`castration-resistant prostate cancer
`Emma K. Beardsley and Kim N. Chi
`
`BC Cancer Agency, Vancouver, Canada
`
`Correspondence to Dr Kim N. Chi, BC Cancer Agency,
`600 West 10th Avenue, Vancouver, British Columbia,
`Canada V5Z 4E6
`Tel: +1 604 877 6000; fax: +1 604 877 0585;
`e-mail: kchi@bccancer.bc.ca
`
`Current Opinion in Supportive and Palliative
`Care 2008, 2:161–166
`
`Purpose of review
`There is an urgent need for systemic treatment options for patients with castration-
`resistant prostate cancer who have progressed after receiving first-line docetaxel
`chemotherapy. The purpose of this article is to review recent developments in this area.
`Recent findings
`Retreatment with docetaxel has been employed with evidence of activity in
`selected populations. Mitoxantrone, the previous first-line standard based on its
`palliative effect, has also been used with clinical responses observed; however, the
`symptom benefit in this setting has not been established. Several classes of cytotoxic
`agents have been tested including platinum agents (satraplatin), epothilones
`(ixabepilone and patupilone) and taxanes (XRP-6258). A number of targeted therapies
`have also been clinically evaluated including inhibitors of cytoprotective chaperones
`(OGX-011) and the vascular endothelial growth factor receptor (sorafenib, sunitinib,
`and cediranib). An area generating great interest has been the development of agents
`that target the androgen receptor axis more effectively (MDV3100 and abiraterone) with
`encouraging early phase trial results.
`Summary
`There is no accepted standard systemic treatment for patients with castration resistant
`prostate cancer and progressive disease after docetaxel. Novel agents are in phase II
`and III clinical testing in this setting.
`
`Keywords
`antineoplastic agents, prostate cancer, second-line therapy
`
`Curr Opin Support Palliat Care 2:161–166
`ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`1751-4258
`
`Introduction
`Castration-resistant prostate cancer (CRPC), also termed
`hormone refractory prostate cancer (HRPC), is defined as
`a rising serum prostate-specific antigen (PSA) in the face
`of castrate levels of testosterone. CRPC is an incurable
`condition projected to cause almost 30 000 deaths in
`America alone in 2008 [1]. Significant morbidity in the
`form of pain and fatigue are associated with this condition
`and the goals of treatment emphasize symptom control in
`addition to prolongation of life.
`
`The current first-line standard of care for patients with
`symptomatic or progressive disease is docetaxel-based
`chemotherapy. This follows the publication of two phase
`III randomized trials [2,3], which demonstrated a survival
`advantage of docetaxel-based chemotherapy over the
`previous standard treatment being mitoxantrone [4].
`Symptomatic and quality of life benefits were also
`observed to be associated with docetaxel.
`
`With the identification of effective first-line therapy for
`CRPC, there is now a need for further treatment options
`after docetaxel. The average duration of treatment was
`6–7 months in these studies and with a median survival
`of 18.2 months, progression-free survival
`(PFS) of
`6.3 months and median time to pain progression of
`3.5–5.6 months; there still remains significant opportu-
`nity for additional therapies. To date, for patients with
`progressive disease after first-line docetaxel, there is no
`accepted standard of treatment. This review will describe
`the most recent developments in this field and the
`novel therapeutics currently in clinical trials for patients
`with disease progression after or during docetaxel
`chemotherapy.
`
`Cytotoxic chemotherapy
`Given the paucity of current treatment options in the
`second-line setting, docetaxel is commonly reused or
`mitoxantrone chemotherapy. Clinical trials of satraplatin,
`
`1751-4258 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`MYLAN - EXHIBIT 1022
`
`
`
`162 Renal and urological problems
`
`epothilones and newer taxane agents are ongoing, and are
`highlighted here.
`
`Retreatment with docetaxel
`Retreatment with docetaxel has been a treatment strategy
`that has been evaluated. Chemo naı¨ve patients who
`achieved a PSA of less than 4 ng/ml and met the criteria
`for PSA response during first-line docetaxel treatment [5]
`were invited to enroll in a study of intermittent docetaxel
`rechallenge on progression [6]. Patients recommenced
`docetaxel when their PSA increased by 50% from post
`chemotherapy nadir and was more than 2 ng/ml or if they
`had other evidence of progression. Of the 250 patients
`who commenced first-line treatment, 56 were eligible with
`45 consenting to participate and 33 evaluable for response.
`Of the patients who resumed docetaxel treatment after a
`‘chemotherapy holiday’ of mean 18 weeks, 45.5% patients
`responded with a PSA decline of at least 50% and 45.5%
`met criteria for stable PSA for at least 12 weeks. This study
`indicates that retreatment with docetaxel could result in
`continued responses; however, this was a highly selected
`population (33 of the initial 250 patients). All had a prior
`excellent response to docetaxel, with a low PSA and short
`intervals between courses of treatment. They also had
`better prognostic indices compared with those not eligible
`for intermittent treatment.
`A retrospective review [7] of the baseline character-
`istics and outcomes of patients retreated with docetaxel
`after first-line use has recently been reported. From
`393 patients receiving first-line docetaxel, 25 (6%)
`patients were retreated with docetaxel with a median
`interval of 11.8 months between end of first-line and
`commencement of second-line treatment. PSA declines
`of at least 30 and 50% occurred in 13 (52%) and 8 (32%)
`patients,
`respectively. Median overall survival was
`9.6 months from the commencement of second-line
`docetaxel. Another retrospective review of patients
`retreated with second-line single agent docetaxel
`reported similar response rates [8] for patients who
`responded to first-line docetaxel with 11 of 26 patients
`(42%) having had a PSA decline of at least 50%.
`
`Thus, docetaxel re-treatment is a reasonable option in
`a selected subgroup of patients who have previously
`tolerated first-line therapy. Patients who appear
`to
`benefit include those who have had a previous response
`to treatment and have few adverse prognostic markers at
`the initiation of treatment.
`
`Mitoxantrone
`Being the previous standard of care prior to 2004, mitox-
`antrone has been utilized post docetaxel. Retrospective
`studies have reported modest activity with PSA response
`rates in 10–20% of patients in this setting [9,10].
`Retrospective crossover results of the practice changing
`
`TAX 327 trial [3] were reported in abstract form in 2007
`[11]. Of 45 patients with data available who received
`mitoxantrone after docetaxel, a PSA response (50%
`reduction) occurred in only 9%.
`
`The low level of activity of mitoxantrone in this setting is
`also highlighted in two randomized phase II trials with
`mitoxantrone as the control arm. Patients progressing
`within 60 days of docetaxel treatment were randomized
`to either mitoxantrone or ixabepilone [12]. The mitox-
`antrone arm induced a PSA response in 20% of patients,
`with a median treatment duration of 2.3 months, a 63%
`rate of grade 3 and 4 neutropenia and median survival of
`9.8 months. Similarly, mitoxantrone was the control arm
`in an abstract presented in 2007 [13]. Patients progressing
`during or within 90 days of docetaxel treatment were
`randomized to one of three treatment arms. Results of the
`mitoxantrone arm reported a median number of two
`cycles being delivered, with a time to progression of
`1.1 months. No PSA responses were seen and the grade
`3 and 4 febrile neutropenia rate was 31%.
`
`From these data, although mitoxantrone has been
`observed to induce PSA responses ranging from 0 to
`20% in the post docetaxel setting, time to progression
`is generally brief and toxicity is clinically significant with
`no clear data on any palliative effect. Mitoxantrone there-
`fore should only be considered in this patient population
`if active treatment is preferred in symptomatic patients
`when clinical trials are not an option.
`
`Satraplatin
`Satraplatin is an orally bioavailable platinum compound
`which in phase II studies demonstrated activity and an
`acceptable toxicity profile in patients with CRPC. A
`phase III study (SPARC) was conducted comparing
`satraplatin in combination with prednisone vs. placebo
`and prednisone [14]. The study’s coprimary end points
`were PFS and overall survival. PFS was determined
`via evidence of radiological progression, symptomatic
`progression or death and not by PSA increases. Nine
`hundred and fifty patients with CRPC progressing
`through a minimum of two courses of one prior cytotoxic
`chemotherapy (51% had received prior docetaxel) were
`randomized in a 2 : 1 ratio. The satraplatin arm resulted
`in significantly better PSA response (25.4 vs. 12.2%;
`P < 0.001), pain response (24.2 vs. 13.8%; P < 0.005)
`and time to pain progression (66.1 vs. 22.3 weeks;
`P < 0.001). Median PFS was 11 vs. 9.7 weeks, with a
`33% reduction in the overall risk of disease progression
`[hazard ratio¼ 0.67; 95% confidence interval (CI) 0.57–
`0.77; P < 0.001]. Although statistically significant, the
`clinical significance of this difference in PFS is open
`to interpretation. Additionally, overall survival was sub-
`sequently shown to not differ between the two arms
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`
`
`(61.3 vs. 61.4 weeks, hazard ratio¼ 0.97, 95% CI 0.83–
`1.13, P¼ 0.80).
`
`Epothilones
`Epothilones, which include epothilones A, B, and D,
`were originally identified as metabolites secreted by
`the myxobacterium Sorangium cellulosum. Like taxanes,
`the principal mechanism of anticancer activity is through
`microtubule stabilization resulting in mitotic arrest at the
`G2 and M phase of the cell cycle and eventual apoptosis.
`Despite a similar mode of action, preclinical studies have
`shown that the epothilones are more potent inducers of
`tubulin polymerization than paclitaxel and inhibit cell
`growth across a broad panel of taxane-sensitive and
`taxane-resistant human tumor cell lines [15]. Epothilone
`B (patupilone, EPO906; Novartis, Basel, Switzerland), its
`semisynthetic derivative ixabepilone (BMS-247550;
`Bristol-Myers-Squibb, New York, USA), and epothilone
`D (KOS-862; Kosan Biosciences, California, USA) have
`been studied in the postdocetaxel setting.
`
`Ixabepilone was investigated as second-line treatment in
`82 patients with metastatic prostate cancer unresponsive
`to paclitaxel, docetaxel or hormone therapy [12]. This
`multicenter trial randomized patients to either ixabepi-
`lone 35 mg/m2 every 3 weeks or mitoxantrone 14 mg/m2
`and prednisone 5 mg twice daily. Median survival was
`similar in both groups (10.4 months with ixabepilone and
`9.8 months with mitoxantrone and prednisone) and PSA
`responses were observed in 17% of the ixabepilone-
`treated patients and in 20% of mitoxantrone-treated
`patients. Neutropenia was the most common grade 3
`and 4 toxicity occurring in 54% of ixabepilone and
`63% of mitoxantrone patients.
`
`A phase II trial of weekly ixabepilone has been reported
`in abstract form [16]. Of the 69 patients enrolled, 37 of
`these had prior exposure to taxanes. Patients were treated
`with intravenous (i.v.) ixabepilone 20 mg/m2 weekly for
`3 of every 4 weeks. Grade 3 and 4 neutropenia was
`observed in five out of 37 (14%) of the prior taxane-
`treated patients. Neuropathy and fatigue were the other
`most common grade 3 and 4 toxicities, both occurring in
`five out of 37 patients previously treated with taxane. PSA
`and objective responses were observed in 22 and 27% of
`patients, respectively.
`
`Epothilone D has been investigated in a phase II trial
`following docetaxel treatment. Beer et al. [17] reported
`on 38 patients treated with 100 mg/m2 i.v. weekly for 3 of
`every 4 weeks. PSA response rates were low at 5.3 and
`73% of patients required dose reduction or cessation of
`treatment because of toxicity.
`
`A phase II study of patupilone administered weekly in
`37 patients has been reported in abstract form [18].
`
`Systemic therapy after first-line docetaxel Beardsley and Chi 163
`
`Twenty-nine of these patients had received a maximum
`of one prior chemotherapy regimen. PSA values were
`available in 30 patients, and eight (22%) had a partial PSA
`response. The two most common side effects were diar-
`rhea, with 19% of patients having grade 3 and 4 symptoms
`and grade 1 and 2 peripheral neuropathy in 19%.
`
`Another multicenter phase II study with patupilone was
`recently reported [19] with patupilone administered on a
`once every 3-week schedule as preclinical data indicated
`that higher less frequent dosing was more efficacious with
`potentially reduced toxicity. In this trial, patients had to
`have progressive disease during or within 6 months of
`docetaxel. At the time of reporting, data were available for
`40 patients who had received a median of four cycles of
`treatment and 38 patients were evaluable for PSA
`response. PSA declines of at least 30 and 50% were seen
`in 20 out of 38 (53%) and 18 out of 38 (47%) patients. No
`grade 3 and 4 hematological toxicities were observed and
`grade 3 and 4 adverse events at 8 mg/m2 dosing included
`fatigue (21%) and diarrhea (12%).
`
`Despite much initial enthusiasm for the epothilones, in
`this chemotherapy-pretreated population both ixabepi-
`lone and KOS-862 have resulted in significant toxicity
`and a low level of activity. Patupilone administered on a
`once every 3-week schedule has promise and mature data
`are awaited from the ongoing phase II study.
`
`Taxanes
`XRP2658 (Sanofi-Aventis, Paris, France) is a semi-
`synthetic taxoid compound with low affinity for the
`P-glycoprotein drug efflux transporter and cytotoxic in
`cell lines with acquired resistance to paclitaxel or doc-
`etaxel [20]. A phase II study of XRP6258 was conducted
`in patients with docetaxel refractory metastatic breast
`cancer and an objective response rate of 14% was
`observed. Two patients achieving a complete response
`with a median response duration of 7.6 months.
`
`A phase II trial with XRP6258 has not been performed in
`patients with CRPC; however, given its activity in the
`docetaxel refractory setting described above, this agent
`is currently being investigated in a phase III multi-
`center, randomized superiority trial comparing 3-weekly
`XRP6258 with prednisone to mitoxantrone with predni-
`sone in patients with castrate resistant metastatic prostate
`cancer previously treated with docetaxel-containing
`treatment. The aim is to recruit 720 patients with a
`projected completion date of May 2010.
`
`Targeted therapy
`A number of targeted agents have been tested in patients
`with CRPC in the postdocetaxel setting. This includes
`agents that target cytoprotective chaperone proteins,
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`
`
`164 Renal and urological problems
`
`angiogenesis through the vascular endothelial growth
`factor pathway, apoptosis associated proteins, mTOR
`and the androgen receptor axis. Several of these agents
`are entering randomized clinical testing and are high-
`lighted here.
`
`Custirsen
`Clusterin is a cytoprotective chaperone protein that pro-
`motes cell survival and confers broad-spectrum treatment
`resistance. Clusterin is overexpressed in prostate cancer
`and expression increases after therapeutic interventions
`[21]. Custirsen (OGX-011; Oncogenex Technologies
`Inc., Vancouver, Canada) is a 20-methoxyethyl-modified
`phosphorothioate antisense oligonucleotide that is com-
`plementary to clusterin mRNA and inhibits clusterin
`expression in vitro, in vivo, and in humans [22]. Recently
`published preclinical work supports the principle that
`custirsen can lead to the resensitization of previously
`docetaxel-resistant prostate cancer cells [23].
`
`A phase II trial evaluating the safety and efficacy of
`custirsen in combination with either docetaxel or mitox-
`antrone as second-line treatment for patients with CRPC
`has been recently presented [24]. Eligible patients had
`progressed during or within 6 months of docetaxel treat-
`ment. All patients received 640 mg i.v. weekly of custir-
`sen and patients randomized to docetaxel and prednisone
`or mitoxantrone and prednisone. Forty-two patients
`received at least one cycle on study. Sixteen patients
`(38%) had prior progressive disease whilst receiving first-
`line docetaxel and therefore this was a relatively refrac-
`tory population. In the docetaxel and mitoxantrone arms,
`PSA declines of at least 50% were seen in 60 and 27% of
`patients and pain response in 67 and 50%, respectively. A
`randomized study of docetaxel with or without custirsen
`is planned in this patient group.
`
`Vascular endothelial growth factor receptor targeting
`agents
`Vascular endothelial growth factor and vascular endo-
`thelial growth factor receptor (VEGF/VEGFR) activation
`has been implicated in the androgen-independent pro-
`gression of prostate cancer. Elevation of VEGF has been
`correlated with poor prognosis and disease progression [25]
`and inhibition of the VEGF and VEGFR pathways in
`experimental models induces an antitumor effect. Sora-
`fenib and sunitinib are orally administered agents that
`potently inhibit the tyrosine kinase activity of VEGFR, as
`well as a number of other kinases. Both agents are already
`approved for use in metastatic renal cell cancer.
`Dahut et al. [26] have published the results of the first
`stage of a two-stage phase II trial evaluating sorafenib
`in 22 patients, 59% of whom had received one prior
`chemotherapy treatment. The primary objective was to
`determine if sorafenib was associated with a 4-month
`
`probability of PFS (including PSA progression) in 50% of
`patients. There was little concordance amongst the pro-
`gression criteria, with 21 out of 22 patients reported as
`progressing; however, 13 out of 21 progressed on PSA
`criteria alone with no evidence of clinical or radiological
`progression. Interestingly, two patients who met criteria
`for PSA progression were found to have reduction of bone
`metastatic lesions at the time of PSA progression. Sub-
`sequent in-vitro studies have suggested a sorafenib-
`induced increase in PSA independent of its cytotoxic
`effects and thus PSA may not be reflective of disease
`progression with this class of agents. The trial was
`amended to remove PSA increase as a progression criteria
`and the second stage of this trial has accrued.
`
`A study investigating sunitinib has been recently pre-
`sented [27]. This trial used clinical and radiological
`determinants of progression, with the primary objective
`being to determine if sunitinib therapy was associated
`with a clinical PFS of 12 weeks in more than 30% of
`patients. All patients had received one or two prior
`chemotherapies including docetaxel. A 12-week PFS
`was attained in 78.9% of patients. Forty-seven percent
`of patients discontinued therapy because of toxicity and
`there were two possibly drug-related deaths. A phase III
`study has been initiated which will randomize patients
`with CRPC progressing after docetaxel to receive either
`sunitinib or placebo in a 2 : 1 fashion. The primary end-
`point is overall survival and a planned 819 patients are to
`be enrolled.
`
`Targeting the androgen receptor
`The term ‘HRPC’ has been replaced with the term
`‘castrate resistant’ as current preclinical and clinical data
`illustrate that the androgen receptor (AR) is expressed and
`continues to mediate androgen signaling even after failure
`of androgen ablation therapy [28]. The mechanisms of high
`expression and continued AR activation are multifactorial
`and result in several potential targets for inducing treat-
`ment responses via manipulation of AR activation [29].
`Two new agents in clinical trials are targeting various
`mechanisms of AR activation: MDV3100 (Medivation
`Inc., San Franciso, California, USA) and abiraterone acetate
`(Couger Biotechnology Inc., Los Angeles, California,
`USA).
`
`MDV3100 is a potent novel small AR antagonist that
`prevents nuclear translocation and DNA binding of AR,
`and posses no agonistic activity. A first-in-men, multi-
`center phase I and II dose-escalation study was recently
`reported and demonstrates encouraging clinical results.
`Treatment has been well tolerated and early results
`indicate that 13 of 14 patients followed for more than
`4 weeks have had PSA declines including patients pre-
`viously treated with docetaxel. The trial is ongoing and
`continues to accrue [30].
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`
`
`Systemic therapy after first-line docetaxel Beardsley and Chi 165
`
`6
`
`Beer TM, Ryan CW, Venner PM, et al. Intermittent chemotherapy in patients
`with metastatic androgen-independent prostate cancer:
`results from
`ASCENT, a double-blinded, randomized comparison of high-dose calcitriol
`plus docetaxel with placebo plus docetaxel. Cancer 2008; 112:326–
`330.
`The first study to prospectively study the use of intermittent docetaxel chemotherapy.
`
`7
`
`Jankovic B, Beardsley E, Chi KN. Rechallenge with docetaxel as second-line
`chemotherapy in patients with metastatic hormone refractory prostate cancer
`(HRPC) after previous docetaxel: a population based analysis [abstract
`#196]. 2008 ASCO Genitourinary Symposium; 2008.
`A retrospective analysis reviewing the activity of and patient population in which
`docetaxel is being reused in current clinical practice.
`
`8
`
`Eymard J, Oudard S, Gravis G, et al. Second-line chemotherapy with doc-
`etaxel (D) in men treated with docetaxel-based regimen for metastatic
`hormone-refractory prostate cancer (mHRPC) [abstract #249]. 2007 Pros-
`tate Symposium; 2007.
`Further retrospective review of docetaxel retreatment, highlighting the need for
`newer treatment options.
`
`9 Michels J, Montemurro T, Murray N, et al. First- and second-line chemotherapy
`with docetaxel or mitoxantrone in patients with hormone-refractory prostate
`cancer: does sequence matter? Cancer 2006; 106:1041–1046.
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`10 Oh WK, Manola J, Babcic V, et al. Response to second-line chemotherapy in
`patients with hormone refractory prostate cancer receiving two sequences of
`mitoxantrone and taxanes. Urology 2006; 67:1235–1240.
`
`11
`
`
`Berthold DR, Pond G, De Wit R, et al. Survival and PSA response of patients
`in the TAX 327 study who crossed over to receive docetaxel after mitoxan-
`trone or vice versa [abstract #225]. 2007 ASCO Prostate symposium; 2007.
`A retrospective follow-up of the practice changing TAX 327 trial, exploring the
`utility of docetaxel and mitoxantrone in second-line treatment.
`
`12
`
`
`Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line
`chemotherapy in docetaxel-refractory hormone-refractory prostate cancer
`patients: randomized phase 2 study of ixabepilone or mitoxantrone and
`prednisone. Cancer 2007; 110:556–563.
`The first study of 3-weekly ixabepilone in second-line treatment revealing similar
`activity to mitoxantrone and significant toxicity. This study highlights the limited
`activity of mitoxantrone in second-line treatment.
`
`13 Berger ER, Ciuleanu T, Hart L, et al. Results of a randomized phase II study of
`irofulven in hormone-refractory prostate cancer patients that have failed first-
`line docetaxel treatment [abstract #5068]. J Clin Oncol 2007;25(18S).
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`14
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`Sternberg CN, Petrylak D, Witjes F, et al. Satraplatin (S) demonstrates
`significant clinical benefits for the treatment of patients with HRPC: results
`of a randomized phase III trial [abstract #5019]. J ClinOncology 2007;
`25(18S).
`A large randomized trial of an oral platinum agent vs. prednisone alone. This was a
`negative study in regards to overall survival with a debatable clinically significant
`progression free survival benefit.
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`15 Altmann KH. Recent developments in the chemical biology of epothilones.
`Curr Pharm Des 2005; 11:1595–1613.
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`16 Wilding G, Chen Y, DiPaola RP, et al. E3803: Updated results on phase II study
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`of a weekly schedule of BMS-247550 for patients with castrate refractory
`prostate cancer (CRPC) [abstract #5070]. J Clin Oncol 2008; 26.
`The first weekly trial of ixabepilone, revealing reduced toxicity to the 3-weekly
`regimen, but limited efficacy.
`
`17
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`
`Beer TM, Higano CS, Saleh M, et al. Phase II study of KOS-862 in patients
`with metastatic androgen independent prostate cancer previously treated
`with docetaxel. Invest New Drugs 2007; 25:565–570.
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`to excess toxicity and limited activity.
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`18 Hussain A, Dipaola RS, Baron AD, et al. A phase IIa trial of weekly EPO906 in
`patients with hormone-refractory prostate cancer (HPRC) [abstract #4563].
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`19
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` Chi KN, Beardsley EK, Venner PM, et al. A phase II study of patupilone in
`
`patients with metastatic hormone refractory prostate cancer (HRPC) who
`have progressed after docetaxel. J Clin Oncol 2008; 265166.
`The first trial of 3-weekly patupilone revealing efficacy and tolerable toxicity,
`maturation of results is awaited before a decision regarding a phase III trial is made.
`
`20 Pivot X, Koralewski P, Hidalgo JL, et al. A multicenter phase II study of
`XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant
`metastatic breast cancer patients. Ann Oncol 2008.
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`21 July LV, Akbari M, Zellweger T, et al. Clusterin expression is significantly
`enhanced in prostate cancer cells following androgen withdrawal therapy.
`Prostate 2002; 50:179–188.
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`Beer TM, Ryan CW, Venner PM, et al. Double-blinded randomized study of
`high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in
`androgen-independent prostate cancer: a report from the ASCENT Investi-
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`22 Chi KN, Eisenhauer E, Fazli L, et al. A phase I pharmacokinetic and pharma-
`codynamic study of OGX-011, a 20-methoxyethyl antisense oligonucleotide to
`clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 2005;
`97:1287–1296.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`Abiraterone acetate is an orally available inhibitor of 17a-
`hydroxylase and C17,20-lyase, both of which are necessary
`for androgen synthesis from cholesterol precursors. Data
`from several ongoing phase II trials have been very
`persuasive with a high rate of response occurring in
`patients with progression after first-line docetaxel
`therapy. In a recent presentation of results on 28 patients
`who had previously received docetaxel, 40% of patients
`were noted to have a PSA decline of at least 50% [31].
`
`Of 18 patients with measurable disease, four (22%) had a
`partial response. Eleven patients remained on therapy for
`more than 6 months and the median time to progression
`was an impressive 167 days. Treatment was well tolera-
`ted with only grade 1–2 adverse events. A randomized,
`double-blind, placebo-controlled trial of abiraterone
`and prednisone has been initiated. Patients are being
`randomized 2 : 1 in favor of abiraterone with a planned
`1158 patients to be enrolled. The trial is powered to detect
`a difference in median overall survival of 15 months in the
`abiraterone group vs. 13 months in the placebo group
`(hazard ratio¼ 0.80).
`
`Conclusion
`There is no accepted standard systemic therapy for
`patients who progress after docetaxel therapy. In the
`absence of proven therapy, foremost consideration needs
`to be given to palliation of symptoms through adequate
`analgesia and radiotherapy. Docetaxel retreatment may
`be an option for a subset of patients who have tolerated
`and responded to first-line docetaxel therapy. Mitoxan-
`trone has become a de-facto second-line treatment but its
`benefit has not been clearly demonstrated in this setting.
`A number of chemotherapy and targeted therapy agents
`are being tested in phase II and III clinical trials and their
`results are eagerly awaited.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (pp. 223–225).
`
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`Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
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`1
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`5
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`166 Renal and urological problems
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`23
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`Sowery RD, Hadaschik BA, So AI, et al. Clusterin knockdown using the
`antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory
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`Encouraging preclinical evidence of OGX-011 activity in prostate cancer cells
`preexposed to docetaxel.
`
`24 Saad F, Hotte SJ, North SA, et al. A phase II randomized study of custirsen
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`(OGX-011) combination therapy in patients with poor-risk hormone refractory
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`Clinical validation of preclinical activity of OGX-011 in docetaxel refractory
`prostate cancer. A phase III trial is to proceed following these results.
`
`25 George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma
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`27
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`Smith M, Kantoff P, Regan M, et al. Phase II study of sunitinib malate in men
`with advanced prostate cancer [abstract #198]. 2008 Genitourinary ASCO
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`The first study of sunitinib in docetaxel pretreated prostate cancer. From this study,
`a phase III trial is recruiting.
`
`28 Linja MJ, Savinainen KJ, Saramaki OR, et al. Amplification and overexpression
`of androgen receptor gene in hormone-refractory prostate cancer. Cancer
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`29 Scher HI, Buchanan G, Gerald W, et al. Targeting the androgen receptor:
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` Scher HI, Beer TM, Higano CS, et al. Phase I/II study of MDV3100 in patients
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`26
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` Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in
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`The first report of sorafenib in post docetaxel treated prostate cancer. This report
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`it also
`questioned the use of PSA as a clinical end point in assessing targeted
`treatments.
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`31
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` De Bono JS, Attard G, Reid AH, et al. Antitumor activity of abiraterone acetate
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`Abiraterone acetate is a new agent targeting the androgen receptor. Results in
`phase II trials in docetaxel pretreated patients have been persuasive and a phase III
`trial is accruing.
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