARAFOR ials, disease p og ession was defined by: ising PSA ( wo consecu i e inc eases in PSA le els 1 wk apa , wi h he lowes alue being 2 ng/ml); adiog aphic disease p og ession (assessed using he modified Response E alua ion C i e ia in Solid Tumou s e sion 1.1); o he p esence o wo o mo e new bone lesions. Exclusion c i e ia we e he p esence o b ain me as ases and p io ea men wi h AR an agonis s, CYP17i o chemo he apy. 2.2. E hics Pa ien s ga e w i en in o med consen and he ials we e app o ed by an independen e hics commi ee a each cen e o by he in es iga ional e iew boa d. The ials we e conduc ed acco ding o he p inciples o he Decla a ion o Helsinki and he guidelines o Good Clinical P ac ice. 2.3. T ea men Pa ien s ecei ed ODM-201 wice daily wi h ood ( o al daily dose o 1200, 1400 o 1800 mg). T ea men con inued un il disease p og ession o an in ole able AE. 2.4. An i umou ac i i y assessmen s In he ARADES and ARAFOR ials, PSA concen a ions we e measu ed a baseline, e e y 4 wk un il he 9-mo isi , e e y 3 mo he ea e , and a he end-o -s udy isi . The pe cen age change in se um PSA was calcu- la ed om baseline un il pa ien s discon inued he s udy. Baseline PSA was defined as he PSA le el be o e he fi s ODM-201 dose. The median ime o PSA p og ession was defined as he ime om ODM-201 ea men ini ia ion un il documen a ion o a 25% inc ease and an absolu e inc ease o 2 ng/ml in PSA om nadi , acco ding o P os a e Cance Wo king G oup 2 c i e ia [21]; his had o be confi med by an addi ional PSA measu emen 3 wk la e . A minimum pe iod o 12 wk was equi ed be o e PSA p og ession could be decla ed. Time o adiog aphic p og ession was defined as he ime be ween he s a o ea men and he occu ence o he fi s p og ession (so issue o bone) as assessed using compu ed omog aphy/magne ic esonance imaging o a bone scan. 2.5. Sa e y and ole abili y AEs we e classified by sys em o gan classes and p e e ed e ms (Medical Dic iona y o Regula o y Ac i i ies coding sys em, e sion 17.1 in he ARADES ial, and 18.0 in he ARAFOR ial) and g aded by he Na ional E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 1 8 ) 5 4 7 – 5 5 3 548 Cance Ins i u e o Common Te minology C i e ia o AEs ( e sion 4.03). Labo a o y assessmen s (haema ology, se um biochemis y, ho mones and u ine analysis) we e pe o med: a baseline, once a week o he fi s 28 d, e e y 4 wk un il he 9-mo isi , e e y 3 mo he ea e , and a he end-o -s udy isi . Ho mone measu emen s we e pe o med up o week 12. 2.6. S a is ical analysis An i umou ac i i y and sa e y analyses included all pa ien s who ecei ed a leas one dose o ODM-201. Time o PSA and adiog aphic p og ession we e calcula ed using Kaplan-Meie es ima es; he median alues wi h associa ed 95% confidence in e als (CIs) and in e qua ile anges (IQRs) a e epo ed. All measu emen s a e summa ised using desc ip i e s a is ics. Analyses we e pe o med using da a collec ed up o he cu o da es o Oc obe 31, 2014 o ARADES and Ap il 30, 2015 o ARAFOR. 3. Resul s 3.1. Pa ien s A o al o 41 pa ien s wi h p og essi e mCRPC we e included in he analyses; hey we e all chemo he apy-naï e and CYP17i-naï e. O hese, 30 (73.2%) we e om he ARAFOR ial and 11 (26.8%) om he ARADES ial. Baseline demog aphic and clinical cha ac e is ics o he pa ien s we e well balanced in he wo ials (Table 1). The median age was 69.0 y ( ange 54.0–86.0) and mos pa ien s (73.2%) we e classi ied as ECOG-PS sco e 0. The o e all baseline median PSA was 27.7 ng/ml ( ange 3.5–1293.8); mos pa ien s had bone disease a sc eening (n = 36, 87.8%), whe eas 16 pa ien s (39.0%) had disease localised in he lymph nodes and h ee pa ien s (7.3%) had isce al disease. Da a o pa ien s om he ARADES ial we e collec ed un il Oc obe 31, 2014; he ini ial esul s we e epo ed in 2014 using a cu o da e o Oc obe 3, 2013 [19]. Pa ien da a om he ARAFOR ial we e collec ed h ough o Ap il 30, 2015 and he ini ial esul s we e published in 2015 wi h a cu o da e o Oc obe 31, 2014 [20]. The di e ence in cu o da es be ween he wo s udies p esen ed he e e lec s he di e en s udy ini ia ion da es [19,20]. All pa ien s om he ARAFOR ial (30/41, 73.2%) ecei ed 1200 mg/d o ODM-201, while ARADES pa ien s ecei ed 1400 mg/d (n = 9/41, 22.0%) o 1800 mg/d (n = 2, 4.9%). O e all, 30/41 pa ien s (73.2%) discon inued he s udy; he mos common cause o discon inua ion was Table 1 – Baseline demog aphics and clinical cha ac e is ics. ARADES ial (n = 11) ARAFOR ial (n = 30) To al (n = 41) Age (y ) 73.0 (62.0–82.0) 68.0 (54.0–86.0) 69.0 (54.0–86.0) PSA (ng/ml) 219.2 (14.9–1293.8) a 18.2 (3.5–554.8) 27.7 (3.5–1293.8) b Tes os e one (ng/dl) 0.7 (0.4–1.7) 0.8 (0.4–1.6) 0.8 (0.4–1.7) LDH (U/l) 193.0 (159.6–515.0) a 323.5 (163.0–559.0) 287.0 (159.6–559.0) b Gleason sco e a diagnosis 2–6 1 (9.1) 6 (20.0) 7 (17.1) 7 4 (36.4) 12 (40.0) 16 (39.0) 8–10 5 (45.5) 12 (40.0) 17 (41.5) Missing c 1 (9.1) 0 (0.0) 1 (2.4) ECOG-PS 0 10 (90.9) 20 (66.7) 30 (73.2) 1 1 (9.1) 10 (33.3) 11 (26.8) Time om diagnosis o SS (mo) 64.1 (10.9–165.7) 39.7 (7.6–133.7) 50.0 (7.6–165.7) P io an iand ogen he apy 11 (100.0) 22 (73.3) 33 (80.5) LHRH he apy 10 (90.9) 30 (100.0) 40 (97.6) Time om LHRH he apy o SS (mo) 40.7 (6.6–153.3) d 22.5 (0.9–126.6) e 22.5 (0.9–153.3) Disease localisa ion Lymph node 4 (36.4) 12 (40.0) 16 (39.0) Bone disease 9 (81.8) 27 (90.0) 36 (87.8) Bone only 7 (63.6) 15 (50.0) 22 (53.7) Bone and so issue 2 (18.2) 12 (40.0) 14 (34.1) So issue only 2 (18.2) 3 (10.0) 5 (12.2) Visce al 1 (9.1) 2 (6.7) 3 (7.3) Bone me as ases a sc eening 0 2 (18.2) 3 (10.0) 5 (12.2) 1–4 3 (27.3) 9 (30.0) 12 (29.3) 5–20 3 (27.3) 4 (13.3) 7 (17.1) >20 o non-coun able 3 (27.3) 14 (46.7) 17 (41.5) ECOG-PS = Eas e n Coope a i e Oncology G oup pe o mance s a us; LDH = lac a e dehyd ogenase; LHRH = lu einising ho mone- eleasing ho mone; PSA = p os a e-specific an igen; SS = s udy s a . Da a a e p esen ed as median ( ange) o con inuous a iables and as n (%) o ca ego ical a iables. a n = 10. b n = 40. c Gleason sco e no a ailable. d n = 8. e n = 29. n = 37. E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 1 8 ) 5 4 7 – 5 5 3 549 disease p og ession (90% o pa ien s), wi h only wo pa ien s (6.7%) discon inuing due o AEs and one (3.3%) o pe sonal easons. Fou ARADES pa ien s whose ea - men was ongoing a e he o iginal da a cu o o Oc obe 3, 2013 [19] discon inued he ex ension s udy be o e he new cu o da e o Oc obe 31, 2014. O he en pa ien s who we e ongoing by Oc obe 31, 2014 in he main ARAFOR ial [20], one discon inued he ex ension ollow-up be o e he new cu o da e o Ap il 30, 2015 and one discon inued s udy ea men , bu no he s udy, be o e he ex ended da a cu o . Al hough he median ollow-up ime was 15.3 mo (95% CI 10.4–16.5, IQR 7.9–25.7; Fig. 1) and he median on- ea men ime was 13.5 mo (95% CI 9.7–15.6, IQR 7.5–22.0), 11 pa ien s (n = 10 ARAFOR and n = 1 ARADES) con inued he s udy a e he da a cu o . O hese, en pa ien s (n = 9 ARAFOR and n = 1 ARADES) con inued ODM-201 ea men a e he da a cu o : wo pa ien s we e on a named pa ien (compassiona e) use basis, wi h one pa ien ecei ing ea men un il he end o Augus 2016, o a o al on- ea men ime o 41 mo. 3.2. Sa e y An AE was expe ienced by 80.5% (n = 33/41) o pa ien s, and 29 pa ien s (70.7%) had mo e han one AE. The mos com- mon AEs o any g ade we e: a igue (g ade 1) in eigh pa ien s (19.5%); nausea (g ade 1–3), pain in ex emi y (g ade 1–2), back pain (g ade 2–3) and dia hoea (g ade 1–2) in i e pa ien s (12.2%); and a h algia (g ade 1–2) in ou pa ien s (9.8%) (Table 2). O e all, 24 pa ien s (58.5%) had only g ade 1–2 AEs and se en pa ien s (17.1%) expe i- enced g ade 3 AEs, including: PCa p og ession, back pain, nausea, bone pain, inc ease in blood alkaline phospha ase, hype ension, hypona aemia, lung adenoca cinoma, all and emo al neck ac u e (Table 2). G ade 4 AEs we e obse ed only in he ARAFOR ial and included espi a o y ailu e and neu oendoc ine ca cinoma ( wo pa ien s), and one pa ien died due o gene al physical heal h de e io a- ion and PCa p og ession (Table 2). The pa e n o AEs epo ed du ing his s udy in chemo he apy-naï e and CYP17i-naï e pa ien s is simila o ha epo ed in he same pa ien popula ion du ing he main ARADES and ARAFOR ials: a he ime o he o iginal cu o da es (Oc obe 3, 2013 o ARADES and Oc obe 31, 2014 o ARAFOR), he mos common AEs o any g ade included g ade 1 a igue/ as henia (8 pa ien s, 19.5%); dia hoea and pain in ex emi y (g ade 1–2) and g ade 1–3 nausea (5 pa ien s, 12.2%); and g ade 2–3 back pain and g ade 1–2 pe iphe al oedema (4 pa ien s, 9.8%). Fu he mo e, du ing he main ARADES and ARAFOR ials he incidence o g ade 3 AEs (4 pa ien s, 9.8%) was simila o ha epo ed du ing he ollow-up (7 pa ien s, 17.1%); o e all, no new AEs (any g ade) we e obse ed in he ollow-up. Du ing his s udy, ea men - ela ed AEs occu ed in en pa ien s (24.4%): ou pa ien s (36.4%) we e om he ARADES ial and six (20.0%) om ARAFOR (Table 3). All ea men - ela ed AEs we e g ade 1; he mos common we e a igue (3 pa ien s, 7.3%) and ho lush (2 pa ien s, 4.9%). 3.3. An i umou ac i i y The pe cen age PSA change om baseline o each pa ien du ing ea men wi h 1200, 1400, and 1800 mg/d o ODM-201 is shown in Fig. 2A. The maximum PSA esponse a e (50% PSA educ ion om baseline a any ime du ing he s udy) was 85% (n = 34/40); his was 80% (n = 8/10) and 87% (n = 26/30) in he ARADES and ARAFOR ials, espec- i ely (Fig. 2B). The median ime o PSA p og ession was 12.4 mo (95% CI 6.3–18.2, IQR 5.5–22.0) o all pa ien s (Fig. 2C). This was sligh ly longe in he ARAFOR ial (12.5 mo, 95% CI 5.4–no eached [NR], IQR 4.6–NR) han in he ARADES ial (9.9 mo, 95% CI 5.5–22.0, IQR 7.6–19.6). Simila da a we e ob ained o he ime o adiological p og ession; his was 15.3 mo (95% CI 9.5–NR, IQR 6.3–NR) in he ARAFOR ial, bu was no eached in he ARADES ial (95% CI 2.6–NR, IQR 14.0–NR). 4. Discussion Analysis o he ex ended ollow-up o pa ien s om he ARADES and ARAFOR ials indica ed ha o up o 25.7 mo (median 15.3), ea men wi h high doses o ODM-201 (1200, 1400 and 1800 mg/d) was well ole a ed and p o- ided du able an i umou ac i i y in chemo he apy-naï e and CYP17i-naï e pa ien s wi h mCRPC. These esul s a e consis en wi h he indings epo ed o he ea lie s ages Fig. 1 – Kaplan-Meie es ima e o (A) ollow-up and (B) ime on ea men . CI = con idence in e al. E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 1 8 ) 5 4 7 – 5 5 3 550 o he wo ials [19,20]: in he ARADES ial, pa ien s wi hou p io chemo he apy and CYP17i ea men who ecei ed 1400 mg/d o ODM-201 we e hose who showed he g ea es PSA supp ession [19]. ODM-201 dose le els used in his s udy we e based on he e icacy obse ed in he main ARADES [19] and ARAFOR [20] ials in pa ien s ecei ing highe doses o s udy medica ion, and a e consis en wi h he s udy design o wo planned phase 3 ODM-201 ials, ARAMIS (NCT02200614) and ARASENS (NCT02799602), in which pa ien s will ecei e he 1200 mg daily dose o ODM-201. The ODM-201 sa e y p o ile a e ex ended use is consis- en wi h da a p e iously epo ed o he ARADES and ARAFOR ials [19,20] and no addi ional sa e y conce ns we e obse ed. Mos pa ien s analysed he e (n = 32/41, 78.0%) expe ienced AEs o g ade 1–2; likewise, in he main ARAFOR and ARADES ials, mos AEs (116/129, 90%, and 82/83, 99%, espec i ely) we e o g ade 1–2 among all he AEs epo ed. O hese, he mos common e en s we e a igue (g ade 1 in 8/41, 19.5%) and nausea (g ade 1–3 in 5/41, 12.2%), which a e clinically ele an AEs in mCRPC and a e commonly obse ed du ing ea men wi h AR an ago- nis s [13,16,22–25]. The incidence o AEs in chemo he apy- naï e and CYP17i-naï e pa ien s analysed he e is simila o ha epo ed in he same pa ien popula ion du ing he main ARADES and ARAFOR ials a he ime o he o iginal cu o da es, demons a ing ha ex ended ODM-201 ea - men is no associa ed wi h any new sa e y conce ns. On he basis o hese da a, he sa e y o ODM-201 com- pa es a ou ably wi h ha epo ed o o he AR an ago- nis s, such as enzalu amide, whose long- e m sa e y p o ile was es ablished in chemo he apy-naï e pa ien s in a phase 1/2 ial [23] om which pa ien s wi h a known isk o seizu e we e excluded. Fo bo h AR an agonis s, he mos commonly epo ed ea men -eme gen AEs ollowing ex ended ea men we e a igue and nausea, obse ed in 19.5% (g ade 1 a igue) and 12.2% (g ade 1–3 nausea) o Table 2 – Ad e se e en s (AEs). Pa ien s epo ing AEs, n (%) G ade 1–2 G ade 3 G ade 4 G ade 5 Any AEs ARADES (n = 11) 11 (100.0) 1 (9.1) 0 (0.0) 0 (0.0) ARAFOR (n = 30) 21 (70.0) 6 (20.0) 2 (6.7) 1 (3.3) To al (n = 41) 32 (78.0) 7 (17.1) 2 (4.9) 1 (2.4) G ade 1 G ade 2 G ade 3 G ade 4 G ade 5 G ades 1–5 Common AEs a (n = 41) Fa igue 8 (19.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 8 (19.5) Nausea 4 (9.8) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) 5 (12.2) Pain in ex emi y 5 (12.2) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 5 (12.2) Back pain 0 (0.0) 4 (9.8) 1 (2.4) 0 (0.0) 0 (0.0) 5 (12.2) Dia hoea 4 (9.8) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 5 (12.2) A h algia 2 (4.9) 2 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 4 (9.8) Bone pain 1 (2.4) 2 (4.9) 1 (2.4) 0 (0.0) 0 (0.0) 3 (7.3) Haema u ia 3 (7.3) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Influenza 2 (4.9) 2 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Abdominal pain 2 (4.9) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Dysu ia 3 (7.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Headache 3 (7.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Ho flush 3 (7.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Hype ension 0 (0.0) 2 (4.9) 1 (2.4) 0 (0.0) 0 (0.0) 3 (7.3) Rash 2 (4.9) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Rhino hoea 3 (7.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) Vomi ing 2 (4.9) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 3 (7.3) P os a e cance 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 1 (2.4) 3 (7.3) a AEs occu ing in 5% o pa ien s. Table 3 – T ea men - ela ed ad e se e en s (TRAEs) a . Pa ien s epo ing g ade 1 TRAEs, n (%) Any TRAE ARADES (n = 11) 4 (36.4) ARAFOR (n = 30) 6 (20.0) To al (n = 41) 10 (24.4) All TRAEs (n = 41) Fa igue 3 (7.3) Ho flush 2 (4.9) Abdominal pain 1 (2.4) Cons ipa ion 1 (2.4) Dec eased appe i e 1 (2.4) Dia hoea 1 (2.4) Dizziness 1 (2.4) Dysgeusia 1 (2.4) Fla ulence 1 (2.4) Gynaecomas ia 1 (2.4) Headache 1 (2.4) Nasopha yngi is 1 (2.4) Nausea 1 (2.4) Poo pe iphe al ci cula ion 1 (2.4) Sola de ma i is 1 (2.4) Somnolence 1 (2.4) Tinni us 1 (2.4) U ina y incon inence 1 (2.4) a All TRAEs we e o g ade 1. E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 1 8 ) 5 4 7 – 5 5 3 551 pa ien s ea ed wi h ODM-201; in enzalu amide- ea ed men, a igue occu ed in 72% (any g ade) o pa ien s, wi h 15% expe iencing g ade 3/4, whe eas nausea (any g ade) was epo ed by 31% o pa ien s [23]. The incidence o a igue du ing ex ended ODM-201 ea men epo ed he e is also lowe han ha seen in phase 3 ials o enzalu amide (36% all g ades and 2% g ade 3) [16] and abi a e one ace a e (39% all g ades and 2% g ade 3) [17] in pa ien s who had no ecei ed chemo he apy. Impo an ly, no seizu es we e epo ed a e ex ended ea men wi h ODM-201. This may be explained by he lowe likelihood o ODM-201 c ossing he blood-b ain ba ie , as shown in p eclinical s udies, and may be ela ed o he unique chem- ical s uc u e o ODM-201; addi ional ials a e needed o con i m hese indings [18,26]. P io enzalu amide ials epo ed ea men - ela ed seizu es [13,23,24], and p eclinical s udies sugges ed ha enzalu amide may c oss he blood-b ain ba ie and bind o GABA ecep o s [13,24,27,28], he eby inc easing he isk o seizu es. In addi ion o a a ou able ole abili y p o ile, p olonged ea men wi h ODM-201 p o ided sus ained an i umou ac i i y: a dec ease in PSA le els om baseline was main- ained o e ime in mos chemo he apy-naï e and CYP17i- naï e pa ien s a all doses es ed (Fig. 2A,B), simila o he ARADES and ARAFOR ials. The median imes o PSA p o- g ession (12.4 mo, 95% CI 6.3–18.2) and adiological p og ession (15.3 mo, 95% CI 9.5–NR) we e simila o da a om he main ARAFOR ial (12.4 mo, 95% CI 5.3–NR; and 15.2 mo, 95% CI 9.4–18.2) bu we e sho e han hose epo ed o chemo he apy-naï e and CYP17i-naï e pa ien s om he ARADES main ial (16.6 mo, 95% CI 5.6–NR; and NR, 95% CI 8.4–NR). A limi a ion o his analysis is ha , being a non- andom- ised phase 1/2 ial, he e was no con ol g oup and a ela i ely small numbe o pa ien s was included (n = 41). The e o e, al hough mul iple doses we e es ed, no de ini- i e conclusion may be d awn ega ding he op imal e i- cacy o each ODM-201 dose. Ne e heless, he p omising an i umou ac i i y and a ou able sa e y p o ile o ODM- 201 p o ide a basis o u u e con i ma o y phase 3 ials [29]. In his ega d, he e icacy and sa e y o ODM-201 a e cu en ly being e alua ed in la ge placebo-con olled phase 3 ials among men wi h high- isk nonme as a ic CRPC (ARAMIS, NCT02200614) and men wi h me as a ic cas a- ion-sensi i e p os a e cance (ARASENS, NCT02799602). Ano he limi a ion is ha QoL measu emen s we e no included du ing his ollow-up analysis. As a spec um o neu ocogni i e psychological e ec s ha e been associa ed wi h ADT and AR inhibi o s, u he s udies a e wa an ed o assess he e ec o ex ended ODM-201 ea men on pa ien - epo ed QoL [30]. 5. Conclusions Ex ended ea men wi h ODM-201 a doses o 1200– 1800 mg/d con inued o show encou aging an i umou ac i i y in pa ien s wi h mCRPC who had no ecei ed p io chemo he apy and CYP17i. No addi ional o unexpec ed sa e y signals we e obse ed beyond hose epo ed a he ini ial analysis poin s o he ARADES and ARAFOR ials. ODM-201 may ep esen a well- ole a ed and e ec i e ea men op ion o pa ien s wi h mCRPC. Au ho con ibu ions: Neal D. Sho e had ull access o all he da a in he s udy and akes esponsibili y o he in eg i y o he da a and he accu acy o he da a analysis. S udy concep and design: Sho e, Aspeg en, Mus onen, Fizazi. Acquisi ion o da a: Sho e, Tammela, Massa d, Bono, Fizazi. Analysis and in e p e a ion o da a: Sho e, Tammela, Massa d, Bono, Aspeg en, Mus onen, Fizazi. D a ing o he manusc ip : Sho e, Fizazi, Mus onen. Fig. 2 – (A) P os a e-speci ic an igen (PSA) pe cen age change om baseline, by subjec , unca ed a +50%. (B) Maximum PSA pe cen age change om baseline du ing s udy, by subjec . (C) Time o PSA p og ession. CI = con idence in e al. E U R O P E A N U R O L O G Y F O C U S 4 ( 2 0 1 8 ) 5 4 7 – 5 5 3 552 C i ical e ision o he manusc ip o impo an in ellec ual con en : Sho e, Tammela, Massa d, Bono, Aspeg en, Mus onen, Fizazi. S a is ical analysis: Aspeg en. Ob aining unding: Mus onen, Aspeg en. Adminis a i e, echnical, o ma e ial suppo : None. Supe ision: Sho e, Fizazi, Mus onen. O he : None. Financial disclosu es: Neal D. Sho e ce ifies ha all conflic s o in e es , including specific financial in e es s and ela ionships and a filia ions ele an o he subjec ma e o ma e ials discussed in he manusc ip (eg, employmen /a filia ion, g an s o unding, consul ancies, hono a ia, s ock owne ship o op ions, expe es imony, oyal ies, o pa en s filed, ecei ed, o pending), a e he ollowing: Neal D. Sho e has pa icipa ed in ad iso y boa ds o Baye , O ion Co po a ion, O ion Pha ma, Abb ie, Amgen, As ellas, Dend eon, Fe ing, Janssen, Medi a ion, Pfize , Roi an , Sanofi, and Tolma . Teu o L. Tammela has ecei ed g an s om O ion Co po a ion, O ion Pha ma, Baye , As ellas, Fe ing, and Medi a ion. Ch is ophe Massa d has ecei ed pe sonal ees and nonfinancial suppo om O ion Co po a ion, O ion Pha ma, and pe sonal ees om Sanofi, Genen ech, Ipsen, As ellas, and Jansen. Pe i Bono has ecei ed pe sonal ees om O ion Co po a ion, O ion Pha ma, BMS, No a is, MSD, and Pfize . John Aspeg en and Mika Mus onen a e employees o O ion Co po a ion, O ion Pha ma. Ka im Fizazi has pa icipa ed in ad iso y boa ds o O ion Co po a ion, O ion Pha ma. Funding/Suppo and ole o he sponso : The ials we e suppo ed by O ion Co po a ion, O ion Pha ma. Medical w i ing assis ance was p o- ided by D . Laila Cancian o Biosc ip Medical (Macclesfield, UK) and unded by O ion Co po a ion, O ion Pha ma (Espoo, Finland). The spon- so played a ole in da a managemen and analysis and in manusc ip p epa a ion and e iew. 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