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`it:
`prostate cancer progresses to androgen independence,
`develops various ‘pathways’ allowing for growth in the
`absence of testosterone. For example, cells. may increase the
`synthesis of androgen receptors, allowing them to flourish
`with very low levels. of testosterone. This is known asthe
`‘hypersensitive pathway’. In the 'promiscuous pathway’, the
`androgen receptor mutates and is activated by-abroad range
`of other circulating steroids, The androgen receptor is
`inactive unless phosphorylated. In the ‘outlaw pathway’, the
`receptor
`is
`aberrantly phosphorylated
`allowing for
`constitutive receptor activation.
`In contrast,
`a.
`‘bypass
`pathway’ allows for cell survival in the absence of androgen:
`receptoractivation, allowing cells toavoid apoptosis in an
`antiandrogen environment [4].
`
`*Tg whom correspondence should be addressed
`
`Current chemotherapeutic approaches for androgen-independent prostate
`cancer
`
`Jon A Rumohr & Sam S Chang*
`Address
`
`Vanderbilt University Medical Cenier
`Department of Urologic Surgery
`A-1302 Medical Center North
`
`Nashville
`TN 37232-2765
`USA
`
`‘Email: sam.chang@vanderbiltedu
`
`
`Current Opinion in Investigational Drags 2006 7(6)520-G35
`The Thomsen Corporation ISSN 1472-4472
`
`
`This review describes the current state of chemotherapy for
`
`- androgen-independent prostate cancer. Landmark clinical. trials,
`
`including TAX 27,4 randomized. trial comparing docetaxel and
`
`prednisone with mitoxantrone and prednisone, and SWOG 9916,
`
`a randomized clinical trial comparing docetaxel and estramustine
`
`with mitoxanivone
`and predvisone,
`are rewiewed: Novel
`
`combination.
`therapies,
`involving taxane administered with
`
`compounds such as calcitrol and thalidoniide, newer cytotoxic
`
`agents, vaccine therapies, and targetedmodalitiesare also detailed.
`
`This review mainlyfoctses.on agents with actioity in phase L/W
`climical trials.
`
`Background to the treatment of AIPC
`Reviews by Yagoda & Petrylak [5] and Raghavan et al [6]
`accurately portrayed the available cytotoxic agents as
`ineffective in treating AIPC. Clinical
`trials evaluating
`anthracyclines, alkylatingagents, afitimetabolites, platinum-
`based agents and topoisomerase inhibitors were reviewed
`[5,6); overall response rates of 8.7% were noted. in 26 clinical
`trials conducted between 1987and 1991. The broad rangeof
`reported response rates and the lack of standardized
`chemotherapy;
`Androgen-independence,
`Keywords
`
`
`objective responses confounded.the. reviewers; who
`hormone-refractory, metastatic, prostate cancer, taxdnes
`described ‘the chemotherapeutic landscape as ‘chaos’ [5].
`Subsequently,
`the PSA response was accepted as the
`standard endpoint when measuring the efficacy of new
`chemotherapeutic agents. A 1999 conserisus .conference
`défined a partial response in a clinical trial as a miinimam
`PSA decline of at least 50% confirmed by a second PSA
`value of similar levels 4.or more weeks later inthe absence
`of clinical or radiographic evidence of disease progression
`during this time period [7]. This is whatis typically meant
`by a "PSA response’ and is used as a measure: of
`demonstrable activity in-phase Il clinical trials:
`
`
`
`introduction
`Adenocarcinoma of the prostate is the most conumon.solid
`tumor in US males, and is second. only to lung cancer asa
`cause of cancerdeath. In 2008, prostate cancer accountedfor
`an estimated 33% of cancer cases and 10% ofcancer deaths.
`in the US [1]. Therapy directed at presumably localized
`disease is successful in the majority of cases, whether by:
`operative mieans or Yadiation. Despite treatment involving
`radical prostatectomy, progression tates at five and ten years
`are estimatedto. be22 and 25%, respectively, as measured by
`prostate-specific antigen. (PSA)
`levels (2). As with any
`metastatic malignancy,
`therapy for non-localized disease
`requires systemic treatment. Until
`recently, miedical or
`surgical castration was the only tenable. systemictherapy
`available to men with metastati¢ prostate cancer. The
`method of androgen deprivation dates back to 1941, when
`Huggins & Hodges reported the efficacy of castration and
`estrogens in. the treatment of advanced. prostate cancer [3¢].
`Unfortunately,
`the efficacy of androgen deprivation is
`limited by the progression to androgen-independent
`prostate cancer (AIPC). In men withmetastatic. prostate:
`cancer, this progression typically occurs within 12 to 18
`months, resultingin a.median survivaloftwo tothreeyears.
`
`The progression to androgen independenceis multifactorial.
`When prostate cancer is androgen-sensitive,
`testosterone
`enters
`the
`cell
`and
`is enzymatically converted to
`dihydrotestosterone (DHT), which exerts its influence in the
`nucleus and activates genes involved in cell. growth. As
`
`Clinical treatment with taxanes
`Docetaxel (Taxotere)
`is a semi-synthetic taxane, which
`disrupts normal mitosis by binding to f-tubulin and
`preventing microtubule disassembly. This event leads to an
`arrest in: the cell cycle at the G:M pliase and, uliimately,
`apoptosis. Various pro-apoptotic mechanisms of docetaxel,
`including inactivation of Bel-2
`-by phosphorylation,
`induction of p53 and overcoming multidrug resistance have
`also been: proposed [4]. Initial phase I] clinical trials with
`docetaxel revealed more encouraging response: rates. than
`any previous agent in AIPC and led to two large phase TI
`tials, both ofwhich were reported in 2004.
`
`Docetaxel plus estramustine versus mitoxantrone
`plus prednisone
`The randomizedclinical trial, Southwest Oncology Group
`(SWOG) 9916 tial, compared. docetaxel and estramustine
`(D/E) with mitoxantrone and prednisone (M/F) in. the
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`JANSSEN EXHIBIT 2027
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`$30 Current Opinion in investigational Druge 2006 Vol 7 No 6
`
`treatment of advanced refractory prostate cancer [Se«]. The
`M/P arm was included based on previous demonstrations
`of a palliative benefit, although this was without any
`observable survival benefit. In a prior study conducted by
`Tannock et al, pain relief and a decline in average analgesic
`consumption were greater in patients receiving M/P than
`prednisone. alone [9s]. In the SWOG 9916 study, 770 men.
`with progressive AIPC received one of two featments, each
`given in 3-week cycles: estramustine (280 mg three times
`daily) on days 1to 5, docetaxel (60 mg/m) on day 2, and
`dexamethasone (60 mg)
`in three divided doses before
`docetaxel: or mitoxantrone (12 mg/m) on day 1 plus
`prednisone (5 mg twice daily). Median survival rates in the
`D/E and M/P groups were 175 and. 15.6 months,
`respectively (p = 0.01). PSA response (50 versus 27%) and
`the objective response rate in patients with known soft tissue
`disease (17 versus 11%) werealso significantlygreater in the
`D/E arm [8ee]. However, the D/E group had_a statistically
`significant higher rate of grade 3 of 4 neutropenic fevers
`versus 2%), cardiovascular events (15 versus 7%), nausea
`and vomiting (20 versus 5%), metabolic disturbances. (6
`versus 1%) and neurologic events (7 versus 2%). There was
`no observed differerice in grade.3 or greater neutropenia
`between the treatment groups [See]. Although the median
`survival benefit was only 2-months, this study set a new
`‘standard for the efficacy of chemotherapentic agents in
`APC,
`
`Docetaxel plus prednisone versus mitoxanitrone
`plus prednisone
`TAX 327 was a multi-institutional, prospective, randomized
`clinical trial comparing docetaxel and prednisone with
`mitoxantroneand prednisone [100+]. In this tial, 1006-men
`with AIPCreceived prednisone (5 mp twice daily) and were
`randouily assigned to three treatment groups: mitoxantrone
`(12 mg/m?) every 3 weeks, docetaxel (75 mg/m?) every 3
`weeks or docetaxel (30 mg/in?) weekly for 5 of every 6
`weeks. Overall survival was the primary endpoint There
`was no statistically significant difference iy the weekly
`docetaxel group, but a difference was observed in the 3-
`week arm compared with mitoxantrone (18.9 versus. 16
`months:p = 0.009). Painreduction frequency, as a. secondary
`endpoint, was only significantly reduced in the 3-week
`docetaxel arm whencompared with miitoxantrone (35 versus
`22%; p = 0.01). The median duration of pain reduction was
`the same across all groups at 3.5 to 5.6 months. The rates of
`PSA response (45 tw 48%; p < 0.001) were significantly
`greater in patients receiving docetaxel compared with
`mitoxantrone,
`regardless of
`the desing schedule. An
`improvement in quality-of-life was more Ukely.in patients
`receiving docetaxel compared with mitoxantrone (22 to 23%
`versus 13%;-p < 0,01). The weekly docetaxel schedule was
`included to determine whether a reduced dose administered
`weekly would result in fewer adverse events or improved
`sirtcomes; however, this effectwas not borne out in the data.
`The adverse event rate in the 3-week. docetaxel arm was
`26%, compared with 29% when administered weekly.
`Significantly more adverseevents occurred in the docetaxel
`treatment arms than with mitoxantrone (20%), In summary,
`an every 3-week regimen of docetaxel (75 mg/m) with
`prednisone (5 mg) twice daily was superior to weekly dosed
`
`to
`side-effect profile
`docetaxel and had a similar
`mitoxantrone and prednisone [10ee], The US Food and Drag
`Administration (FDA) approved this
`regimen shortly
`thereafter for the treatment of AIPC.
`
`Role of estramustine in AIPC
`Results from the SWOG 9916 and TAX 327 studies defined
`the role of estramustine in the treatment of AIPC, and
`altered the treatment paradigm for this cancer type [11e]. In
`comparable patient populations, a similar efficacy (48 to 50%
`PSA response) was observed for patients
`receiving
`estramustine and docetaxel (GWOG 9916) and prednisone
`and docetaxel (TAX 327). However, the toxicity profiles in
`the two clinical trials differed significantly. In the TAX 327
`study, none of the patients reported grade 3 nausea. and
`vomiting, compared with.a 20% incidence in the SWOG 9916
`estramustine. arm, Additionally, no patients ix the TAX 327
`study suffered grade 3-or higher cardiovascular. or clotting
`adverse’ events, while a 15% incidence was noted in the:
`SWOG
`9916
`study.
`Nausea,
`vomiting
`and
`cardiovascular/clotting
`events
`are
`well
`known
`complications of estranvustine administration because. of its:
`high estrogen content
`[4]. Thus, estramustine, when
`administered with docetaxel, does. not appear to offer
`increased efficacy over prednisone and. docetaxel, and is
`likely
`the <ause of
`increased
`gastroiritestinal
`and
`vardiovascular
`toxicities. Therefore,
`it appears.
`that’ the
`administration. of estramustine with docetaxel for AIPC is
`«unwarranted, and possiblyharmful,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Docetaxel as adjuvant therapy
`‘The benefits of adjuvant chemotherapy observed in breast and
`eolon cancer patients led to this treatment option being
`
`evaluated in a phase TT clinical
`trial of docetaxel after
`prostatectomy. Post-prostatectomy patients(n=77) with a high
`
`tisk of prostate cancer
`recurrence received docetaxel (35
`mg/m?) on days 1,8 and. 15 of a 38-day cycle. Docetaxel was
`
`well tolerated; however, the oncological outromes of this shady
`
`are pending. The TAX 3501 study is-a-phase JU, randomized,
`controlled trial.comparing observation, androgen deprivation
`
`therapy (ADT) and ADT/docetaxel im the adjuvantsetting.
`Enrollment ‘for ‘this clinical tial began in late 2005. Those
`
`patients who progress in the observation group will be
`
`randomized to either ADT orADT/docetaxel. The results of the
`
`TAX 3501 trial. with a projected extollment of over 2000
`
`patients, should highlight the roles. of both hormonal therapy
`and chemotherapyin the adjuvantsetting[12].
`
`
`Other taxane combination tiais
`
`After the exicouraging reselis from investigations of the
`effect of single-agent docetaxel inthe. TAX 327 study,
`interest has tumed to several taxane combination therapy:
`
`protocols. The combinationofcalcitriol or thalidomide with
`
`docetaxel has penerated considerable interest: Calcitriol, the
`
`most active metabolite of vitamin D, decreases. prostate
`caricer cell proliferation.and increases. the -cytotoxicity’.of
`
`taxanes independent of Bcl-2 [13]. Based on encouraging
`phase II trials data, the Androgen-Independent Prostate
`
`Cancer Study of Calcitriol Enhancing Taxotere (ASCENT)
`trial was initiated. This randomized, placebo-controlled
`clinical trial was designed to evaluate the efficacy of high-
`
`
`
`
`
`

`

` | i
`
`Current chemotherapeutic approaches for AIPG Rumohr & Chang 534
`
`dose calcitriol combined with docetaxel. Patients with AIPC
`(n = 250) were randomized to receive either placebo and
`docetaxel, or a capsule formulation of calcitriol (DN-101
`(Novacea Inc), 45 pg orally once weekly) and docetaxel,
`Docetaxel was administered according to the 30-mg/m?
`weekly dose schedule described in the TAX 327 study,
`rather than the every-2-week regime. The primary endpoint
`of this study was PSA response. Interim results of this study
`have been reported in abstract form [14]. PSA response within 6
`months was 58% for patients receiving calcitriol/docetaxel
`compared with 40% for those receiving placebo/docetaxel;
`- however, this was. not a statistically significant difference (p =
`0:16). In patients with measurable disease, a trend, toward
`improved objective response rate was rioted (28 versus 20%; p>
`. 0.05). Serious adverse events were less commonin the DN-101
`group (24 versus 36%; p.» 0,058). A full report on the ASCENT
`trial is pending,particularly details of secondary endpoints and
`progression-free survival,
`
`>»
`
`Figure 7. The structure. of satraplatin.
`
`Epothilones are microtubule inhibitors with an action
`similar to that of taxanesbut with the added advantage of
`activity in taxane-resistant tumors. The epothiloneB analog
`ixabepilone (BMS-247550, Bristol-Myers Squibb; Figure 2)
`has demonstrated clinical activity in a phase Il clinical trial
`[18]. PSA response was observed in 21 outof the 44 patients
`receiving ixabepilone, and in 31 out of the 45. patients
`-yeceiving.
`ixabepilone plas. estramustine phosphate [18].
`Phase ll andIf clinical trials areongoing.
`
`
`
`Figure 2.Thestructure ofixabepiione. Ixabepiione
`
`in
`are currently evaluating docetaxel
`trials
`Several
`combination with agents
`that
`interfere with tumor
`neovascularization. Thalidomide is a potent tetatogen with
`anti-angiogenic properties, as evidenced by the stunted limb
`growthin exposed fetuses: A randomized, phase Ilclinical
`trial of docetaxel plus thalidomide. versus single-agent
`docetaxel has been reported [15]. In this. study, 75 patients
`with AIPC were randomized to receive docetaxel G0
`mg/m), or thalidomide (200 mg) daily plus docetaxel (30
`mg/m). The PSA response -was.37% in the docetaxel alone
`arm and 53% in the combination arm, although-this did not
`reach statistical significance (p = 0.32). However,
`the
`response tates did satisfy criteria for further evaluation. The
`18-month survival rate was-42.9 and 68.2% for the docetaxel
`alone and combination arms,
`respectively (p = 0.11).
`Although the observed response did not reach statistical
`significance,
`improvement was demonstrated in all
`the
`standard ovtcome measures: PSA response,
`time-to-
`progression (TIP) and overall survival. Only a small
`number of patients were included in this study and it was
`not designed to evaluate overall survival; therefore, larger,
`randonrized clinical trials are necessary to better evaluate
`the efficacyof this regimen in patients with AIPC.
`
`Future treatment modalities
`Cytotoxic agents
`Satraplatin (GPC Biotech AG; Figure 1) is a third-generation
`oral platinum(IV) complex anticancer agent, with clinically
`demoristrated antitumor activity [16]. On the basis of
`promising. phase II clinical trials data, the Satraplatin and
`Prednisone Against Refractory Cancer (SPARC) trial was
`initiated in 2003, and expanded in. 2004 t include several
`more European sites. SPARC is a multicenter, randomized,
`double-blind, phase Of
`study designed to evaluate
`satraplatin as a second-line chemotherapy.in. patients with
`metastatic AIPC that have failed previous cytotoxic
`chemotherapy [17]. Curveritly there are no approved agents
`for the second-line treatment of hormone-refractory prostate
`cancer, and the US FDA has granted accelerated approval
`status to satraplatin in the SPARC clinical trial, which is
`currently ongoing.
`
`(BristolMyers Squinb)
`
`
`Vaccines
`As cancer is-increasingly being viewed, atleastin part, as a.
`breakdown of immune system surveillance, researchers are
`seeking ways to increase the effectiveness of the immune
`system. Thus, tumorvaccine. therapy is a promising area of
`research.
`
`GVAX(Cell Genesys Inc) is a vaccine in whichirradiated
`patient-derived. prostate cancer cells are transduced.
`in
`vitro. with granulocyte-macrophage colony-stimalating
`factor. The role of this vaccine is to recruit andstimulate
`peripheral blood monocytes and macrophages -against
`malignanté¢ells. A phase III clinical trial comparing GVAX
`with docetaxel plus prednisone is underway. Additional
`combination studies of docetaxel and GVAX are also being
`designed[4].
`
`Provenge (APC-8015; Dendreon Corp) has beendesigned to
`help the bedy develop an immune. response to prostate
`‘cancercells, Autologousantigen-presenting cells (APCs) are
`loaded with afusion protem combining a prostate-specific
`protein and a moleculespecificallytargeting an APC surface
`receptor. Results
`from a phase Il. clinical
`trial are
`encouraging, with reportsof amedian timeto progression:of
`118 days. One patient with AIPC hada decrease in PSA
`from 221 ng/mi to undetectable levels, which remained
`undetectable for four years [19]. A. randomized, phase I
`trial in patients with asymptomatic, mietastatic AIPC is
`underway, in which 275 patients will be randomized to
`Provenge or inactivated APCs [206].
`
`

`

`532 Current Opinion in investigational Drugs 2006 Vol 7 No 6
`
`Onyvax-P (Onyvax Ltd) is a cell vaccine composed of three
`irradiated allogeneic cell
`lines. Cells from primary and
`metastatic disease are included in this vaccine, and
`theoretically, the broad. range of antigens will improve its
`efficacy and help avoid resistance. Based on encouraging
`phase Il clinicaltrials data in AIPC patients, a phase III trial
`is to be initiated [4],
`
`Targeted therapies
`Targeted therapy refers to the inhibition of specific signal
`transduction molecules that are important for cell. growth.
`Vascular endothelial growth factor (VEGE) and endothelir-1
`(ET-1) ave two targets that are being evaluated in clinical trials.
`
`is a monoclonal antibody that
`Bevacizumab (Avastin)
`targets VEGF, binding and inactivating i,
`thereby
`neutralizing its primary pro-angiogenesiseffects. The effect
`of bevacizumab bi combination with docetaxel and.
`estramustine (CALGB 90006) was initially evaluatedin 79
`patients with AIPC. Of this patient set, 32 had measurable.
`disease, with. nirie (53%) of. these’ demonstrating a partial
`response. Furthermore, a > 50% decline in PSA levelswas
`noted in.65% of 20 evaluable patients [21]. CALBG 90401is a
`randomized, phase Iclinical
`trial currently accruing
`patients with AIPC. The trial will compare: the effect of
`combining bevacizumab with docetaxel plus prednisone
`with docetaxel plus prednisone on overall survival [22].
`
`is a potent vasoconstrictor that plays a role in the
`ET-i
`mediation. of osteoblast growth and function. Blocking the EI-
`I/ET,. receptor pathway may.
`therefore block. the tele of.
`osteablasts, which. play a pathological role in bone metastases
`i AIPC [23]. Atrasentan (Xinlay, AbbottLaboratories; Figure3)
`is an ofally administered, selective. ET, receptor antagoriist
`which hasdemonstrated activity in clinical trials[24,25]. A
`randomized,
`phase
`TH.
`clinical
`trial
`comparing. daily
`administration of atrasentan (10 mg po)-with placebo in 941
`patients with AIPC (M00 244), with a primary endpointoftime
`fo progression, is underway [20], To investigate the effect of
`comibination therapy in patients with AIPC, a endomized;
`placebo-controlied, phaseHil clinical trial comparing atrasentani
`in combination with docetaxelplus prednisone with docetaxel
`plus prednisoneis planned (GWOG50421). Thetrial has been
`approved butis notyetunderway [20¢]
`
`Figure 3. The structure of atrasentan.
`
`Conclusion
`After decades without significant progress inthe treatment
`of AIPC, new and innovative therapies are being developed
`
`in earnest. Encouraging response rates have been obtained.
`from landmark clinical
`trials evaluating docetaxel
`in
`combination with estramustine or prednisone, and results
`from these studies have influenced future treatment
`regimens for AIPC. Promising chemotherapeutic agents,
`emerging tumor vaccines,
`targeted therapy, and novel
`combination regimes are all under active investigation.
`These studies will hopefully play a role both in current
`investigational therapy and as a bridge to future modalities.
`
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`« This Paperreported.a palliative banefit for mitoxentrone chemotherapy.
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`10. Tannock IF. de Wt R, Berry WR, Hort J, Phaanska A; Chi KN, Oudard
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`os The TAX 327 study daccribed in this paper demonstrated superior survive!
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`dosing schedule wes superior
`to weekly
`prodnisone,..The Sweekly
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`44. Ghang'$6, Benson MC, Campbell SC, CrookJ, Dreicer Evans CP,Hall
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`cancer:
`Oh WK: High+isk . localized prostate
`chemotherapy. Oncologist (2008) 1e(Supol 218-22.
`
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