Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`Seminar article
`New drug development in metastatic prostate cancer
`
`Andrew J. Armstrong, M.D., Sc.M.a,b,c,*, Daniel J. George, M.D.a,b,c
`a Division of Medical Oncology, Department of Medicine, Duke Comprehensive Cancer Center, DUMC, Durham, NC 27705, USA
`b Division of Urology, Department of Surgery, Duke Comprehensive Cancer Center, DUMC, Durham, NC 27705, USA
`c Duke Prostate Center, Duke Comprehensive Cancer Center, DUMC, Durham, NC 27705, USA
`
`Abstract
`
`In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially
`viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of
`mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and
`focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative
`studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify
`patient populations that may derive a greater benefit from these molecular agents. © 2008 Elsevier Inc. All rights reserved.
`
`Keywords: Drug development; Prostate cancer; Hormone refractory; Novel agents; Chemotherapy; Angiogenesis; mTOR; Immunotherapy; Vitamin D;
`HDAC inhibitors; Castration-resistant
`
`Introduction
`
`Prostate cancer in 2007 remains the second most com-
`mon cause of cancer death [1]. Docetaxel and prednisone
`(DP) were approved by the United States Food and Drug
`Administration (USFDA) in 2004 for the palliative manage-
`ment of men with castration-resistant prostate cancer
`(CRPC), based on improved survival, tumor response, pain
`and quality-of-life responses, and tolerability [2]. As such,
`the 3-weekly schedule of DP has replaced mitoxantrone and
`prednisone (MP) as the standard of care in men with met-
`astatic CRPC, and has become the backbone of current drug
`development in CRPC, either as a comparator arm or the
`foundation on which to add novel agents [3]. For example,
`Cancer and Leukemia Group B (CALGB) 90401 is cur-
`rently enrolling patients in a phase III trial of DP vs. DP
`with bevacizumab to evaluate the survival benefits of anti-
`angiogenic therapy in CRPC. The remainder of this review
`will discuss the development of these targeted agents and
`trial designs for men with CRPC, summarized in Table 1, as
`an active list of select agents that are in phases II and III
`clinical trials for this disease. Previously approved agents,
`such as docetaxel, mitoxantrone, hormonal (including novel
`
`* Corresponding author. Tel.: ⫹1-919-668-8108; fax: ⫹1-919-668-
`7117.
`E-mail address: andrew.armstrong@duke.edu (A.J. Armstrong).
`
`1078-1439/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
`doi:10.1016/j.urolonc.2007.11.006
`
`anti-androgens) agents, and bisphosphonates are addressed
`elsewhere in this seminar.
`
`Perspectives on drug development in CRCP
`
`As molecularly targeted agents enter clinical trials in
`CRPC, one dilemma is how to ascertain response or clinical
`benefit to these agents. While 3-month PSA declines are
`generally expected in the evaluation of cytotoxic agents,
`PSA response criteria have not been developed for molec-
`ularly targeted cytostatic or anti-angiogenic agents [4,5]. As
`PSA simply represents a biomarker and a potential interme-
`diary between treatment exposure and survival as an out-
`come, a surrogacy evaluation of this biomarker should be
`considered before using it as a primary endpoint in trials of
`novel agents [4,5]. Molecularly targeted agents may act
`independently of the androgen receptor that drives PSA
`production, and may even temporarily increase PSA as
`tumor volume declines due to differentiating effects, or
`provide clinical benefit without major alterations in PSA
`dynamics [6,7]. In addition, definitions of progression re-
`main problematic in CRPC, such that skeletal events, pain,
`visceral tumor measurements, and quality-of-life may all be
`potentially valid measures of clinical benefit [8,9]. A rigor-
`ous definition of progression-free survival that captures the
`
`002005
`
`AVENTIS EXHIBIT 2005
`Mylan v. Aventis, IPR2016-00712
`
`

`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`431
`
`Table 1
`Select ongoing clinical trials of molecularly targeted agents in development for treatment of CRPC
`
`Target
`
`Angiogenesis
`VEGF
`VEGF receptor
`
`PTEN/PI3 kinase mTOR
`pathway
`
`EGFR/HER2
`
`Bone interface
`
`ET-A receptor
`RANK ligand
`Immunotherapy
`
`Agent
`
`Phase
`
`Overview of trial
`
`Bevacizumab (Avastin®)
`Sorafenib (Nexavar®)
`Sunitinib (Sutent®)
`Vatalinib
`Everolimus (RAD 001)
`
`AP23573
`Lapatinib (Tykerb®)
`
`Atrasentan (Xinlay)
`
`ZD4054
`Denosumab (AMG 162)
`Provenge® (Sipuleucel-T)
`Prostate GVAX®
`
`III
`II
`II
`II
`I/II
`
`II
`II
`II
`
`III
`
`III
`III
`III
`
`Anti-CTLA4 antibody (MDX-010)
`
`I/II
`
`CALGB 90401: DP ⫾ bevacizumab, first line metastatic CRPC
`CRPC single agent (NCI)
`First-line CRPC: DP ⫹ sunitinib (Pfizer)
`DP ⫹ vatalinib, first line (Novartis)
`DP⫹ RAD001 first line metastatic CRPC (Novartis, Dana Farber/
`DOD)
`Non-metastatic CRPC (Novartis, Duke)
`Metastatic taxane-resistant CRPC (Ariad)
`Rising PSA only (ECOG) or asymptomatic CRPC (GSK, UNC, and
`Duke)
`SWOG 0421: First-line metastatic CRPC DP ⫾ Atrasentan, first line
`(Abbott)
`Phase III in CRPC (AstraZeneca)
`Denosumab vs. zoledronic acid for palliation in CRPC (Amgen)
`D9902B: Provenge vs. placebo in asymptomatic CRPC (Dendreon)
`VITAL 1: DP vs. GVAX in asymptomatic CRPC (Cell Genesys)
`VITAL 2: DP vs. D ⫹ GVAX in symptomatic CRPC (Cell Genesys)
`CRPC (DOD) first line (Medarex)
`
`Nuclear targets
`Vitamin D
`
`DN-101
`
`Histone deacetylase (HDAC)
`
`Androgen receptor
`
`SAHA (Vorinostat, Zolinza®)
`LBH 589B
`Abiraterone acetate
`
`MDV-3100
`
`III
`
`II
`II
`III
`
`I/II
`
`ASCENT II: DP ⫾ DN-101 (calcitriol) first line metastatic CRPC
`(Novacea, DOD)
`Second line CRPC (Michigan, DOD)
`First line CRPC (Novartis)
`Second line with prednisone vs. prednisone alone after docetaxel
`failure (Cougar Biotechnology)
`CRPC (Medivation)
`
`DOD ⫽ Department of Defense Prostate Cancer Consortium; CRPC ⫽ castration-resistant prostate cancer; DP ⫽ docetaxel and prednisone.
`
`full effects of overall survival would be a significant ad-
`vance in clinical trial development for men with CRPC. It is
`possible that a composite of tumor measures and pain mea-
`sures may provide both a quantitative and qualitative mea-
`sures of clinical benefit in symptomatic patients [8,10].
`In 2007, overall survival remains the necessary primary
`endpoint in phase III clinical trials in men with CRPC, given
`the uncertain validity of other surrogate measures for clin-
`ical benefit [4,5,8]. However, phase II studies do require
`shorter term endpoints to assess clinical activity without the
`cost of a trial powered to detect an overall survival advan-
`tage. As tumor response by RECIST (Response Evaluation
`Criteria in Solid Tumors) criteria may not capture the full
`clinical benefits of cytostatic, anti-angiogenic, cancer stem
`cell, and immunomodulatory agents, trial designs that cap-
`ture clinical benefit using other endpoints are likely to be
`necessary [11]. These endpoints may include progression-
`free survival, time to new metastasis, or composites of pain,
`tumor, and/or PSA progression. One such design is the
`randomized discontinuation trial (RDT). In the RDT, all
`patients are initially treated with the active agent, and ran-
`domization only occurs in those patients with stable disease
`after a period of observation [12]. Responding patients
`continue the agent, while primary progressing patients are
`removed quickly from the study. In this trial design, ran-
`domized patients are followed to a prespecified progression
`endpoint. One caveat to this design is the large number of
`
`patients who must be initially enrolled, especially if the
`stable or responding proportion is low, and the concerns
`over small numbers of patients whho actually make it to
`randomization [13]. This design, however, was relatively
`successful in the evaluation of sorafenib in renal cell carci-
`noma, and may encourage others to evaluate this design in
`prostate cancer.
`Finally, trial designs that enrich for a molecular target or
`predictive biomarker may also lead to the more efficient
`identification of active molecular agents [14]. As in the case
`of the target Her2 and the agent trastuzumab in metastatic
`breast cancer, using a targeted agent in an unselected pop-
`ulation may dilute the effects of that agent, and an otherwise
`active drug for a select population of cancer patients may go
`unnoticed. As genomic signatures and molecular targets are
`identified in prostate cancer, designs that take advantage of
`these markers will advance the field [15].
`The collection of tumor or surrogate tissue for biomarker
`analysis, validation of molecular targets, prospective iden-
`tification of drug mechanisms, and biologic basis for disease
`progression is highly encouraged and feasible in men with
`CRPC. While obtaining adequate tissue from bone biopsies
`can be challenging due to logistics, crush artifact, sample
`yield, and quality control, it is essential for moving the field
`forward by understanding resistance to our current therapies
`and identifying subgroups of patients who may benefit from
`these agents.
`
`

`
`432
`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`Fig. 1. Schema for CALGB 90401. Correlative science to evaluate and validate Halabi nomogram risk groups, PSA kinetics, plasma angiokine and cytokine
`levels, and PSA RT-PCR.
`
`Molecular targets
`
`Angiogenesis
`
`As with many solid tumors, angiogenesis has an impor-
`tant position in prostate cancer progression. Microvessel
`density in clinically localized prostate cancer is an indepen-
`dent prognostic for progression and survival [16,17]. More-
`over, through the CALGB, we demonstrated that the plasma
`level of vascular endothelial growth factor (VEGF), a potent
`angiogenic growth factor, is an independent prognostic fac-
`tor in men with metastatic CRPC [18]. Anti-angiogenic
`agents utilizing monoclonal antibodies to VEGF, such as
`bevacizumab (Avastin®; Genentech, San Francisco, CA)
`have been studied in prostate cancer. While single agent
`studies have failed to demonstrate significant results, a
`phase II trial conducted by the CALGB added bevacizumab
`to docetaxel and estramustine in men with CRPC with 79%
`of patients having a greater than 50% PSA, median time-
`to-progression of 9.7 months, and overall median survival
`of 21 months [19]. Based upon these promising results, a
`randomized, double-blind placebo-controlled phase III trial
`has been designed comparing docetaxel 75 mg/m2 every 3
`weeks with prednisone 10 mg orally daily with either bev-
`acizumab 15 mg/kg IV or placebo every 3 weeks (CALGB
`90401), shown in Fig. 1. The primary endpoint for this trial
`is overall survival, and accrual of 1,020 patients is now
`complete.
`Thalidomide and its analogs may inhibit angiogenesis
`and prostate tumor growth through multiple potential
`mechanisms, including inhibition of pro-angiogenic sig-
`nals such as VEGF as well as immunomodulatory effects
`by affecting T-cell co-stimulatory activity [20]. A recent
`randomized Phase II study of thalidomide in combination
`with docetaxel
`in hormone-refractory disease demon-
`strated an impressive 53% PSA decline (⬎50% decrease
`in PSA), and improved TTP and OS [21]. The study was
`underpowered and toxicities of this combination therapy
`
`included high rate of thrombosis, sedation, and neurop-
`athy. Interest in the continued development of more po-
`tent thalidomide analogs, such as lenalidomide (Revlimid®;
`Celgene, Summit, NJ), has led to its development in a
`Phase II trial through the Department of Defense Prostate
`Cancer Consortium in men with a rising PSA after local
`therapy.
`Evaluation of tyrosine kinase inhibitors (TKI), which
`inhibit angiogenic growth factor receptors signaling in ad-
`vanced prostate cancer, has recently begun. In addition to
`VEGF, another potential angiogenic growth factor target
`inhibited by several TKI is platelet derived growth factor
`(PDGFR). Prostate cancer cells have been shown to express
`high levels of platelet-derived growth factor
`receptor
`(PDGFR), which in turn enhances the PI3 kinase/Akt path-
`way leading to prostate cancer progression [22]. Sorafenib
`(Nexavar®; Bayer Pharmaceuticals, West Chester, PA) is
`an oral agent that inhibits RAF kinase, VEGF receptor
`tyrosine kinase, and the PDGF receptor, and is currently
`approved for metastatic renal cell carcinoma based on
`improved progression-free survival [23,24]. A Phase II
`study of 22 patients evaluated the activity of sorafenib in
`CRPC [25]. Of the 19 patients who progressed, 10 pro-
`gressed with PSA rise only and 2 patients with PSA pro-
`gression where found to have dramatic resolution of bony
`disease. Vatalinib (PTK787/ZK 222584; Novartis Pharmaceu-
`ticals, East Hanover, PA) is another multi-targeted TKI inhib-
`iting VEGFR 1–3 and PDGFR at nanomolar concentrations
`[26]. We performed a small Phase I study to evaluate prelim-
`inary efficacy in metastatic CRPC patients. Overall, 1 out 19
`patients demonstrated ⬎50% reduction from baseline in serum
`PSA level and duration of response of 12 months; 2 other
`patients demonstrated ⬎40% reductions in PSA with duration
`of 4 and 5 months, respectively [27]. These results have
`raised the question of the validity of PSA response and
`progression measures for the evaluation of this class of
`agents, and further study using clinical endpoints seems
`warranted.
`
`

`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`433
`
`Provenge IV
`weeks 0, 2, and 4
`
`Primary outcome: overall survival
`
`Leukopheresis control
`
`RANDOMIZE
`
`• Asymptomatic
`metastatic
`CRPC
`(cid:127) No prior
`chemotherapy
`
`
`
`(N=500)(
`
`A.
`
`B.
`
`PAP
`
`TCR
`
`Leukopheresis
`CD4 T Cell
`
`GM-CSF
`
`Class II MHC
`
`TCR
`
`Class I MHC
`
`IV
`infusion
`CD8 T Cell
`
`Dendritic Cells
`pulsed with
`PAP-GMCSF
`proprietary
`peptide
`cassette
`
`Fig. 2. Schema (A) and diagram (B) of the IMPACT study investigating autologous dendritic cell vaccination in men with CRPC. (Color version of figure
`is available online.)
`
`Cell survival and growth pathways
`
`The growth and survival addiction to mutated oncogenic
`signaling pathways may be both the source of cancer pro-
`gression and a potential weakness for therapeutic exploita-
`tion [28]. Strategies that target these molecular lesions in
`prostate cancer are rational and dynamic as the mechanisms
`of prostate cancer progression and resistance to current
`therapies are dissected. One such molecular lesion is the
`tumor suppressor phosphatase and tensin homolog deleted
`on the chromosome 10 (PTEN), whose expression is lost in
`the majority of advanced prostate cancer cases [29,30]. Loss
`of PTEN leads to unrestrained phosphatidylinositide 3-ki-
`nase (PI3K)/Akt activity and cellular survival signaling.
`One downstream target of this pathway is mTOR kinase
`mammalian target of rapamycin (mTOR), which regulates
`cell size, translation of key growth, survival, and angiogenic
`signals [31,32]. Multiple mTOR inhibitors exist, including
`temsirolimus (CCI-779; Wyeth, Collegeville, PA), everoli-
`mus (Novartis, Cambridge, MA), AP23573 (Ariad, Cam-
`bridge, MA), and rapamycin itself. Phase I and preprostate-
`ctomy studies of these agents have demonstrated early signs
`of successful target inhibition in prostate cancer and are
`ongoing [33,34]. RAD001 is also being evaluated in com-
`bination with docetaxel and prednisone in men with CRPC,
`given the potential for mTOR inhibitors as chemosensitiz-
`ing agents [35].
`Another potential target involved in cellular growth in-
`cludes the HER2/neu (ErbB-2) tyrosine kinase. HER 2
`
`expression has been shown to increase androgen receptor
`activation leading to growth of prostate cells [36]. Phase II
`studies of the EGFR TKI gefitinib (Iressa®; AstraZeneca,
`Waltham, MA) and the anti-Her2 monoclonal antibody trastu-
`zumab (Herceptin®; Genentech, San Franciso, CA) showed
`low levels of efficacy in CRPC, possibly due to the low
`prevalence of HER2 over-expression [37,38]. Phase II studies
`are ongoing in men with PSA relapse and CRPC using the
`dual EGFR/HER-2 kinase inhibitor, Lapatinib (Tykerb®;
`GlaxoSmithKline, Philadelphia, PA) [39]. Understanding
`resistance to EGFR/HER2 directed therapies may lead to
`the identification of additional targets [40].
`
`Immunotherapy
`
`Entraining the immune system to overcome tumor-in-
`duced tolerance is the goal of nearly every cancer vaccine
`program. In prostate cancer, strategies to target the immune
`system have included autologous (self) and allogeneic (non-
`self) vaccines, protein-based and whole cell vaccines, and
`blockade of immunosuppressive signals [41]. Induction of
`the immune system against normal and cancerous prostate
`tissue has been demonstrated by vaccination with prostate
`specific proteins/peptides including PSA (prostate-specific
`antigen), prostatic acid phosphatase (PAP), and prostate
`specific membrane antigen (PSMA) [42]. Two types of
`immunotherapies that are in phase III trials include autolo-
`gous dendritic cell-based immunotherapy and allogenic
`whole cell-based immunotherapy (Figs. 2 and 3). Most of
`
`

`
`434
`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`Prostate GVAX
`intradermal
`q14d* x 12,
`then every 28 days
`
`Docetaxel 75 mg/m2 q21d
`+
`prednisone 10 mg/d
`
`RANDOMIZE
`
`(cid:127) Asymptomatic
`metastatic
`CRPC
`(cid:127) No prior
`chemotherapy
`
`(N=600)
`
`Prostate
`antigen A
`
`TCR
`
`CD4 T Cell
`
`Irradiated PC-3
`and LnCAP cells,
`virally transduced
`with GM-CSF
`
`Class II MHC
`
`TCR
`
`Prostate
`antigen B
`
`Class I
`MHC
`
`Intradermal
`injection
`
`CD8 T Cell
`
`A.
`
`B.
`
`Fig. 3. Schema (A) and diagram (B) of the VITAL-1 study investigating off-the shelf whole cell allogeneic prostate cancer vaccination in men with CRPC.
`(Color version of figure is available online.)
`
`the current vaccine-based therapeutic approaches use gran-
`ulocyte-macrophage colony stimulating factor (GM-CSF), a
`cytokine that improves antigen presentation and activation
`of T-cells.
`Provenge (Sipuleucel-T; Dendreon, Seattle, WA) is an
`example of dendritic cell-based therapy. Leukopheresed
`dendritic cells are collected from patients and then are
`pulsed with a proprietary fusion product of GM-CSF and
`PAP. A phase II-III placebo-controlled trial studied 127
`patients with asymptomatic CRPC and found a trend to
`increased time to progression (1.7 week difference, P ⫽
`0.052). A statistically significant improvement in overall
`survival in the vaccine treated group was noted as a sec-
`ondary endpoint (25.9 vs. 21.4 months, P ⫽ 0.01) [43].
`Vaccine was well tolerated, with the most common side
`effects including infusion reactions such as rigors and pyr-
`exia. Although the trial was not powered to show survival
`benefit, the initial results show promise, and a confirmatory
`phase III trial (IMPACT, D9902B) is ongoing in men with
`minimally symptomatic CRPC (Fig. 2).
`Prostate GVAX® (Cell Genesys, San Francisco, CA) is
`immunotherapy using inactivated allogenic prostate carci-
`noma cell lines (PC-3 and LnCaP), which are modified
`genetically through adenoviral transfer to secrete GM-CSF
`[44]. The advantage is that the vaccine can be manufactured
`in large quantities and multiple tumor antigens can be tar-
`geted. A disadvantage is the relative weakness of individual
`antigens in this approach, requiring repeat dosing. Two
`phase II trials have demonstrated activity with one trial
`
`showing an overall survival of 26 months and another trial
`showed improvement of osteoclast activity in a majority of
`patients and expected overall survival data to be greater than
`24.4 months [45]. As these were uncontrolled trials in an
`asymptomatic population with an expected survival to be
`relatively high, it remains unclear as to the true benefit of
`this approach. The vaccines were well tolerated, with com-
`mon side effects including injection site reactions, fatigue,
`malaise, myalgias, and arthralgias, without any dose-limit-
`ing toxicities. Two phase III trials that are currently ongoing
`will further test the response to vaccines vs. standard che-
`motherapy. VITAL-1 has accrued 600 men with asymptom-
`atic in hormone-refractory prostate cancer with no prior
`chemotherapy, and randomized these men to GVAX vs.
`docetaxel/prednisone, with the primary end point being
`overall survival (Fig. 3). VITAL–2 plans to accrue 600 men
`with symptomatic CRPC and randomize to docetaxel with
`or without GVAX.
`
`Nuclear receptors targets
`
`Multiple epidemiological studies have shown an increased
`risk of prostate cancer with relative vitamin D deficiency [46].
`Vitamin D receptors are expressed in prostate cancer cells;
`prostate cancer cells are deficient in converting 25-hydroxyvi-
`tamin D to 1,25-hydroxyvitamin D, an active differentiating
`agent in prostate cancer [47]. In vitro studies have shown
`that calcitriol (1,25-dihydroxycholecalciferol) may be able
`to inhibit growth and promote differentiation of prostate
`
`

`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`435
`
`Fig. 4. Schema for ASCENT II. Primary endpoint is overall survival, while secondary endpoints are risk of blood clots and fractures.
`
`cancer cells [48]. This finding led to the development of
`calcitriol and related products for men with CRPC. DN-101
`is a proprietary oral formulation of 1,25-dihydroxychole-
`calciferol that is able to provide supraphysiological doses
`of vitamin D without side effects such as hypercalcemia.
`Docetaxel, prednisone, and DN 101 were recently eval-
`uated in a randomized placebo-controlled phase II multi-
`institutional study (ASCENT) of 250 men with progres-
`sive CRPC [49]. The primary endpoint was PSA response
`rate. There was a trend towards improved PSA response rate
`in the combined group but it was not statistically significant.
`The study was underpowered to detect survival differences;
`yet, the estimated median survival was significantly pro-
`longed, from 16.4 to 23.5 months in the unadjusted analysis
`(HR 0.70, P ⫽ 0.07), with a favorable toxicity profile. An
`ongoing phase III trial (ASCENT 2) will compare patients
`on docetaxel/prednisone with and without DN-101 with
`power to detect a survival benefit as the primary endpoint
`(Fig. 4). Other endpoints will include skeletal-related events
`and reduction of blood clots. Early reports from this trial
`suggest, however, that the primary endpoint was not met,
`calling into question the validity of this target in CRPC [50].
`An additional class of nuclear agents with broad effects
`includes the histone deacetylase (HDAC) inhibitors. His-
`tones maintain DNA in a closed and genetically silent con-
`figuration, and this activity is mediated by a complex and
`reversible epigenetic process through acetylation and meth-
`ylation. Phase II studies are ongoing of HDAC inhibitors in
`men with CRPC, including Zolinza (Vorinostat or SAHA;
`Merck, Whitehouse Station, NJ) and LBH 589B (Novartis,
`Cambridge, MA) [51]. The development of these agents in
`prostate cancer will require careful attention to pharmaco-
`dynamic endpoints and the potential for differentiating ef-
`fects such as transient PSA rises [52].
`
`Novel chemotherapeutics
`
`Palliative care options for patients with CRPC who have
`failed frontline docetaxel-based chemotherapy include clin-
`
`ical trials, best supportive care, radiation to symptomatic
`bony metastases, radiopharmaceuticals, bisphosphonates,
`corticosteroids, alternative hormonal agents, and a plethora
`of cytotoxic agents with some activity [53,54]. Median
`survival following progression is about 12 months, and is
`dependent on the type of progression [8,55]. Second-line
`chemotherapy has not been rigorously studied, but in gen-
`eral has a short median progression-free survival of just a
`few months. Agents that satisfy the endpoints of improved
`duration of survival, improved palliation, or both are greatly
`needed. These agents, including satraplatin and novel cyto-
`toxics, are discussed elsewhere in this seminar [56,57].
`
`Androgen receptor
`
`The androgen receptor remains the most validated target
`to date in metastatic prostate cancer, with a number of
`groups identifying over-expression and persistent activation
`as a hallmark of prostate cancer progression [15,58,59].
`While a discussion of hormonal therapy and anti-androgen
`development is beyond the scope of this current seminar,
`currently available secondary and tertiary hormonal manip-
`ulations are typically of only short-lived clinical benefit
`with modest, if any, survival advantages over GnRH agonist
`therapy alone [60]. Based on the findings of persistent
`androgen signaling and adrenal androgen synthesis in
`CRPC, several novel anti-androgen and androgen synthesis
`inhibitors are in phase I-III trials in CRPC with some prom-
`ising early results. One such agent, abiraterone acetate, is an
`oral cytochrome P17 (17,20-lyase and 17␣-hydroxylase)
`inhibitor, and has passed through phase I and II trials alone
`or in combination with glucocorticoids [61– 63]. This agent
`has demonstrated a high proportion of prolonged PSA de-
`clines (⬎50%) and partial responses in metastatic CRPC
`and even in patients who had failed docetaxel chemother-
`apy. A phase III study of abiraterone acetate and prednisone
`vs. prednisone alone is just underway to evaluate the overall
`survival impact of adrenal androgen lowering in this che-
`morefractory population.
`
`

`
`436
`
`A.J. Armstrong and D.J. George / Urologic Oncology: Seminars and Original Investigations 26 (2008) 430 – 437
`
`Conclusions
`
`In 2007, men with CRPC have more clinical trial options
`than ever before, including several large phase III studies of
`anti-angiogenic therapy, immunomodulatory therapy, and
`differentiating therapy. Advances in our understanding of
`prostate cancer progression, including both genomic and
`cancer stem cell biology, will certainly expand our arsenal
`of molecularly targeted agents and trial designs in the near
`future. Maintaining focus on the small but incremental steps
`of translational medicine combined with an emphasis on
`important clinical endpoints will continue to advance this
`field in cancer prevention and in transforming advanced
`prostate cancer into a chronic symptom-free disease.
`
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