New drugs in prostate cancer
`Andrew J. Armstrong and Michael A. Carducci
`
`Purpose of review
`The survival of hormone-refractory metastatic prostate
`cancer patients has improved with the use of docetaxel-
`based chemotherapy. The survival benefits, however, are
`modest suggesting that rationally designed therapeutic
`approaches are needed. We discuss recent
`developments in the therapeutic approach to advanced
`metastatic hormone-refractory prostate cancer, including
`molecularly targeted therapy, signal transduction
`inhibitors, stem-cell targeted therapy, anti-angiogenic
`compounds, vaccines and immunomodulating agents,
`differentiation agents, cytotoxics, and pro-apoptotic
`agents.
`Recent findings
`Over 200 compounds have entered clinical development
`for use in advanced prostate cancer, alone or in
`combination with cytotoxic agents such as docetaxel, or in
`other combinations. This article will review the results of
`emerging targets since the approval of docetaxel in 2004,
`concentrating on some of those compounds that, in our
`opinion, have the greatest potential and rationale for use.
`Summary
`The growing field of targeted molecular therapy of prostate
`cancer has opened up numerous opportunities for
`therapeutic impact. Knowledge of the molecular
`determinants of progression, relapse after local therapy,
`chemotherapeutic resistance, and hormone refractoriness
`remains essential in the rational design of clinical trials of
`these agents. Given the complexity, heterogeneity, and
`crosstalk of molecular pathways and the molecular lesions
`in prostate cancer, combination or sequential therapy may
`be a necessary step towards significant therapeutic
`progress. Novel translational clinical trial methodologies
`may assist in a more rapid identification of active
`compounds at biologically active doses for phase-III testing.
`
`Keywords
`angiogenesis, apoptosis, hormone refractory, metastatic
`prostate cancer, novel agents, prostate cancer, targeted
`therapy
`
`Curr Opin Urol 16:138–145. # 2006 Lippincott Williams & Wilkins.
`
`Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer
`Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
`
`Correspondence to Michael A. Carducci MD, Associate Professor of Oncology
`and Urology, Prostate Cancer Research Program, Sidney Kimmel Comprehensive
`Cancer Center, Johns Hopkins School of Medicine, CRB 1M51, 1650 Orleans
`Street, Baltimore, MD 21231, USA
`Tel: +1 410 502 9746; fax: +1 410 614 9006
`
`Current Opinion in Urology 2006, 16:138–145
`
`138
`
`Abbreviations
`
`EGFR
`epidermal growth factor receptor
`HRPC
`hormone-refractory prostate cancer
`PDGFR platelet-derived growth factor receptor
`PSA
`prostate-specific antigen
`VEGF
`vascular endothelial growth factor
`
`# 2006 Lippincott Williams & Wilkins
`0963-0643
`
`Introduction
`In 2004, docetaxel (Taxotere, Sanofi-Aventis, Bridge-
`water, NJ) with prednisone was US Food and Drug
`Administration (FDA) approved for the treatment of
`metastatic, progressive, hormone-refractory prostate can-
`cer based on findings from TAX327 and SWOG 9916
`[1(cid:127)(cid:127),2]. Survival was increased in TAX327 by a median
`of 2.5 months from 17.4 to 18.9 months as compared
`with mitoxantrone and prednisone, the previous stan-
`dard of care, and was similar to results seen with doce-
`taxel and estramustine in SWOG 9916. Importantly,
`quality-of-life and pain measures were improved despite
`the higher risk for severe neutropenia, fatigue, alopecia,
`diarrhea, stomatitis, nail changes, tearing, peripheral
`edema, and neuropathy. While docetaxel represents an
`improvement in care and the first demonstrable survival
`advantage in this patient population, treatment remains
`palliative and survival benefits are modest. The identi-
`fication of molecular lesions that reproduce the aggres-
`sive cancer phenotype, which are not present in normal
`tissues, is essential to further the field beyond the cur-
`rent cytotoxic plateau and to move towards the develop-
`ment of targeted novel agents.
`
`Growth factor and signal transduction
`pathways
`The last decade has witnessed the identification of hun-
`dreds of cell-signaling molecules important in the devel-
`opment of prostate cancer. Crosstalk between hormonal
`and growth factor signaling pathways creates a redun-
`dancy and complexity to drug development efforts [3].
`Abnormal expression of a target protein may be insuffi-
`cient as a surrogate marker for a therapeutic target, with-
`out independent validation of that target’s role in repro-
`ducing the cancer phenotype and in mediating the
`response to a drug [4]. Indeed, the androgen receptor
`represents the most valid target to date in prostate can-
`cer, and novel strategies to more potently target the
`androgen axis are in development [5(cid:127)(cid:127)]. Unfortunately,
`it is often the expensive failure of a certain drug class to
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`JANSSEN EXHIBIT 2043
`Mylan v. Janssen IPR2016-01332
`
`

`

`impact response, time-to-progression, or survival in pros-
`tate cancer that triggers a reconsideration of the under-
`lying biological model for a known potential target.
`Table 1 provides an overview of the most advanced
`novel agents in clinical trials in prostate cancer.
`
`cancer
`prostate
`hormone-refractory
`In metastatic
`(HRPC), several classes of agents that modify growth
`factor pathways hold some promise and are in early
`phase trials. These include rapamycin analogs that tar-
`get the Akt/PI3 kinase/mTOR pathway, monoclonal
`antibodies, and inhibitors of upstream growth factor
`receptors
`such as HER-2/3,
`IGF-R,
`IL-6R,
`and
`platelet-derived growth factor
`receptor
`(PDGFR).
`PTEN is a tumor suppressor that is lost in a majority
`of metastatic prostate cancers, leading to unrestrained
`activation of the Akt/PI3 kinase pathway and autono-
`mous growth and survival [6,7]. Akt activation and/or
`PTEN loss have been linked to hormonal resistance,
`chemotherapeutic insensitivity, biologically aggressive
`behavior, high Gleason sum, and relapse after local ther-
`apy [8,9]. Mouse models of PTEN loss or Akt activation
`have demonstrated growth inhibition, restoration of che-
`mosensitivity, and improved time-to-progression with
`inhibitors of this pathway, including rapamycin analogs
`[10–12]. Mechanistic dose-finding pre-prostatectomy
`studies are in progress in prostate cancer with three
`rapamycin analogs: CCI-779 (Temsirolimus, Wyeth,
`Collegeville, PA), RAD001 (Everolimus, Novartis, Cam-
`bridge, MA), and rapamycin itself [13–16]. The devel-
`opment of these agents will be dependent on the estab-
`lishment of surrogate markers of biologic effect, the
`identification of subgroups of responders, and drug char-
`acteristics such as dose, pharmacokinetic variability, and
`tolerability. Everolimus,
`in combination with the
`upstream epidermal growth factor receptor (EGFR) tyr-
`osine kinase inhibitor gefitinib, is in phase-II develop-
`ment and the Ariad agent AP23573 (Cambridge, MA) is
`being evaluated currently as a single agent in metastatic
`
`New drugs in prostate cancer Armstrong and Carducci 139
`
`HRPC. All agents in this class have a well described
`pattern of toxicity, including stomatitis, acneform rash,
`glucose intolerance, nausea, fatigue, mild thrombocyto-
`penia, arthralgias, electrolyte abnormalities, and possibly
`increased risks of infection [17]. Their long-term immu-
`nosuppressive safety in prostate cancer patients has yet
`to be tested, but they have been evaluated favorably in
`renal cell carcinoma and other tumor types [18(cid:127)]. The
`use of these agents in combination with docetaxel is
`under
`investigation and requires careful monitoring
`owing to metabolic and myelosuppressive interactions.
`As these agents are primarily cytostatic in prostate can-
`cer, combination therapy with other biologic agents will
`likely be necessary.
`
`While agents targeting the EGFRs such as gefitinib and
`trastuzumab have not been successful in metastatic pros-
`tate cancer, it is likely that the EGFR and HER-2 targets
`for these drugs may not be causal in prostate cancer [19–
`21]. Indeed, HER-2 overexpression in prostate cancer is
`rare, unlike the case in subsets of breast cancer [21].
`Recent studies, however, may point to other growth fac-
`tors and paracrine signals that may be of greater impor-
`tance, such as HER-3, IGF-R, and cytokine receptors,
`such as the receptors for TGF-β and IL-6. Mellinghoff
`et al. [22(cid:127)] found that HER-2/HER-3 dimerization and
`activation led to optimization of androgen-receptor sig-
`naling in the setting of androgen depletion, pointing to
`a potential novel therapeutic target. The ligand for
`HER-3 is neuregulin, and potential therapeutic agents
`that may target HER-2/HER-3 signaling include the
`monoclonal antibody pertuzumab (Omnitarg, Genen-
`tech, San Francisco, CA) and the intracellular inhibitor
`lapatinib (GlaxoSmithKline, Philadelphia, PA) [23,24].
`
`The endothelin axis has been proposed as an important
`mediator of the bone–prostate cancer interface and para-
`crine signaling target. Endothelin receptors are overex-
`pressed in metastatic HRPC and higher
`levels of
`
`Table 1 Selected novel agents in phase-II/III development in metastatic hormone-refractory prostate cancer
`
`Target
`
`Agent, sponsor
`
`Phase
`
`Brief eligibility overview
`
`Vitamin D receptor
`
`Calcitriol (DN101), Novacea
`
`Endothelin axis
`Vascular endothelial growth factor
`
`Atrasentan (Xinlay), SWOG
`Bevacizumab (Avastin), CALGB
`
`Vaccine strategies
`
`Prostate GVAX (Cell Genesys), Provenge
`(Dendreon), TRICOM (NCI, ECOG)
`
`Epidermal growth factor receptor
`(HER-2/HER-3)
`PTEN/Akt and mTOR pathway
`
`Lapatinib, ECOG
`
`Temsirolimus (Wyeth), Everolimus (No-
`vartis), Rapamycin (Johns Hopkins),
`AP23573 (Ariad)
`
`HRPC, hormone-refractory prostate cancer.
`
`III
`
`III
`III
`
`III
`
`II
`
`I–II
`
`ASCENT II: docetaxel ± DN101 in metastatic
`HRPC
`Docetaxel ± atrasentan in metastatic HRPC
`CALGB 90401: docetaxel ± bevacizumab in me-
`tastatic HRPC, first line
`GVAX (VITAL-1), Provenge (D9902B) – first-line
`metastatic, asymptomatic HRPC VITAL-2: doc-
`etaxel ± GVAX in symptomatic HRPC
`Rising PSA setting (nonmetastatic)
`
`Preoperative pharmacodynamic and dose-finding
`studies; combination with docetaxel in meta-
`static HRPC (Dana Farber and MSKCC)
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`140 Prostate cancer
`
`endothelin correlate with progressive disease [25]. While
`endothelin is a potent vasoconstrictive agent, it may also
`regulate cellular mitogenic pathways in prostate cancer
`and osteoblasts, and may play a role in the mediation of
`bone-related pain from metastatic prostate cancer. Atra-
`sentan (Xinlay, Abbott Labs, Abbott Park, IL) has been
`developed as highly selective ET-A receptor antagonist
`and is the most clinically developed agent of this class in
`prostate cancer [26]. In the phase-III trial, 809 patients
`with metastatic HRPC were randomized to placebo or
`10 mg of oral atrasentan, with the primary clinical end-
`point being time to progression (TTP) [27]. Although
`TTP was not found to be statistically significantly dif-
`ferent from placebo in the intent-to-treat analysis, sev-
`eral secondary endpoints indicated clinical activity,
`including improvements in quality-of-life scores, pain
`scores, and reductions in the rise of laboratory markers
`including alkaline phosphatase and prostate-specific
`antigen (PSA). While atrasentan was not approvable on
`the basis of these data and out of concerns for cardiovas-
`cular toxicity, these results clearly point to biologic
`activity of the endothelin axis in modulating osteoblastic
`metastases, and underscore the importance of
`trial
`design in this population. Further development of this
`agent in combination with docetaxel or in select bone-
`only subgroups of patients may continue. Another ET-A
`receptor antagonist, ZD4054 (Astra Zeneca, Waltham
`MA), is also in phase-II development at this time [28].
`
`Prostate cancer cells express high levels of platelet-
`derived growth factor receptor (PDGFR), and this sig-
`naling pathway utilizes the PI3 kinase/Akt pathway,
`which has been implicated in prostate cancer progres-
`sion [29]. A phase-I study of imatinib (Gleevec, Novar-
`tis, Cambridge, MA) a small-molecule PDGFR tyrosine
`kinase inhibitor used to treat chronic myeloid leukemia
`and gastrointestinal stromal tumor, has been conducted
`in advanced prostate cancer alone and in combination
`with weekly docetaxel. The combination of imatinib
`600 mg and docetaxel 30 mg/m2 weekly for four out of
`six weeks demonstrated a more than 50% PSA reduction
`in eight of 21 patients (38%), with several durable (>18
`month) responses [29]. A second-line randomized trial of
`this combination sponsored by the National Cancer
`Institute Prostate Cancer SPORE clinical consortium is
`underway.
`
`Prostate cancer stem-cell targeted therapy
`While a true prostate cancer stem-cell phenotype has
`yet to be identified, several molecular stem-cell targets
`overexpressed in prostate cancer have been described
`and include elements of the hedgehog signaling path-
`way, human telomerase, and CD133 [30(cid:127),31–33]. Tar-
`geting the hedgehog embryonic pathway, which is over-
`expressed in many metastatic prostate cancers, has been
`
`shown to prevent prostate regeneration after androgen
`withdrawal and to lead to prolonged responses in PC-3
`xenograft models [30(cid:127)]. Novel cyclopamine analogs,
`which inhibit a downstream hedgehog signal, are in pre-
`clinical development.
`
`Human telomerase is responsible for the maintenance of
`chromosome stability and length during cell division,
`and is overexpressed in nearly all cancers. In prostate
`cancer, telomerase may be regulated by androgen or
`growth factors, and is overexpressed as compared with
`normal and benign prostatic hypertrophy tissue [31,32].
`Strategies targeting telomerase have been reviewed in
`detail by Biroccio and Leonetti [31]. Other markers of
`basal epithelial prostate cells that may indicate a subset
`of cancers derived from putative prostate stem cells
`include lack of androgen receptor, CD133, α2β1 integrin
`overexpression, Bcl-2, TGF-β signaling, high-molecular-
`weight cytokeratins, hepsin, and potentially TMPRSS2-
`ETS fusion proteins [30(cid:127),31–33,34(cid:127)(cid:127),35,36]. The identi-
`fication of clonogenic populations of cells in prostate
`cancer with the ability to self-renew and differentiate
`would allow the testing of novel agents directed at
`these cells, provided there was tolerability to normal
`stem-cell populations.
`
`Anti-angiogenic agents
`Prostate cancer
`is known to overexpress vascular
`endothelial growth factor (VEGF) and its receptors,
`and VEGF levels correlate with disease stage and per-
`haps survival in the metastatic setting, with levels falling
`after surgical resection of primary tumors [37,38]. The
`mechanism of action of anti-VEGF therapies is unclear,
`and potentially includes a normalization of vasculature
`for facilitated delivery of chemotherapy, a decrease in
`oncotic interstitial pressure from leaky capillary mem-
`branes, improved recruitment of mature dendritic cells
`and immunostimulation, and true antineovascularization
`effects [39–42]. A phase-III study CALGB 90401 that
`will randomize patients in a phase-III trial to docetaxel
`compared with docetaxel and bevacizumab (Avastin,
`Genentech, San Francisco, CA), including prednisone
`in each arm, is now open with a goal accrual of 1020
`patients over 3 years. This follows on the heels of a
`large phase-II study, which demonstrated the safety
`and efficacy of docetaxel, estramustine, and bevacizu-
`mab in combination for HRPC [43].
`
`agents with anti-angiogenic properties
`Additional
`include thalidomide and its analogs, Revlimid and Acti-
`mid (Celgene, Summitt, NJ), as well as small-molecule
`inhibitors of the VEGF receptor tyrosine kinase such as
`Sorafenib (Onyx, Emeryville CA and Bayer, West
`Haven CT) and Sutent (SU11248, Pfizer, Cambridge,
`MA) [44–46]. These agents are in phase-II development
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`in HRPC. Thalidomide analogs likely have multiple
`mechanisms of action, including inhibition of VEGF as
`well as improved T-cell costimulatory function, TNF-α
`inhibition, and a decrease in IL-6 levels [44,45]. A
`phase-II randomized study of thalidomide and docetaxel
`in HRPC demonstrated impressive PSA declines, TTP,
`and overall survival but was complicated by a high rate
`of thrombosis, sedation, and neuropathy in the experi-
`mental arm, necessitating the introduction of therapeu-
`tic
`low-molecular-weight heparin prophylaxis
`[47].
`Novel thalidomide analogs are in phase-II development
`in prostate cancer, and are expected to have a lower inci-
`dence of vascular and neurotoxic adverse events [48].
`The high potency of these agents in terms of T-cell sti-
`mulation, anti-angiogenic properties, and oral availabil-
`ity make them attractive as therapeutic agents.
`
`Immunologic approaches
`Several vaccination strategies have progressed beyond
`phase-II testing in prostate cancer, including Provenge,
`a PAP-activated dendritic-cell-based vaccine, and Pros-
`tate GVAX, a whole-cell allogeneic vaccine. Both of
`these agents are under evaluation in the phase-III set-
`ting [49(cid:127)]. Provenge (Sipuleucel-T, Dendreon, San
`Francisco, CA) is a proprietary process of antigen deliv-
`ery to activated antigen-presenting cells, collected from
`patients through leukapheresis, stimulated with fusion
`PAP-GMCSF protein, and reinjected intradermally
`every 4 weeks [50]. Initial results from small phase-III
`studies (D9901 and D9902A) involving a total of 225
`patients with asymptomatic metastatic HRPC did not
`significantly demonstrate improved time to disease or
`pain progression, the primary endpoints [51]. While not
`originally powered to detect a survival benefit, overall
`survival was improved by an average of 4 months in
`each study. Analyses based on chance imbalances in
`prognostic factors and use of chemotherapy after vacci-
`nation did not seem to reduce this survival finding. Den-
`dreon is submitting a Biologics License Application to
`the FDA for marketing approval.
`
`Prostate GVAX (Cell Genesys, San Francisco, CA) is a
`form of active immunotherapy using whole-cell allo-
`geneic prostate cell
`lines (PC-3 and LnCaP) virally
`transduced to express an immune adjuvant GM-CSF,
`lethally irradiated, and injected intradermally. Given
`that GM-CSF likely facilitates the maturation and acti-
`vation of dendritic cells, initial work extrapolated early
`melanoma studies to mouse models of prostate cancer
`with results showing prolonged survival and tumor
`regression [52,53]. A phase-II study of prostate GVAX
`was conducted in 34 patients with metastatic HRPC.
`Median survival in this trial was 26 months, historically
`very favorable, but again, observed in select, asympto-
`matic patients [54]. A further evaluation of 80 patients
`
`New drugs in prostate cancer Armstrong and Carducci 141
`
`with metastatic HRPC treated at higher doses demon-
`strated one partial PSA response and improvement in
`markers of bone turnover, with survival analysis still
`ongoing [55]. A phase-II trial of GVAX compared with
`docetaxel (VITAL-1) in 600 men with minimally symp-
`tomatic metastatic HRPC is currently accruing patients,
`and a second phase-III study examining docetaxel and
`prednisone with or without GVAX has been initiated
`(VITAL-2).
`
`Finally, two other vaccine approaches are in early testing
`and include the Prostvac-VF recombinant vaccinia–
`fowlpox PSA vaccine (TRICOM) and the BLP25
`MUC1 liposomal vaccine MUC-1 [56,57]. The use of
`vaccines alone or in combination with chemotherapy or
`biologic agents, such as CTLA4 blocking antibodies, is
`an exciting area of preclinical and clinical development
`[58].
`
`Differentiation and apoptotic therapy
`Two strategies to exploit the latent and resistant nature
`of tumor growth in prostate cancer are differentiation
`therapy and the use of agents that target the apoptotic
`machinery of cancer cells. In prostate cancer, epidemio-
`logic data suggest that the vitamin D receptor is a poten-
`tially valid target, given the link of vitamin D deficiency
`with prostate cancer development, reviewed elsewhere
`[59]. In vitro, calcitriol may have growth inhibitory, pro-
`apoptotic, and differentiating properties in prostate can-
`cer, as well as potential chemosensitizing properties,
`thus leading to a rationale for clinical trials [60,61].
`Based on favorable phase-II results of calcitriol and doc-
`et al.
`[62,63(cid:127)]
`etaxel
`in combination, Beer
`recently
`reported interim results from a phase-II randomized
`trial (ASCENT) of docetaxel and prednisone with or
`without DN-101 (Novacea, San Francisco, CA), a pro-
`prietary oral calcitriol analog. In this randomized multi-
`institutional study of 250 men with progressive meta-
`static HRPC treated with weekly docetaxel with or
`without DN101,
`the primary endpoint was PSA
`response rate, a typical phase-II endpoint. With a med-
`ian follow-up of 18.3 months, neither PSA nor clinical
`response endpoints were met (6-month PSA response
`58% compared with 49%, P = 0.07, and measurable dis-
`ease response rate 29% compared with 24%, P = 0.58 in
`the placebo compared with treated subjects, respec-
`tively). Despite being underpowered to detect a differ-
`ence in survival, however, the estimated median survival
`was nonsignificantly prolonged,
`from 16.4 to 23.5
`months [hazard ratio 0.70, 95% confidence interval (CI)
`0.48–1.03, P = 0.07], and better tolerated than docetaxel
`alone [63(cid:127)]. This difference became significant with a
`prespecified multivariate adjustment based on chance
`imbalances in this small sample size. A larger study
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`142 Prostate cancer
`
`with typical phase-III survival endpoints is planned
`(ASCENT II) to confirm these findings.
`
`Other differentiation strategies include inhibitors of his-
`tone deacetylase and DNA methyltransferase, enzymes
`responsible for the epigenetic silencing of gene expres-
`sion. Histones maintain DNA in a closed, coiled config-
`uration, and this activity is mediated by a reversible
`acetylation process, in which acetylation of lysine resi-
`dues on select histone tails favors transcription. Aberrant
`hypermethylation and gene silencing of specific promo-
`ter regions in prostate cancer has been described, such
`as the antioxidant enzyme GST-II and the tumor sup-
`pressor p21 [64]. The rationale behind agents that target
`histone deacetylase or DNA methyltransferase is their
`ability to induce broad gene re-expression in preclinical
`models of prostate cancer, which may induce apoptosis,
`upregulate p21 signaling, and arrest growth [65(cid:127)]. Phase-
`II studies are planned using SAHA (Merck, Whitehouse
`Station, NJ), an orally bioavailable histone deacetylase
`inhibitor,
`in metastatic HRPC. The development of
`these agents in prostate cancer will require careful atten-
`tion to pharmacodynamic endpoints, toxicity, potential
`differentiating effects such as transient PSA rises, and
`the potential for interactions with chemotherapy and
`other biologic agents [66,67].
`
`As the anti-apoptotic Bcl-2 protein is overexpressed in
`metastatic HRPC, and resistance to cell death seems to
`be dominant over proliferation in these tumors, pro-
`apoptotic strategies are attractive therapeutically [68].
`The mechanism of Bcl-2 overexpression is unclear, how-
`ever, and could be related to PTEN loss and/or Akt
`pathway activation, thus providing a common mechan-
`ism for the observed joint occurrences with tumor pro-
`gression [69(cid:127),70]. Two agents that have progressed to
`the phase-II setting include the antisense Bcl-2 mole-
`cule oblimersen sodium (Genasense, Berkeley Heights,
`NJ) and the proteasome inhibitor bortezomib (Velcade,
`Millenium Pharmaceuticals, Cambridge, MA) [71,72].
`Current results have demonstrated feasibility and safety
`but unclear efficacy or target validation in prostate can-
`cer.
`
`Novel cytotoxics
`The dose limitations of docetaxel therapy in metastatic
`HRPC are predominantly those of peripheral neurotoxi-
`city and myelotoxicity, and the search for well tolerated
`novel cytotoxic compounds continues, both in the front
`line and in the second-line setting. One agent in devel-
`opment for second-line therapy is satraplatin (Spectrum
`Pharmaceuticals, Irvine, CA), a novel oral platinum ana-
`log that may fulfill a niche in second-line therapy if it is
`well tolerated and shown to improve survival over corti-
`costeroids in the ongoing SPARC phase-III trial [73].
`The epothilones are a class of microtubule targeting
`cytotoxic agents in development for second-line and
`relapsed HRPC. While sharing a common mechanism
`of action with the taxanes, they are not apparently sus-
`ceptible to P-glycoprotein induced drug efflux [74]. The
`epothilone-B analog BMS-247550 (Ixabepilone, Ingenta,
`Cambridge, MA) has been studied in a phase-II trial of
`men with HRPC [75]. Initial results demonstrated com-
`parable PSA declines and progression-free survival to
`that seen with docetaxel-based therapy. Use of these
`drugs may be limited by dose-limiting neurotoxicity
`similar to that seen with the taxanes. The use of BMS-
`247550 in taxane-resistant HRPC is being investigated
`currently in the second-line setting as compared with
`mitoxantrone and prednisone, and has shown similar
`PSA declines of about 20% [76]. Finally, monoclonal
`antibodies (mAbs)
`targeted to prostate cancer cells
`with tagged cytotoxic agents represent a novel approach
`to therapy. One agent, MLN2704 (Millenium Pharma-
`ceuticals, Cambridge, MA), is a prostate-specific mem-
`brane antigen conjugated maytansinoid agent and is in
`phase-I/II trials currently in HRPC [77]. Radiopharma-
`ceuticals tagged to mAbs have also shown some promise
`and are also in phase-II trials [78–81]. Table 2 provides
`an overview of second-line clinical trials that are ongoing
`in metastatic HRPC.
`
`Conclusion
`Metastatic HRPC in 2006 remains an incurable disease
`with a median survival of 18–20 months with current
`docetaxel-based chemotherapy regimens. Patients that
`are asymptomatic or have slow PSA doubling times
`
`Table 2 Agents in phase-II/III trials for use in second-line therapy after docetaxel failure in metastatic hormone refractory
`prostate cancer
`
`Agent
`
`Satraplatin
`
`Epothilone B Analog BMS-247550 (Ixabepilone)
`Targeted cytotoxics and radiopharmaceuticals: MLN2704,
`177Lu/ 90Y J591,
`PDGFR: Imatinib(Gleevec)
`
`Phase
`
`Trial, sponsor
`
`III
`
`II
`II
`
`II
`
`SPARC trial (Spectrum Pharmaceuticals):
`prednisone ± satraplatin
`ECOG: BMS compared with mitoxantrone and prednisone
`MLN2704: MSKCC, Millenium Pharmaceuticals; J591:
`Cornell University
`MD Anderson and Prostate Cancer Foundation with docetaxel
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`New drugs in prostate cancer Armstrong and Carducci 143
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`may have a survival of over 2 years; thus, it is important
`to stratify patients based on symptoms, disease sites,
`PSA kinetics, performance status, and other prognostic
`markers to facilitate adequate comparisons of different
`agents in clinical trials [82]. As the number of novel
`agents has increased dramatically in recent years, and
`combination therapy in phase-III trials is accelerating,
`attention to prognostic factors, survival, and quality-of-
`life endpoints, and the mechanism of action is essential
`in the rational development of these drugs. Early studies
`of surrogate assays for survival and the mechanism of
`action of these targeted agents are essential for their
`future development.
`
`Disclosures
`Funding for some of the studies described in this pre-
`sentation was provided by Aventis and Abbott Labora-
`tories. Dr Carducci is on the Speakers Bureau for Aven-
`tis and is a consultant to Abbott Laboratories. He has
`participated as an investigator in studies described in
`this presentation. The terms of this arrangement are
`being managed by the Johns Hopkins University in
`accordance with its conflict of interest policies.
`
`References and recommended reading
`apers of particular interest, published within the annual period of review, have
`been highlighted as:
`(cid:127) of special interest
`(cid:127)(cid:127) of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (pp. 197–198).
`1 Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitox-
`antrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;
`351:1502–1512.
`This largest phase-III trial ever conducted in meta