European Journal of Cancer (2014) xxx, xxx– xxx

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Review

Molecular alterations and emerging targets in castration resistant prostate cancer D. Lorente, J.S. De Bono ⇑ Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, SM2 5PT Sutton, Surrey, UK

KEYWORDS Castration resistant prostate cancer Molecular biology Androgen receptor Novel therapeutics

Abstract Prostate cancer is the most common malignancy in Western Europe, of which approximately 10–20% presents with advanced or metastatic disease. Initial response with androgen deprivation therapy is almost universal, but progression to castration resistant prostate cancer (CRPC), an incurable disease, occurs in approximately 2–3 years. In recent years, the novel taxane cabazitaxel, the hormonal agents abiraterone and enzalutamide, the immunotherapeutic agent sipuleucel-T and the radiopharmaceutical radium-223 have been shown to prolong survival in large randomised trials, thus widely increasing the therapeutic armamentarium against the disease. Despite these advances, the median survival in the first-line setting of metastatic castration-resistant prostate cancer (mCRPC) is still up to 25 months and in the post-docetaxel setting is about 15–18 months. There is an urgent need for the development of biomarkers of treatment response, and for a deeper understanding of tumour heterogeneity and the molecular biology underlying the disease. In this review, we attempt to provide insight into the novel molecular targets showing promise in clinical trials. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.

1. Introduction Prostate cancer is the most common malignancy in men in Western Europe with 93.1 new cases per 100.000 inhabitants in 2008 [1], of which approximately 10–20% present with advanced-metastatic disease. ⇑ Corresponding author: Address: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Section of Medicine, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK. E-mail address: [email protected] (J.S. De Bono).

Initial response with androgen deprivation therapy is almost universal, but progression to castration resistant prostate cancer (CRPC), an incurable disease, occurs in approximately 2–3 years [2]. Until 2010, docetaxel was the only agent with proven survival benefit in CRPC [3]. Since then, the chemotherapeutic agent cabazitaxel [4], the hormonal agents abiraterone [5] and enzalutamide [6], the immunotherapeutic agents sipuleucel-T [7] and the radiopharmaceutical radium-223 [8] have been shown to prolong survival, widely increasing the therapeutic armamentarium (see Fig 1, Tables 1-2).

0959-8049/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.12.004

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Despite these advances, the median survival of metastatic castration-resistant prostate cancer (mCRPC) is still up to 25 months in the first-line setting [7,9] and about 15–18 months the post-docetaxel setting [5,6]. There is an urgent need for the development of biomarkers of treatment response and for a deeper understanding of tumour heterogeneity and the molecular biology underlying the disease. In this review, we attempt to provide insight into novel molecular targets showing promise in clinical trials. Other relevant topics in drug development for prostate cancer such as epigenetics and immunotherapy, reviewed in detail elsewhere [10–12], were considered outside the scope of this review.

2. Methods A review of the literature searching Pubmed and major cancer conferences was performed in May 2013. The search strategy included the terms metastatic prostate cancer, castration resistant prostate cancer, molecular biology, androgen receptor, phosphoinositide 3-kinase (PI3K), poly (ADP-ribose) polymerase (PARP), MET, angiogenesis and SRC.

3. Common genomic aberrations in prostate cancer Molecular studies have identified potentially relevant genomic alterations in human prostate cancer, some of which are associated to key regulatory genes [13] (see Table 3). These include loss of chromosome 8p (NKX3.1), the most frequent alteration in the prostate onco-genome; deletion of phosphatase and tensin homologue (PTEN) on 10q23.31; Retinoblastoma tumour (RB1) on 13q14.2; TP53 on 17p31.1; and the interstitial 21q22.2-3 deletion spanning ERG and TMPRSS2 [14]. Although the overall mutation rate in CRPC is low, mutations in SPOP, MED12, p53, in the histone-modifying MLL2 and the pioneer factor FOXA1 genes can play a role as can androgen receptor (AR) mutations in castration resistant disease [15,16]. The NKX3.1 gene, located in chromosome 8p21, a region with a high rate of LOH, encodes a tumour-suppressor protein that is postulated to decrease cell survival by enhancing ATM activity after DNA damage [17]. Loss of 8p21 is an early event in prostate carcinogenesis [18]. The Myc oncogene is located in 8q24, a broad amplicon that contains multiple genes associated with prostate cancer [13]. The role of c-Myc as a ligand-independent AR target gene has been proposed although this remains controversial [19]; studies report no effect of the androgen ligand R1881 or the antiandrogen MDV3100 on c-Myc expression in cell lines [20]. Recently, the BET bromodomain inhibitor JQ1 [21] was reported to suppress c-Myc overexpression and cell

proliferation. P53 (17p31) has an essential role in the transcription of genes involved in apoptosis, cell cycle arrest and DNA repair. P53 alterations have been associated with recurrence after radiation and androgen suppression [22] as well as reduced docetaxel-induced apoptosis [23]. Retinoblastoma tumour (RB1) suppressor gene pathway aberrations have been identified in 34% of primary and 74% of metastatic prostate cancers [14]. Loss of RB1 function may be linked to castration resistance through activation of AR signalling by unsuppressed E2F transcription factors [24]. A differential therapeutic approach has been proposed, where CDK inhibitors could enhance AR suppression in RB positive while RB negative tumours could be particularly susceptible to radiotherapy or DNA damaging agents [25]. Deletions in the CHD1 gene (5q21) have been identified in 10–17% of prostate tumour samples, possibly second only to PTEN loss as the most frequently homozygously deleted gene in the prostate cancer genome, increasing invasiveness in prostate cancer cell lines [26,27]. CHD1 deleted tumours appear to have a high frequency of intrachromosomal rearrangements and may have a worse prognosis. 3.1. ETS fusion positive prostate cancers The ERG oncogene is one of the most frequently expressed genes in prostate cancer [28], and its fusion to the TMPRSS2 gene is a common and probably early event in prostate carcinogenesis [29]. Members of the ETS family of transcription factors (ERB, ETV1, ETV4) are placed under the control of the TMPRSS2 promoter which is activated by AR signalling [30]. ERG can disrupt AR signalling through epigenetic silencing of target genes, and ETS activation may promote epithelial-mesenchymal transition (EMT) and tumour-invasive properties [31]. The presence of ERG rearrangements has been associated with higher response-rates to abiraterone [29]. 3.2. ETS fusion negative prostate cancer Recent studies have identified aberrations that are mutually exclusive with ETS fusions. SPOP mutations characterise a distinct subtype of ETS negative prostate cancer that has been associated with recurrent somatic deletions at 5q21(CHD1) and 6q21(FOXA1) [16]. Up to 96% of tumours with CHD1 deletion are ETS rearrangement negative, possibly identifying ETS-/CHDtumours as a distinct molecular subtype [15]. Overexpression of SPINK-1, a trypsin inhibitor associated with bad prognosis in multiple malignancies [32] is mutually exclusive with ERG/ETV1 overexpression and defines an aggressive molecular subtype [33]. Knockdown of SPINK-1 is able to inhibit cell proliferation and invasion in xenograft models [34].

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3.3. Prostate cancer with neuroendocrine differentiation (NEPC) Overexpression of N-Myc (2p24) and Aurorakinase A (AURKA, 20q13) has been associated with the development of NEPC, characterised by low prostate-specific antigen (PSA) levels, poor response to hormonal agents and aggressive behaviour. Overexpression and gene amplification of AURKA and NMyc is present in 40% of NEPC and 5% of (PCA) tumours with TMPRSS2-ERG rearrangements present in 50% of NEPC samples. Treatment of neuroendocrine prostate cancer xenografts with PHA-739358, an AURKA inhibitor caused significant tumour shrinkage [35]. Single agent PHA-739358 (danusertib), an AURKA inhibitor, failed pre-specified criteria for efficacy in a phase II clinical trial in the post-docetaxel setting with no histological selection [36]. Other AURK inhibitors in evaluation are MLN8237, an AURKA inhibitor currently being evaluated in histologically confirmed NEPC (NCT01799278) and AMG900, a pan-AURK inhibitor that is currently undergoing phase I testing in solid tumours (NCT00858377).

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4. The androgen receptor (AR) The AR gene (Xq11-12) encodes a cytoplasmic steroid receptor that consists of an amino-terminal domain, DNA binding domain and a carboxy-terminal ligand-binding domain (LBD). Binding to its ligand, dihydrotestosterone (DHT) causes AR internalisation to the nucleus, where it interacts with target genes via androgen-responsive elements (AREs). These interactions are modified by coactivating (SRC1-NCOA1, SRC2-NCOA2) and co-repressing (NCoR, SMRT) proteins [37]. Several mechanisms are responsible for progression to castration resistance. AR genomic amplification occurs in up to approximately 60% of CRPC metastasis [14]. Modifications in cofactor expression levels, activation by androgens converted from adrenal precursors and constitutive activation by AR splice variants are amongst other proposed mechanisms. 4.1. AR cofactors FoxA1 is a transcription factor with an essential role in the expression of AR-dependent proliferative genes [38], acting as a pioneer factor for AR transcriptional

Table 1 Reported phase III trials. Agent

Line of therapy

Experimental arm

Control arm

Median survival

Cabazitaxel [4]

Cabazitaxel

Mitoxantrone

Satraplatin [121]

Post-computed tomography (CT) Post-CT

Satraplatin

Placebo

Abiraterone [5] Abiraterone [45]

Post-CT Pre-CT

Abiraterone + prednisone Abiraterone + prednisone

Placebo + prednisone Placebo + prednisone

Enzalutamide [6] Bevacizumab [106] Sunitinib [122]

Post-CT Pre-CT Post-CT

Enzalutamide DP + beva Sunitinib + prednisone

Placebo DP + placebo Placebo + prednisone

Aflibercept [107] Atrasentan [114]

Post-CT Pre-CT

DP + aflibercept Atrasentan

Placebo + aflibercept Placebo

Atrasentan [123] Zibotentan [115]

Pre-CT Post-CT

DP + atrasentan Zibotentan

DP + placebo Placebo

Lenalidomide [108] Calcitriol [124] Dasatinib [120] Radium-223 [125]

Pre-CT Pre-CT Pre-CT Post-CT

DP + lenalidomide D (weekly) + calcitriol DP + dasatinib Radium-223

DP + placebo DP DP Placebo

Sipuleucel-T [7]

Pre-CT

Sipuleucel-T

Placebo

Ipilimumab*

Post-CT

Orteronel**

Post-CT

Single dose RT + ipilimumab Oteronel

Single dose RT + placebo Placebo

15.1 versus 12.7 m; p30% PSA decline rate of 55% and a 60% Common Toxicity Criteria (CTC) conversion rate in its initial 22 patients [73]. Secretory clusterin (sCLU) is a stress-activated, ATPindependent cytoprotective chaperone associated with the development of treatment resistance [74] by inhibition of mitochondrial apoptosis and suppression of p53-activating stress signals [75]. The CLU gene (8p21) is up-regulated following androgen suppression, chemotherapy and radiotherapy-induced stress [76,77]. Custirsen (OGX-11), an antisense oligonucleotide (ASO) against sCLU, produced a >90% knockdown of sCLU and increased apoptotic rates in a phase I study [78]. A subsequent randomised phase II study in combination with docetaxel showed significantly improved OS and sCLU reduction despite no difference in PSA declines (primary endpoint) or PFS [79]. Custirsen is currently being evaluated in two large, phase III trials in combination with docetaxel (NCT01188187) and cabazitaxel (NCT01578655) in metastatic CRPC.

5.4. PARP inhibition 5.3. Molecular chaperones Heat shock proteins (HSPs) are molecular chaperones involved in the post-translational stability of client proteins. The heat shock response is a stress-protective mechanism for oncoproteins such as ERBB2, C-RAF, CDK4, AKT/PKB, AR, mutant p53, hypoxia-inducible factor (HIF)-1a and survivin [64] from deranged folding and degradation [65]. A dynamic association between accessory co-chaperones (HSP70, HSP40, HOP, AHA, P23) and client proteins is established; upon binding to ATP, the complex adopts a closed conformation that enables stabilisation of client proteins [66]. HSP-90 inhibition can disrupt the nuclear localisation of AR, a known client protein [67]. The first generation HSP90 inhibitor geldanamycin (17-AAG) was shown to inhibit HSP90 in prostate cancer cells [68] albeit with concerns of liver toxicity [69]. PF-04928473, a novel oral HSP90 inhibitor induces in vitro apoptosis and degradation of Her2, AR, Akt and ERK and inhibits osteoclastogenesis. Delays in tumour growth without PSA declines suggested that PSA would not be a valid biomarker to evaluate its efficacy [70]. Early phase studies of the HSP90 inhibitor AT13387 in combination with abiraterone in patients progressing on abiraterone are currently underway (NCT01685268). HSP27 is an HSP90 co-chaperone that increases invasiveness and metastatic potential of prostate cancer cell

Poly (ADP-ribose) polymerase 1 (PARP-1) is an enzyme involved in response to DNA damage through base excision repair. Inhibition of PARP causes an increase in DNA single-strand breaks with a subsequent accumulation of double strand breaks at replication forks, repaired by the BRCA1 and BRCA2 proteins in normal cells [80]. In patients with inactivating BRCA mutations, inhibition of PARP mediated DNA repair leads to cell death, a term known as ’synthetic lethality‘. The PARP inhibitor Olaparib has shown significant clinical activity and an acceptable toxicity profile in BRCA mutation carriers [81]. In prostate cancer xenografts, growth inhibition by PARPi has been observed in fusion positive cancers only [82], indicating that non-homologous end-joining DNA repair could be important in the generation of ETS rearrangements. AR signalling can promote site-specific DNA doublestranded breaks at AREs, leading to rearrangements [83]. Recent studies with the PARP inhibitor ABT888 in prostate cancer cell lines reported that increased PARP1 enzymatic activity in advanced prostate cancer models supported AR transcriptional function and maintained a castrate-resistant phenotype. Targeting PARP 1 potently suppressed tumour cell proliferation [84]. A potential role of PARP inhibitors in combination with radiotherapy has been proposed. Combination of ABT888 with radiotherapy was able to delay growth and induce senescence in the PC-3 cell line [85]. Other

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preclinical studies have suggested that the combination of RT and PARP inhibition is most sensitive in ERG fusion and PTEN negative cell lines [86]. The PARP inhibitors Olaparib, as single-agent in metastatic CRPC (NCT01682772, TOPARP trial) and Veliparib, in combination with abiraterone (NCT01576172) are currently under evaluation in clinical trials for the treatment of CRPC. 5.5. The PI3k-Akt-mammalian target of rapamycin (mTOR) pathway Alteration of the PTEN/PI3K/Akt pathway is a late event in prostate carcinogenesis, with around 70% of late-stage samples showing PTEN loss or PI3K activation. Deregulation of this pathway can occur through gain of function mutations of PI3KCA, PTEN loss of function, amplification or mutation of AKT/PKB or tyrosine kinase upstream activation [87]. PTEN loss has been associated with TMPRSS2/ERG rearrangement in the development of invasive prostate carcinoma [88]. PI3K signalling serves a compensatory role allowing continued prostate cancer cell proliferation in low-androgen environments [89] by posttranslational modification, increased coactivator activity or reduced corepressor activity. Cells lacking PTEN display an increased PI3K-Akt activity on androgen withdrawal [90]. Single agent inhibition of the pathway has so far yielded disappointing results. The mTOR inhibitor ridaforolimus failed to show any objective responses as a single agent in a phase II trial of 38 post docetaxel CRPC patients [91], Minimal activity has been reported in similar trials evaluating single agent temsirolimus [92,93] and everolimus; for the latter, PTEN deletion was suggested as a potential predictive biomarker [94]. The PI3K pathway is hypothesised to play a significant role in resistance to abiraterone and enzalutamide. Crosstalk between the AR and PI3K pathways with PI3K pathway inhibition resulting in activation of AR through HER2/HER3 signalling, and AR inhibition activating Akt in mouse models has been reported [95]. This has provided a rationale for potential combinations of PI3K pathway inhibitors with hormonal treatment and with HER-2 inhibitors. BEZ235, an oral PI3K and mammalian target of rapamycin (mTOR) inhibitor, is currently being evaluated in combination with abiraterone in a phase 1b/2 trial (NCT01634061). The AKT-inhibitor GDC-0068 in combination with abiraterone is being evaluated in a threearm phase 1b/2 trial [96]. The combination of PI3KAkt-mTOR inhibitors with AR-targeted therapy is clinically challenging due to potential toxicity. 5.6. IGF The insulin growth factor receptor 1 (IGF-IR) is a widely expressed receptor tyrosine kinase that has been

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linked to cancer progression through activation of the mitogen-activated protein kinase (MAPK) and PI3K/ Akt signalling pathways [97]. Higher circulating IGF-I levels have been associated with prostate cancer detected by PSA screening [98]. Preoperative figitumumab, an IGF-1R antibody, has been reported to decrease IGFIR expression as evaluated by immunohistochemistry (IHC), associated with declines in PSA levels and decreased AR expression in prostatectomy samples [99]. Ganitumab, another IGF-IR antibody, inhibited growth in VCap (androgen sensitive) but not in 22Rv1 (androgen insensitive) cell lines. Inhibition was most effective with a more complete androgen deprivation, supporting combination studies with abiraterone or enzalutamide in PTEN wildtype tumours [100]. Combination with mTOR inhibitors or SRC inhibitors has also been proposed [101]. Trials evaluating IGF-IR monoclonal antibodies in combination with mTOR inhibitors (cixumumab and temsirolimus, NCT01026623), chemotherapy (figitumumab and docetaxel, NCT00313781) or neoadjuvant hormone therapy (IMC-A12, NCT00769795) are underway.

5.7. C-Met C-Met is a transmembrane tyrosine kinase receptor involved in a variety of human cancers. Activation of c-Met by its ligand, the hepatocyte growth factor (HGF) leads to activation of signalling pathways related to increased proliferation, survival, motility, invasiveness and angiogenesis, transducing invasive growth signals from mesenchymal to epithelial cells [102]. Activation occurs mostly through a ligand-dependent, paracrine positive feedback loop induced by HGF-secretion of stromal cells [103], causing induction of stem cell like phenotypes and epithelial-mesenchymal transition (EMT) through the RAS-MAPK pathway [104]. In prostate cancer, expression of c-Met is higher in advanced stages and in bone metastases compared with lymph nodes or primary tumours [105]. Androgen receptor signalling has been reported to repress the expression of c-Met in a ligand dependent manner [106]. AR blockade can increase c-Met signalling, inducing EMT and stem-cell like phenotypes. C-Met has been postulated to be the main target for cabozantinib, although this remains controversial. Cabozantinib (XL184) also inhibits vascular endothelial growth factor receptor (VEGFR), RET, platelet derived growth factor receptor (PDGFR), KIT, AXL, and FLT3 receptor tyrosine kinases [107]; this agent improves survival from medullary thyroid carcinoma [108]. A randomised discontinuation phase II trial in patients with metastatic CRPC was halted after a first interim analysis due to significant benefit in the treatment arm, with a median PFS of 23.9 versus 5.9 weeks (HR 0.12, p < 0.001) [109]. A non-randomised expansion cohort using a 100 mg daily dose reported a reduction

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of measurable disease in 70% of patients, 60% bone-scan partial responses and a 39% rate of CTC conversion. 12% of patients had to discontinue cabozantinib due to adverse events, mainly fatigue, nausea and anaemia [110]. Cabozantinib at a 40 mg daily dose has been reported to improve tolerability with no major changes in activity [111]. Cabozantinib is being evaluated in a large, placebo-controlled phase III clinical trial in the post-abiraterone/enzalutamide, post-docetaxel setting (Comet-1 trial, NCT01605227) and in a phase III trial in patients with symptomatic bone disease, against mitoxantrone and prednisone (Comet-2 trial, NCT01522443), both at daily 60 mg doses.

The SRC-k inhibitor dasatinib has been evaluated in phase II trials as a single agent [127] and in combination with docetaxel where a 41% PSA response rate was reported [128]; however, the subsequent phase III READY trial, evaluating the combination of docetaxel and dasatinib showed no advantage in OS or PFS [129]. Saracatinib (AZD0530), an oral SRC-k inhibitor, is currently undergoing single-agent phase II evaluation in metastatic CRPC (NCT01267266). Question marks remain about the utility of SRC inhibitors for the treatment of CRPC.

5.8. Angiogenesis

CRPC treatment and research has been transformed in the past few years, and is currently one of the most interesting and dynamic areas in cancer research. Challenges such the development of predictive biomarkers, and a better understanding of the molecular heterogeneity of the different ‘CRPC molecular subtypes’, is paramount. Optimal sequencing of the different available treatments to maximise patient benefit, and a deeper understanding of the mechanisms of disease progression will guide research efforts in the next years.

Despite the established role of angiogenesis in prostate carcinogenesis, clinical results with antiangiogenic agents have been disappointing. Initial encouraging activity of bevacizumab in combination with docetaxel and estramustine [112] failed to translate into OS benefit in the phase III CALGB 90401 trial evaluating the combination of bevacizumab and docetaxel against docetaxel alone [113]. Aflibercept, a VEGF-trap, also failed to demonstrate survival benefit in combination with docetaxel in the phase III VENICE tria [114]. Lenalidomide, an antiangiogenic and immunomodulatory agent, failed to show survival benefit in combination with docetaxel in the phase III Mainsail study, where the experimental arm had a worse outcome than the control arm [115]. Despite high activity reported for the combination of lenalidomide with bevacizumab and docetaxel [116], concerns for potential toxicity have been raised. Tasquinimod, an oral quinolone derivative with antiangiogenic and immunomodulatory properties significantly increased PFS in a randomised trial [117] with concerns for increased rates of grade 3–4 deep venous thrombosis (0% versus 4%). A significant increase in OS in the subgroup of patients with bone metastases has been reported [118]. Zibotentan and atrasentan, two oral endothelin-A antagonists that showed increased PFS in two different phase II placebo-controlled clinical trials [119,120] failed to confirm OS benefit in subsequent phase III trials in the pre-chemotherapy [121,122] and post-chemotherapy [123,124] settings. 5.9. SRC-kinase (SRC-k) inhibition SRC is a non-receptor tyrosine kinase involved in bone metabolism [125] with an established role in normal osteoclast activity and bone metastasis formation. Enhanced co-expression of c-SRC and AR results in changes in prostate tubule structure that promote invasiveness. Activation of the SRC kinase pathway stimulates AR activity and is associated with strong activation of the MAPK pathway [126].

6. Conclusion

Conflict of interest statement Funding: D.L. and J.S.d.B are employees of the Section of Medicine that is supported by a Cancer Research UK programme grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401) as well as Biomedical Research Centre funding to the Royal Marsden. J.S.d.B. Received consulting fees from Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol – Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi – Aventis, Supergen, and Takeda, and grant support from AstraZeneca and Genentech. References [1] Prostate cancer incidence statistics. Cancer Res. UK, pp. 1–8; 2013. [2] Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995;346:265–9. [3] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502–12. [4] De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376(9747):1147–54.

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Molecular alterations and emerging targets in castration resistant prostate cancer.

Prostate cancer is the most common malignancy in Western Europe, of which approximately 10-20% presents with advanced or metastatic disease. Initial r...
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