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`529
`
`it-
`prostate cancer progresses :30 aruirogen independence,
`develops various ‘pathways’ allowing for gmwth in the
`absence of besmstemne. Fm‘ wcampie, cells may increase the
`synthesis of androgen receptors, aflowing them in flourish
`with very low Ieveis of tzesfnstzarmae. Thix is known as the
`‘hypersensitive pathway‘, In the ‘pronzaiscuous pathway‘, the
`androgen receptmt mamas and is activated by a. broad range
`sxf mixer circulatfing‘ steroids. The ancimgen remeptaor
`is
`imcfive nnlees phczsphorylaimi. In me ‘outlaw gaiihway‘, the:
`receptor
`is
`aeberrantiy
`phosphoryiated
`ailnwing for
`constitutive receptor acfivafion,
`In cantrast, a ‘bypass
`pathway‘ allows fer ca-II survivai in tire absence of aYt'£§rt1g&n\
`recepmr activation, afiowirxg.-céfls in avnid apoptmfifi in an
`antimncirogen environment {4}.
`
`Eackground to: the treatment of AIPC
`If-Gaviews by Yagoda 32: ?etryIak {5} and Raghavan at al [iii
`Aaccurateaiy gwartragréd the availabfe cytotoxfic agents as
`ineiferziive in treafing AEPC. Ciinicai
`trials: evaluating’
`antixmstycfiraesg alkylatixzgagfintfi.
`pia€i‘num~
`based agents and tnpoisvmcmse ixthibimrs were
`{5,6}; Dvaarali response rates of 8.7% were noted in 2:3 ciinicafi
`triais conducted between 198'.?_and 1991. The imoad range of
`xeporced response rates ami
`the lack of stanéaxdizeé
`objective mpmzm confcsszmied
`the
`reviewers; wfm
`dwzriiaefi fie chexnoflmeragaezxizic Ianciscagxe as ’-cham‘ £5}.
`$uE3seqnenfly,
`the 983% xesptmse was a;:<:ey!:Fed_ as fine
`standard, mdpoizzbwiaen’ measuring the
`0:? new
`chenmtiiterapeutk: agents. A 1999 mrmsensus .wnfe_xex1_<:e
`clefimd a partial
`in ;a cziinizzai {Tia} as: 3; :mim'xm:n_t;
`FSA xiecline of at least 50% cmxfirmed by 3 aeccmd PEA
`vaéue 9% aimilar levek 4 or more weeks mar in the abseme
`xaf ckinicai at mdiographic eviiience of disease: pragxassinn
`during this time pericd {V}. Tifm is what is tygnicaiiy meant
`by a ‘’PSA respanse‘ and
`used 33 a measure cf
`demonstrable agtiviiy in phase {I clinical
`
`Qiinicak treatment with taxanes
`Doeetaxel {Taxotere} is a mfiynflwfic ifixaxte. which
`disnzfpisz nonnai miwsis iay binciing to 8«€u}m‘iin
`and
`prexnznmg micmmbukz disasaembly. This event: leads in an
`arrest in tiias ceii cy<:1e»a:Hhe 62M phase and, uiitimabeiy,
`apopinsis. Varinus prcwapophotic meeharfisxns of dczcemxei,
`fincludfngt
`inastivatiorz of Bela by phasphcryiafinn;
`inductizéon of p53 anei overcoming mukiémg resisiarxze have
`aim been praposed [41 Znitiai phase 21 clinical triais wiflx
`aacetaxei revealed meme encxmraging respume rates than
`any previous agent in AIPC and led in two large phase 311
`trials, bath ofwhisch were rvapimed its 200$
`
`The progression to androgen inciependencre is Lrauitifatztotial,
`when prosizabe camzer is arxdzogenr-serusiiive, hesmsterme
`enters
`the
`set!
`and
`is enzymaticaiiy ccznveriued
`ho
`dihydmwsmsmmne (DHT’}, which experts its influence in the
`nucleus and activates genes involved in cell growth. A9
`
`Docefaxe! plus estramusiine versus mitoxantrone
`plus predniscme
`Southwest Oncology Group
`The randamizzed clinical
`(SW06) 9916 trial, compared docetaxe} and ‘esimmustine
`(D/B) with ndmxantmne ami gyrednisone {M/P), in. the
`
`JANSSEN EXHIBIT 2027
`
`Wockhardt v. Janssen lPR2016-01582
`
`"Current chemotherapeutic‘ approaches for androgen-«independent prostate
`smcer
`Jon A Rumohr & Sam 8 Chang*
`Address
`Vanderbik University Medical Center
`fiepartznam of Urologic Surgery
`A-1302 Medial Center Nod}:
`Naséwifle
`TN 37232«27I35
`usxx
`Emaiiz sam.::txang@vanderbi!t.edu
`
`
`
`‘Tao whcem oorrespcmtkencs should be addressed
`
`{mmmi Optician In Inwstigatimtal Drugs 2606 ‘2'(8):529v5$_3
`@‘The‘l’I'mmsr.m 3u+rpofation ISSN 14?2-#372
`
`the current state of cizematlzerapgg for
`This review aiesczfiifyes
`- andragewéraaiepenxient prosizete saucer. Lzmdrwzrk ciirticzzl trials,
`i1zc¥miing’TAX 32.7, a rczmiomfzed trial earzsgvrzrfzzg dacelmel mu!
`preénisatze wit}: mitoramfrmae emu’ pzredztismte, and SW06 993 (3;
`:2 nmdomized cfiniaai trial cbmpm-iszg daeetaxzi and estrzzirzzzsttizre
`‘with méfoxrmtrame
`and predyzisme,
`are reviewed. Nomi
`combination tizmzpies,
`involving mane adnziniséered with
`compazmds such as crzlcéfraf maxi
`t¥z::a}z‘:£amide, newafr cytafoxic
`agents, ma;-fine therapies, rzmi targeieni yszuaialiiiemajve aziso -demifed‘
`This reviezxr mainlyfamses an agents with act.£vit_a; in phase £3,/III
`itfirzicfzzi .£rz‘zz£5.
`
`chemotherapy,
`A:1dmgen~im1ependex:ce:,-
`Keywords
`hormone-refrachary, n:tetasta&, prostate carwer,
`
`ksfroduction
`
`Adenocaminoma of the pmstahe: isthe meat camnxonsolid
`hxmur in {ES males, and is saccmsi ozniy tn lung carwer as a.
`cause» of cmcerdeafli. In 2365, pmstate Carma: accamzifié for
`an estimabaci 33% of cancer cases; and 16% ofszancer deaths.
`in the US {I}. fimapy directed at presxzmalaiy locaskized
`disease is succeasfui fin the majarity of cases, whether by
`operative megam’ or tatdiasiimx.
`treatment invofvirxg
`radical proshatectomy, pmgnession ram at five ané tan years
`are estimates! in E25222 and 25%, ramprectixseiy, as measured by
`prostate-sgzeacifitx anifigen, {RA} Ieveis {2}. As with: any
`metastatic maiiignancy,
`therapy for nor:-Iocaiizeé éisease
`requires
`iifeaimzettt. Uxtfii
`recerfifly,
`03'
`surgical castration was the only tenable
`tiaetgspy
`avaifabie to men with meuastafic promae cancer; The
`method of atndmge-.n deprivation dams back in 1941, when
`Huggins 8:: Hodges repezted the efficacy of castzraticrxyartci
`estmgens in the treatxnent of advanced pmstathe carncer [i-3:}.
`Unfertumabely,
`the efficacy of andsogetz deprivation is
`iixniteci by the grogressiozx in androgexviridepezmdent
`prostate cancer (A3322). in men with meeastatic pmsbate
`cancer, this progression typically occurs within 12 to 18
`mandxs,
`in amedian .surviva_1_of. two mfiuteeymrs.
`
`JANSSEN EXHIBIT 2027
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`
`
` §
`
`& 1
`
`
`
`£13
`side-effect pmfile
`similar
`a.
`haci
`ami
`docetaxel
`mitomntrone ami pneénjsong [1{)u}. The US Focd and Drug
`Admirifstratéun (FDA)
`approveci
`this
`regimen shortly
`thereafter for the tteafment of AIFC.
`
`Rafe of estramustine in MP6
`«Results fram the SWOG 9916 and TAX 32’? smciies defined
`the take of estramuafine in the treatment: of MPG, and
`aifered the maatxnent paraciigm for this cancer type £116}. In
`comparable patient gmpulations, a similar efficacy (48 to 59%
`PSA naspcmsa) was observed for patients veceiving
`estramustfine and dcscetaxei (SWOG 9916) and preénismre
`and docetaawi {TAX 327}. E-Iuwever, the boxzfctity profiles in
`the we sziinicai i:ria}s differed sig1if1‘<:an‘fiy’. In axe TAX 32?’
`study, none of $19 patients reported grade 3 nmxsea and
`"vomiting, compared with a 20% inciéexme in flu: SWCJG 9916
`estraxnustine am. Addétianaiiy, no patients in fix: TAX ‘323?
`study suffered grade 3 or higher cardiovamular or clotting
`advarse events, while a 15% fincidence was noted in €he~
`9916
`atudy.
`Nausea,
`vomiwxg
`and
`cardiovascuiar/clntfing
`evenis
`are
`W811
`Imovm
`complicaiinns o£ estrazmxstim ‘aximfinisttatiorc. because of its.
`estwgém cement
`{4}. Thus,
`estraxxmstfiime, Wham
`aximinisfizerred witit ziocetaxel, dew not appear to offer
`incneased efficacy over prednisane and iiocetaxel, and is
`Zikeiy
`the
`cause
`(:35
`gassixtzitxiaesiairzai
`and
`cardimrascuiax toavzicities. Therefore,
`it .appe_a*r.s
`that the
`aziminisfiration of estraxxtiastizle w.it§x docretaxel for AIPC 53
`atxmvarranted, and poss;ib13r‘hatmfu1.
`
`Bacetaxe! as aqimranf therapy
`'I'.hfi' benefits of adjuvant chexxtoiimrapy observed ix; 11:88:52 and
`veoIoncarmerpatiez13siedtothistteaimez1tu;m?ur1%aing
`exraiuatecfirxaguhaseiiclinicaliriaitzfdtycefnxfielafixer
`gzmossatecirsmy. fiomnyxmmwcmmy patémha {xi «-4 177) witfz a high
`of prasinile cancer
`reoeiveé daceiaxek {S5
`mgfmi’) on xiays L 3 and 1540f a 28-day cycie. Docefawei was
`weii tnierahed; howexrean the
`mzhcomsas {sf this study
`are penéing. ‘me YAX 3501 study is a phase m, ranclczmized,
`controlled trial tampering obsezrvafixm, androgen ifeprfivation
`therapy (ADT) and AEDT/doaetaxel in the ‘adjuvant sa-tfing.
`I3nrolhne:nt for {this clinical ~tria£
`in Jane 2005. Those
`93:59.-£115 wlm prngrm in the abaewatitntz gimp wafi be
`raridonfimed to either ADI‘ c:rADT/doceta3;3eL The resxxlts saf the
`TAX3561h*iai,wi&1apmjec!2dem0Hmeatcfmrer2i}0B
`.;;a:iz’a1ts, should &w ralesof-both hcmnmxai therapy
`2123*
`
`other taxarm eambinalion Maia
`After the eneautaging results from invesiigafiutts of the
`effect of singhzaagent docetagxel. in the ‘FAX. 32‘? smdy,
`interest has turned in
`cnmbirxaiion the-zapfy
`pmmccla The combination of cakitrinl or tiixaiidomide -with
`flocetaxel has generated considerable interest; Calcitrioi, the
`most active metabolite of vitamin D; decreases prostate
`—ca:'xVer szell pmliferaticm and
`thiegcybamxicity of
`taxanes ’mdepc-zndent of Bel-2 113]. Based on encouragmg
`phase II trials data, the Anciiogenvltxdeperudent Prostate
`Cancer Study cf Cakitxiol Enhancing Taxotem: (
`txfial was
`This rmmdomizaed, piacebe-szontroiied
`clinical
`was designed to evaluate the
`of high-;
`
`
`
`536 Current Opirzian in lmesflgationat Drugs 2006 Vof ‘F No 6
`
`treatment of axivance-<1 refractory prostafae cancer £80}. The
`My’? arm was imslucied bases? on previmzs demmstrations
`of a pafiiative benefit, alflwugh this was without any
`observable aurvival benefit. In a prior stuéy conducted by
`Tannock ea’: at, pain refief and a decline in average analgesic:
`consumption were gfaaher in 1::atients receiving M/P than
`prednisone alone {Qt}. In the SW06 9916 study, 770 men
`with progressive AJPC receiveci one of two treatments, each
`given in 3~week cycles: estramustine {280 mg three times
`ciaily) an days “I. to §, fiooemxei (68 mg/m2} on day 2, and
`deecamathaaona (60 mg)
`in three divided doses before‘:
`éoceiaxei; Of mibaxanfrcne (12 mg] 1113) on flay I pius
`pxeazinisaxte (35 mg twice ziaiiy} Median survival rates in am
`13/E and 311/? groups were 17.5 and 15.6 months,
`respectively (3) m 0.01). PS1’: re$pon$.e (59 Versus 23%) and
`me objective mspcnse rains: in patients with known scoff tissue
`disease (17 versus 11%) watt: also sigrxificantly greater in the
`13/13 arm E800}. However, the D./E gmup had a *.;baiistica1Iy'
`significant higher rate of graée 3 or 4 netfitropenic fevers (5
`versus 2%}, carniiovastrular wants {I5 versus 7%); nausea
`anti vomifing (26 vezsus 5%}, meiaboiia: cirbhzrbannes (6
`versus 1%) and neurolopkr events (:7 versus 2%). ’I'Emre was
`:25 obsemsxf difference in grade 3 er greater
`between the treatment groups £8--}. Aiéxough me mefiian
`survival benefit was uréy 2 months,_ this study set a new
`smndaré far firm efficacy of chemotherapeutic agents in
`AIIFC.
`
`bacetaxet plus prednfsone versus mitaxantrone
`pius prednisone
`TAX 327 was a muiti-instit-utionaf, 'pr0spectiVe,:. randomized
`ciinical trial comparixtg ducetaxei and pmedrnisene witft
`miimanixozne. and prednisamz {1fluL In tifia trial, 1986 men
`wifl:
`prednisane (5 mg twice ciaily) and were
`randcxxxly xawiguzd to three txwunent graxzps: mifoxamzrcme
`(12 mg/m2) wary 3 weeks, docseiaxei (75 zxkgfmfij every 3
`weeks or ziocyetasxeri (38 mg/ml) weeidy for 5 sf every 6
`weeks. ‘Overall survivai was the prfmzxxy endpoint. There
`was no s'mfiS>‘:f:ca:EEy significani differexzce in flue weekiy
`docetaxei group, but a difference was abserved .511 me '3»
`week am compared with mitoxantrone (18.9 versus 16
`m:mths;_p * 0.009}. £’aiz1,raecI21ction.frequerm:y, as a secandaty
`endpoint, was oniy significantly reduced in the fiwweek
`docemxel arm when, mmparexfi with miinxantmna (35 versus
`22%; p 3 £3.61). The madizm tiuraiion of pain reductierm was
`thesame across 33 gwups at 35 to 5.6 _mcniE1a. Time was of
`PSA response {45 in 48%; y < 0.001) were significantly
`greater in patients
`dacetaxei comparesd with
`mibaxantrone, xegardiess of
`the éosing schedule. An
`ixnpmvement in quality-cf-iife was more Ziitefy in patienis
`1-eceiving tiocetaxel cempared with mimxantrcme (2241:: 23%
`versus 13%; p <1 0.01). The weekly doceizixei sszheéule was
`irrcludeci -in debenznine whether a reduced dose adaxixxisttred
`
`weekly woulci resnit in fewer aciverség events or improved
`ouitomes; however, this effectwas not
`wt in the data.
`adverse event mine in tire Ewweék doeemxel mm was
`2.6%. ccvznparecl wftit 29% when administeresi weekfy.
`‘significanéiy more adverse-evenis occurred in than dcxtetaxel
`treaunent amas than with mimxantrone (29%), In summazy;
`an every Swweek regimext onf docefaxei (75 mgfmz} with
`yrednisone (5 mg} twice éaily was superim ms weekiy doseci
`
`

`

`Currant cherncthorapeutic approacrm for AIPC Rumohr & Chang 531
`
`dose calxzitrioi combined wifiz aiocetaxek Fatienis with AIPC
`(xx == 25$) were rmxiomized 2:0 receive either placebo and
`docetaxel, or a capsuia forxxxxxiaiabn of caicihrinl (DN-101
`{Novacea Inc), 45 gzg wally {mm weekiy} and ziocetaxel
`Docemxei was aciministamd accozssiirzg to the 3(}~mg/m?
`weekly ciose scheéule ciescrihezi in the TAX 327 shsdy,
`rather than the every-3-week regime. The primary endpoint
`of this study was PSA tespcmse. Interim restzfits of this study
`havebemmyortad inabstractform [14},PSAvesponsewiti1in&
`months was 58% for patienis
`cakitziol/docnemxaezl
`ccsmpared with 49% for iiwse receiving pfaeebo/docetaxel;
`hmzaevezc, fizis was mi: :1
`difiference {p =-'~
`0.16). In pafienfs with measurabfie disease, a trend inward
`improvved ebjevctive response rate was :‘iol1a~d(28 vetsus 20%; p '2'
`. 0.05). Serious aclverse events were less caomman in the DN40
`gmup(24versus3fi93;pW{J.€)38).Afu11reportonthe
`V.
`'
`trial is pendi:ng.-
`ciavlafis of meondaxy
`and
`p &w sunrival
`
`'
`
`in
`evakzixting docemeei
`are acumreniziy
`trs?aIs
`Several
`gzlomhination with agems
`tint
`iriierfere with tumor
`xxeovascularizatiorm ’§“ha_ii:ioxni:ie is a potent
`with
`antiwangiagenic pmper&s, as evidenced by ‘$19 stxmteci limb
`growth. in exgased fietuw. A rancicmizeci, ‘phase
`triai of docefzzxel pins tiza3id‘onu‘deV versus single-agem:
`dmemxel has been repozdaed E15]. f1‘£ShIdy,; 75 patienm
`with AIPC were randomized to receive doeewxel
`(36
`mgfx:§§ , or thalidomide (2012! mg) riaify pins daoeraxei (30
`mg/m2}. ’I’he« PSA response was 317% in the docetaxel aione
`arm and 53% in the combinatiun arm, although this did not
`reach statisiicai
`sigtrtifisztarxce
`(5:
`~“» 9.32). Hawezver,
`thét
`response rates did satisfy criteria far further evaluation. The
`?E8~month survival rate was 42.9 and 68.2% far the docehaxel
`aionet ami aombinatinn amxs,
`respectiveiy (33 = 0.11).
`Although the absenned respcmse did not reach sisaiisticai
`significance,
`ixxspmvememt W35 demmnstratneé in all
`the
`start&ard
`euhtome measures: PSA respanse,
`fime-m»~
`progzsesaion ('I'I3?} and ovarafi survival. Only a amall
`number af patients ware included in this study and it was
`xtof designad in evaltzatae overaii survival; fherefme, Iarget,
`ramlomizexi clinical iariais are
`ta batmr evaluate
`the efficacy of this regimen: in patients with A{PC‘.
`
`Future treatment modatities
`
`Cytotoxic agents
`Sat:-apiatzén (CJPC Biobecia AG; Figure 1) is a third~generatior1
`oral pIatinum(IV) complex anticancer’ agent. with clixmically
`demonstrated antifiumor activiiy {I6}. On the basis of
`promising phase II clinical trials dam, the Satrapiafiin and
`,F1'ednisone_Agains€ Refractory Cancer (SPARC)
`was
`irtitiahed in 2003, and expanded in 200% in inciude seveml
`more ‘European sites. SFARC is a muliicenier, randomized,
`dauble-biind, phase Lit
`study designed to _evaluate
`satrapfatin as a se<:a‘nd«1f1ne ch_emo£herapyL in patimis with
`metnstatiac AH-‘C that have faiieeni previous
`cytomxfic
`civetnoiherapy [WE Curzentiy there are no appmved agents
`for me secancblixxa meaimmt of homommfimwry gsrosbaie
`carnceac, anti the US FDA has
`acceierated appmvai.
`‘status to satmplatin in the SPARC cffnicai triai, which is
`curremty ongoing.
`
`figure 1. The structure of sat-apmin.
`
`
`
`Epothilanes are microtubuie inhihitoxs with an acfion
`similar to that ef taxama-s‘ but with 11:12 addeé advantage at
`activity in taxanewesistant tumors.
`epoflzflonéfi analog
`ixabapiloxua {BMS~247550, Brisi2aI~Myers Squibb; Figure 2)
`has '&2mmxstrahed rziirticai .activity in a phase flclinical
`{I8}. PSA response was observed in 21 outaf the 44 .patiez:ts
`ixahepilcne. and in 31 out cf five 45 patietits
`’receiving bcabepficné pf£;s.e5tramv$ti11€
`phosphate {:8},
`Phase II and IE ciixtfcal
`areongoing.
`
`2.
`
`stwcmre affixabepilone.
`
` lxdhgpiiann
`
`(Bduéot-Myam Squisb}
`
`Vacaines
`As camtzer isincreasitxgly beingxzieweci, atvleastin part, as a
`breakdown of immune system sursreillamse, researvgiisers are
`séseking ways in
`the
`rsf tfhe
`system. Thus, mmn‘r,va;:<:?xxe. ‘therapy is a promising am: af
`researcir.
`
`GVAX (Cel1,Genafesys Inc} is a vaccine in wi1x’:c':h_ ixmdiabed
`patient-derived. pmstafne cancer cefis are tranaduoed in
`izififa with gmnniocyteemacmphage coiorsyrsiimuiating
`factsor. The raise of this vaccina is ts rearuzit and, samnzam
`peripherai Road mosnoctytes and m_acm;:shages.- -against
`malignant cfelis. A {ahase III ciinical triai camparirzg {W-AX
`with eiocetaxel plus’ pmdnisone is undenvay. Adciitional
`eambiziafion studies at". diocetaxel and GVAX are alsnbeing
`éesigxediféj.
`
`Pmvenge (APC-8915; Dendreon Corp) has been designed tn
`‘help the heady develop an ixmmme response Iifio prosmfie
`=cancer‘_ cells. Auba1ogaus—.anh]gen-presentirig cells (APCS) are
`loaded with K‘ fusion pmtefn combizting a prostate-specific
`pfotaein and a molecule specificaiky targeting an ABC surface
`receptor. Results {mm a. phase II clinical
`triai are
`emzonragixxg, with teportsof amedism »!:ime.t;:s progjnsssimx-of
`118 tiays. ‘One paiiierxt with AL¥l"C Emmi‘ a decrease in P523
`from 221 ngfmi to uzadetaectable levels, which
` k for four years {I9}. A ramiomizzed, phase III
`aria: it patients with asymptomatic, ~meIas&tx',e: AIFC
`underway, in which 275 patfimts wili be -randomized. to
`Pmvenge or
`AFCs I2(}vr}i.
`
`EI
`
`i
`
`

`

`in earnest. Ezwoumgmg ‘response ram have been Qhtaireed
`from landmarl-2 clinical
`trials evaluating doceiaxei
`in
`combinatian with estramustine O? predrxisona, and results
`from these studies have influenceci
`future treatment
`
`regimens for AEPC. Promising’ chemotherapeutic agenm,
`emerging tumor vaccines,
`targeted therapy‘, and naval
`combination ‘regimes are all under active investigation,
`These studies will hopefully play a role both in current
`investigaticmal therapy ami as a bridge to f-utxxre modalities.
`
`References
`
`1.
`
`2.
`
`f:£mJ6vww.cancar.mg
`
`my Ustqml
`
`Hull SSW, Rabcba:‘«lF,AbbasF.Wxeeier1'M.Ka1:anM\lVL$cat$na$7‘£‘:
`Game: contra with radiate}
`’
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