seminar prostate cancer -...

Seminar

www.thelancet.com Published online June 12, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61947-4 1

Prostate cancerGerhardt Attard, Chris Parker, Ros A Eeles, Fritz Schröder, Scott A Tomlins, Ian Tannock, Charles G Drake, Johann S de Bono

Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identifi cation of rare but high-risk mutations (eg, BRCA2, HOXB13) and low-risk but common alleles (77 identifi ed so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specifi c antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classifi cation of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS-gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratifi cation of patients for diff erent management strategies. Presently, men with localised disease can have very diff erent prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years fi ve new drugs have shown effi cacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specifi c treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.

IntroductionProstate cancer is the most common malignancy in men and a major cause of cancer deaths. Its incidence diff ers between countries due to coverage of prostate-specifi c antigen (PSA) screening,1 but in both populations with and without PSA screening, prostate cancer is the cause of 1–2% of deaths in men. Its greater prevalence in the west2 and migrant population data implicate lifestyle and environmental risk factors.3 Large advances have been made in the treatment and understanding of the underlying biology. These include the approval of several novel eff ective drugs that improve survival in men with advanced prostate cancer and the recognition that the terms hormone refractory and androgen independent were misnomers, with most cancers remaining hormone-driven despite castration resistance (fi gure 1).4–10 Nonetheless, several areas of urgent unmet need remain—fi rst, a validated biomarker to complement PSA for screening; second, molecular diff erentiation of indolent and aggressive disease and prognostic biomarkers with clinical utility; third, molecular stratifi -cation methods and predictive biomarkers; fourth, adjuvant therapies to increase cure rates in higher-risk locally advanced disease; fi fth, treatment of metastatic disease; sixth, imaging of bone metastasis for staging and response measures; and seventh, surrogate bio-markers for overall survival benefi t. In this Seminar, we give an overview of the latest data on the biology and treatment of prostate cancer.

Causative mechanismsAside from age and race, the only established risk factor for prostate cancer is a family history of the disease. The risk for fi rst-degree relatives of men with prostate cancer is about twice that for men in the general population.11,12

This familial risk is more than four times higher than that for the general population for fi rst-degree relatives of men with prostate cancer diagnosed younger than 60 years.13 A 50% higher risk in monozygotic twins than in dizygotic twins14–16 and the higher incidence in African Americans (and lower rate in Americans of Asian ancestry) supports genetic factors as an important determinant of the variation in risk at the population level.17

Genetic predisposition can result from rare highly penetrant mutations, from genetic variants conferring lower risk, or from a combination of these two (fi gure 2). Studies of prostate cancer pedigrees suggest dominant, recessive, and X-linked models.18–20 Genetic linkage studies in multiple-case families have suggested co-segregation of multiple genetic regions; from these genetic regions, only one defi nite prostate cancer predisposition gene, the homeobox gene HOXB13, has been identifi ed.21

Published OnlineJune 12, 2015http://dx.doi.org/10.1016/S0140-6736(14)61947-4

Division of Clinical Studies, The Institute of Cancer Research, London, UK (G Attard MD, Prof J S de Bono MB ChB); Prostate Cancer Targeted Therapy Group (G Attard, J S de Bono), Academic Urology Unit (C Parker FRCR), and Clinical Academic Cancer Genetics Unit (R A Eeles FRCR), Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK (R A Eeles); Erasmus University Medical Center, Rotterdam, Netherlands (Prof F Schröder MD); Departments of Pathology Urology, Comprehensive Cancer Center and Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA (S A Tomlins MD); Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada (I Tannock MD); and Division of Medical Oncology, Johns Hopkins Hospital, Baltimore, MA, USA (C G Drake MD)

Correspondence to:Prof Johann S de Bono, Division of Clinical Studies, The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, [email protected]

Search strategy and selection criteria

We searched Medline, PubMed, and the Cochrane Library database for papers published in English between January, 2002 and January, 2014. We used the search terms “prostate cancer”, “aetiology”, “carcinogenesis”, “screening”, “diagnosis”, “adjuvant treatment”, “molecular prognostic and predictive markers”, “castration-resistance”, and “cost implications”. We cross-checked reference lists from our results, and asked other colleagues to recommend references. We prioritised references that we considered to have had a signifi cant impact or introduced new ways of thinking. We cited review articles to provide readers with more details and more references than this Seminar has room for. Our reference list was modifi ed on the basis of comments from peer reviewers.

http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(14)61947-4&domain=pdf

Seminar

2 www.thelancet.com Published online June 12, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61947-4

More than 20 genome-wide association studies (GWAS) of prostate cancer have been published, reporting 77 SNPs to be associated with prostate cancer.22 The fi rst region identifi ed was 8q24, which (similar to most identifi ed SNPs) is in a non-coding region23 in the vicinity of the oncogene c-MYC. Chromatin conformation assays report that this aff ects c-MYC expression.24

Rare germline BRCA2 mutations occur in families with high rates of breast and ovarian cancer and confer a fi ve to seven times higher risk of prostate cancer;25,26 1·2% of all young-onset patients (<65 years) have a germline BRCA2 mutation.27 The relative risk in carriers of BRCA1 mutations is controversial, but data indicate

that BRCA1 mutation carriers have a 3·8-times increased risk of prostate cancer up to age 65 years than do the general population.28 Investigators have analysed several other DNA repair genes, including CHEK2, PALB2, BRIP1, and NBS1. Truncating mutations in CHEK2 and PALB2 (the Finnish founder mutation) and BRIP1 are associated with a moderate risk of breast cancer, whereas NBS1 mutations, common only in Slavic populations, are the cause of Nijmegen breakage syndrome. In each case, some evidence of an association has been shown with prostate cancer.29–33

Increased testing has led to the identifi cation of more BRCA2 carriers with prostate cancer; men with this genetic aberration have a higher Gleason score34 and worse prognosis than do non-BRCA2 carriers.35 Targeted screening in this group is being studied in the IMPACT study. The development of drugs (poly ADP ribose polymerase [PARP] inhibitors) for tumours with BRCA36,37 loss of function provides a new therapeutic option for these patients and encourages broader BRCA testing. Profi ling of a European population for the described 77 prostate cancer risk SNPs (from blood or saliva) could identify the population at highest risk (4·7-times risk compared with the general population)22 to allow target screening. However, more data are needed to confi rm the clinical signifi cance of these strategies.

Screening and diagnosisPSA concentrations in blood at mid-life (50–70 years)have been shown to powerfully predict lifelong risk of patients developing prostate cancer metastases and dying of the disease.38 These fi ndings could translate into a reduction in prostate cancer mortality from PSA-based screening. Discussions on early diagnosis must diff erentiate between population screening and screening upon request. The agreed endpoint of

Figure 1: Disorders in androgen receptor signalling that associate with CRPC4–10

AR=androgen receptor. GR=growth hormone receptor. CRPC=castration-resistant prostate cancer. PSA=prostate-specifi c antigen.

Mutant

D Increased GR expression; glucocorticoidscould activate GR and bypass enzalutamide-mediated AR blockade

E Increased conversion of adrenal androgens to higher-affinity AR ligands

F CRPC de-novosteroidogenesis;upregulation of CYP17A1

G AR splice variants without a ligand-bindingdomain lead toactivation of AR signalling in the absence of ligands

A AR amplification

B Increased AR expression

H Activation of receptortyrosine kinases that can lead to activation of AR signalling

C Point mutations of the AR that result in activation by glucocorticoids, progestins, oestrogens, and other ligands

AR-driventranscriptionalactivation eg,TMPRSS2-ERG, PSA

AR

AR

PTEN

GRGR

AR

V567

V7

AR

AR

CYP17A1

PI3K/AKT

ARE

Figure 2: Susceptibility variants for excess familial risks of prostate cancerVariants include rare mutations conferring high risk of prostate cancer, rare variants conferring moderate risk, and common alleles identifi ed through genome-wide association studies (GWAS).

BRCA2, BRCA1, HOXB13, MMR, NBS1, and CHEK2~5%

GWAS identified:76 loci 30%

Unexplained:~65%

For the IMPACT study see http://www.impact-study.co.uk/

Seminar


screening studies is prostate cancer mortality; the evaluation of overall mortality serves quality control purposes. Although the prolongation of life on a population basis is an important endpoint, it cannot be reached by any screening trial because of insuffi cient power. The eff ect of prostate cancer screening on mortality is controversial because of divergent opinion on the level of evidence provided by diff erent trials,39

and inability to match harms and benefi ts appro-priately.40 This controversy has resulted in worldwide agreement that population-based screening should not be imple mented despite evidence that screening reduces prostate cancer mortality.41,42 Nevertheless, men wishing early detection should arguably not be refused PSA testing. Professional advice is best based on decision aids that use open questions, available on the websites of the Society International d’Urology and the Movember website.

Meta-analyses on randomised screening trials,43

including an updated Cochrane review,44 have been limited by variable study quality. For example, criteria required in the European Randomised study of Screening for Prostate Cancer (ERSPC) were not required in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial,45 in which only 40% of participants were compliant with biopsy indications,46 44% were PSA-tested before randomisation, and there was more than 70% contamination by PSA testing in the control group.47 The ERSPC study has shown signifi cant reductions in prostate cancer mortality41,42 and the numbers of men required to be invited for screening and treated to prevent one prostate cancer death have decreased from the 2009 (1410 and 48, respectively) to the 2012 publication (936 and 33, respectively). Nonetheless these results remain preliminary since less than 30% of participants have died and these might decrease further with longer follow-up.

A report to address the balance of harms and benefi ts by modelling quality-of-life adjusted life-years for the total expected lifetime of participants in screening studies was published in 2012.40 Based on the 11 year follow-up data of ERSPC, the model predicted that with yearly screening in men aged 55–69 years, 73 life-years would be gained, of which, after deduction of 23% for loss of quality of life, 56 adjusted life-years remained. The researchers identifi ed overdiagnosis as the most relevant harm that limits the acceptability of population screening of men at risk. Assuming no overdiagnosis, the quality-of-life adjusted life-years in this setting would increase from 56 to 79 years. Obviously, testing for PSA alone cannot resolve this issue and the application of risk stratifi cation is necessary.

The likelihood of identifi cation of prostate cancer on biopsy based on the commonly used PSA threshold of 4 ng/mL is about 21%. This represents overtesting (in about 75% of people) and overdiagnosis (in 30–50%, depending mainly on age) of cancers that may have remained undetected. An available risk stratifi cation

instrument, the SWOP risk calculator (appendix), could reduce this;48 when digital rectal examination and ultrasound studies for prostate volume and suspicious lesions are also used, the risk of a positive biopsy is reduced to 8% with a chance of aggressive disease of only 1% if these are normal with a prostate volume of more than 50 mL. A recent update of the website shows that prostate volume estimation by rectal examination can replace volume measurement by transrectal ultrasonography. Application of this strategy with a probability cutoff of 12·5% would decrease biopsy rate by 33%, although some potentially deadly cancers could be missed. Other instruments supporting risk stratifi cation are available and include those of the Foundation for Informed Medical Decision Making, the American Cancer Society, the American College of Physicians, the pending National Institute for Health and Care Excellence update, the Canadian Task Force-Draft Statement, and US Preventive Services Task Force. In consideration of any decision method, the level of external validation should be taken into account.

Because of space restrictions, the only novel diagnostic marker that we will discuss is urinary PCA3. mRNA of the prostate cancer antigen 3 (PCA3) gene, formerly known as DD3, was identifi ed in 1999 and was strongly overexpressed in more than 95% of tissue specimens of primary prostate cancer and prostate cancer metastases.49

PCA3-containing cells are detected in urine after prostatic massage and a PCA3 score obtained by normalising of urinary PCA3 mRNA concentrations with PSA. PCA3 testing improves the positive predictive value and sensitivity of detection of cancer on biopsy compared with PSA in a prescreened population.50 Several studies have so far proven inconclusive as to whether PCA3 is useful to selectively detect aggressive prostate cancers. One strategy to improve the performance characteristics of PCA3 could be to combine this with analysis of the TMPRSS2-ERG fusion gene.

MRI could also decrease overdiagnosis and un-necessary biopsies; level one evidence to support MRI use is not available, although several small studies have used MRI-guided biopsies, template-based biopsies based on MRI data, or MRI-transrectal ultrasonography fusion-guided biopsies. These strategies might also be used to detect more aggressive lesions and ventrally located transition-zone prostate cancers.51

Carcinogenesis and molecular subclassifi cationNext-generation sequencing has allowed characterisation of the clonal hierarchy of genomic lesions in prostate tumours, providing information about carcinogenesis52 and identifi cation of genomic rearrangements that result in androgen-driven ETS gene expression. These rearrangements are clonal, suggesting that they occur early and might result from activated androgen receptors generating DNA damage through transcription at androgen-receptor binding sites.53 Occurrence of

For Society International d’Urology see www.siu-urology.orgFor more on Movember see www.movember.com

For the updated risk calculator see www.prostatecancer-riskcalculator.com

Seminar


concomitant genotoxic insults that result in DNA double-strand breaks (eg, infl ammation, infection) might accelerate this process by impairing high-fi delity DNA repair.54 However, ETS gene fusions alone are not suffi cient to result in cancer; other genomic events, such as activation of the PI3K/AKT pathway by PTEN loss, are needed.55,56

More than 50 complete prostate cancer genomes have been reported, along with hundreds of exomes.52,57–60 The prostate cancer genome is characterised by relatively few focal chromosomal gains or losses (most commonly focal loss of PTEN) and overall low mutation rate (roughly one per megabase).58 SPOP, which encodes a substrate binding unit of a Cullin-based E3 ubiquitin ligase, TP53 and PTEN are among the most frequently mutated genes across several studies of localised prostate cancers.57,60–62 About 50–60% of PSA-screened prostate cancers in white patients have recurrent gene fusions, typically fusing the 5ʹ untranslated region of an androgen-regulated gene (eg, TMPRSS2) to nearly the entire coding sequence of an ETS transcription factor family member (eg, ERG).63 Many 5ʹ fusion partners, some of which are constitutively expressed and not androgen regulated (eg, HNRPA2B1), and other ETS family members are also less frequently involved (fi gure 3A).64 ETS gene fusions are highly clonal within a given cancer focus (although foci with diff erent ETS status can occur in the same prostate65), and can be detected by both fl uorescence in-situ hybridisation and immunohistochemistry.66 Whole-genome sequencing shows that some prostate cancers have relatively large numbers of chromosomal rearrangements, particularly in early onset cases, many involving known cancer-associated genes (commonly including ETS genes) in a distinctive closed chain pattern of rearrangement.58

The cell of origin for prostate cancer is controversial, with reports of prostate cancer deriving from both

luminal and basal epithelial cells, as well as evolution of basal-cell-initiation cancer evolving to adenocarcinoma maintained by luminal-like cells.67–70 Of note, overt basal-cell diff erentiation in prostate cancer is extremely rare (absence of basal cells is a diagnostic feature of typical prostatic adenocarcinoma), and gene-expression profi ling studies of prostate cancer do not support intrinsic molecular subtypes based on luminal versus basal diff erentiation, as in breast and bladder cancer.71,72

However, genomic, epigenetic, and expression profi ling studies support the premise that tumours with ETS fusions (ETS-positive) are distinct from those without (ETS-negative); driving changes in several genes have been identifi ed that occur exclusively in ETS-negative prostate cancers (fi gure 3B).58,66,73 For example, SPINK1, which encodes a serine protease inhibitor, is markedly overexpressed in about 5–10% of prostate cancers, and SPINK1-positive cancers are exclusively ETS-negative.66 Rare gene fusions or known activating mutations in RAF, RAS, and FGFR family members have also been identifi ed in prostate cancer (about 1–2%); RAF-RAF-FGFR-mutant tumours are exclusively ETS-negative. Similarly, mutations in SPOP, which cluster in the encoded protein’s substrate binding cleft, occur in about 5–10% of prostate cancers, and SPOPmut cancers are exclusively ETS-negative.53,57–60 Mutations and homozygous deletions in CHD1 have been identifi ed in 5–15% of prostate cancers, with CHD1-negative cancers also being exclusively ETS-negative.57,60,62,74,75 Although nearly always occurring in ETS-negative tumours, SPOPmut, CHD1-negative, and SPINK-negative frequently co-occur, with these tumours being commonly PTEN and p53 wild-type. Loss or mutation of the tumour-suppressor genes PTEN and TP53 are among the most frequent events in prostate cancer, and occur in both ETS-positive and ETS-negative cancers, but occur more

Figure 3: Prostate cancer subtypes and driving molecular lesions(A) More than half of prostate cancers arising in prostate-screened white individuals have fusions of the 5` untranslated region of genes normally expressed at high levels in the prostate with members of the ETS transcription factor family. The most common 5` fusion partners, including TMPRSS2 and SLC45A3, are positively regulated by the androgen receptor (AR). Other 5` partners include ubiquitously expressed genes, such as HNRP2AB1. The most commonly involved ETS member is ERG. (B) The distribution of prostate cancer molecular subtypes in prostate-specifi c-antigen-screened white individuals is shown. ETS gene fusions (ETS-positive; including those involving ERG, ETV1, ETV4, ETV5 and FLI1), are mutually exclusive with tumours with activating gene fusions or mutations in RAS and RAF family members (RAS-RAF-positive). A subset of ETS-negative and RAS/RAF wild-type tumours have SPINK1 outlier expression (SPINK1-positive), disruption of CHD1 (CHD1-negative), and SPOP mutations (SPOPmut). About 25% of prostate cancers have unclear or unique drivers.

AHealthy prostate Prostate cancer Unknown

or unique

B

ARTMPRSS2

ARETS

ARSLC45A3

ARETS

HNRP2AB1 ETS

ETS

ETS+

ERGETV1ETV4ETV5FLI1 SPINK1+

SPOPmut

CHD1–

RAS-RAF+

FGFR2+

IDH1mut

Seminar


frequently in ETS-positive cancers.57,60 These data represent approximate frequencies in white individuals; diff ering frequencies of certain events have been reported in men of other ethnic origins.76 Robust, reproducible, assays for several subset-defi ning lesions are available including multiplexed immunohistochemistry,77 suggest ing that a simple molecular barcode (ie, ETS/SPINK1/SPOP/CHD1/RAS-RAF/PTEN/TP53 status) can be used to defi ne molecular prostate cancer subtypes (fi gure 3B). Immuno-histochemistry for ERG, which detects the TMPRSS2-ERG gene fusions, is more than 99·9% specifi c for prostate cancer,78,79 supporting its diagnostic use in atypical cases of prostate cancer.80 Research into other changes commonly seen in prostate cancer, such as PTEN and CHD1 loss or SPOP mutations, might also have clinical use.

Multiple histologically distinct foci of prostate cancer are common in one prostate; these can be genetically heterogeneous, suggesting independent clonal origins.66,81,82 Identifi cation of the focus that will aff ect prognosis (index focus) is crucial; the main focus is usually selected based on being the largest or highest grade, but the index focus might be less easily identifi ed. Molecular studies suggest that lethal metastatic disease is clonal66,83,84 and the role of subclonal evolution in prostate cancer, particularly in progression and response to treatment, is under investigation. Although interpatient heterogeneity is well recognised, lower-grade cancers are relatively homogeneous unlike aggressive prostate cancers.60,85 Frequent reactivation of androgen-receptor signalling secondary to several mechanisms (fi gure 1) has been reported in studies of castration-resistant prostate cancer as well as frequent disruption of chromatin and histone modellers and tumour suppressors including PTEN, TP53, and RB1. Given the many therapies directed at the androgen receptor signalling axis, real-time evaluation of androgen receptor signalling status could aff ect future clinical management.60,86–88

Apart from the androgen receptor, several commonly disrupted genes and pathways are under active investigation, such as the PI3K/AKT/TOR pathway. Additionally, rare potentially targetable lesions, such as RAF fusions, focal high-level CDK4 amplifi cation, PIK3CA mutation, FGFR1 amplifi cation, and focal somatic loss of BRCA2 and other genes involved in DNA repair have been identifi ed in advanced cancers.60,62,89 These fi ndings suggest that therapy for advanced prostate cancer needs to be increasingly individualised. Furthermore, neuro endocrine prostate cancer can evolve after endocrine therapy, although this disease is uncommon at diagnosis. Neuroendocrine prostate cancer might suggest resistance to antiandrogen therapies and needs diff erent treatment, even after evolving from a previously androgen-sensitive cell. Specifi c molecular changes, such as AURKA and MYCN amplifi cation, have been reported in neuroendocrine prostate cancer that might be amenable to therapeutic targeting.90–92

Treatment of localised diseaseMen with localised disease can have very diff erent prognoses and face a wide array of treatment options. Men are advised on treatment based on risk assessments that often combine patient age, clinical tumour stage, serum PSA, PSA density, Gleason score, number of positive prostate biopsies, and amount of malignant tissue per core to select patients for treatment ranging from active surveillance alone through to multimodality treatment. Mostly, this choice is not guided by robust randomised trials.

Many low-grade (Gleason score of 6 or less) localised prostate cancers are harmless. Active surveillance off ers patients the hope of avoiding unnecessary, potentially harmful, treatment.93 Surveillance policies vary, but typically patients with assumed low-risk tumours are monitored with measurements of serum PSA, repeat prostate biopsies, and MRI. Changes on these assessments that suggest initial undersampling or disease progression should lead to radical treatment. Large studies indicate that most men with low-risk disease can safely avoid treatment with a risk of death from prostate cancer of 1% at 10 years,94,95 although the longer-term outcomes of active surveillance are not known.

Radical prostatectomy, external-beam radiotherapy, and brachytherapy are all standard local treatments for prostate cancer but have never been compared in robust randomised trials (table 1).96–101 Newer modalities such as cryotherapy, high-intensity focal ultrasound, and photodynamic therapy are also used. The best data for the effi cacy and safety of local treatment are from two randomised trials that compared radical prostatectomy against watchful waiting.97,102 The Scandinavian Prostate Cancer Group 4 trial96 randomly assigned 695 men with localised prostate cancer between 1989 and 1999. Importantly, the men in this trial had clinically detected cancers—88% had palpable disease on rectal examination. The results should therefore not be extrapolated to men with impalpable, PSA-detected cancers. Overall, mortality at 18 years was 56% for radical prostatectomy and 69% for watchful waiting (hazard ratio [HR] 0·71, 95% CI 0·59–0·86, p<0·001).102 The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomly assigned 731 men with localised prostate cancer from 1994 to 2002, in the early era of PSA testing, resulting in mainly low-risk cases. Mortality at 12 years was 41% for radical prostatectomy versus 44% for observation (HR 0·88; 95% CI 0·71–1·08). Radical prostatectomy was, however, associated with a trend towards decreased overall mortality in men with intermediate risk (HR 0·69; 95% CI 0·49–0·98). In the low-risk subgroup of 296 men, the risk of death from prostate cancer was less than 3% at 12 years, with no signifi cant benefi t from surgery. The HR for overall mortality favoured watchful waiting rather than surgery but this was not signifi cant (HR 1·15; 95% CI 0·80–1·66). At 2 years, surgery was also associated with greater urinary incontinence (17% vs 6%, p<0·001)

Seminar


and erectile dysfunction (81% vs 44%, p<0·001). Taken together, these two trials provide support for a conservative approach in men with low-risk disease and a curative approach for some men with higher-risk disease.

The role of external-beam radiotherapy to the prostate for men with prostate cancer has been established by two randomised controlled trials done mainly in men with high-risk or locally advanced disease. The SPCG-7 trial included 875 patients between 1996 and 2002 who were randomly assigned to hormonal treatment alone (3 months of total androgen blockade followed by fl utamide alone) or to the same hormonal treatment combined with radiotherapy.98 Radiotherapy signifi cantly improved 10 year overall mortality (30% vs 39%, p=0·004). The National Cancer Institute of Canada-PR3 trial99 randomly assigned 1205 patients between 1995 and 2005 to lifelong androgen deprivation (bilateral orchiectomy or luteinising-hormone-releasing hormone agonist) with or without radiotherapy. The addition of radiotherapy signifi cantly reduced 7-year overall mortality from 34% to 26% (HR 0·77 [95% CI 0·61–0·98], p=0·033). Toxic eff ects associated with radiotherapy were slight in both trials; rectal bleeding was reported in 13% of patients after radiotherapy versus 6% on androgen deprivation alone in the PR3 trial. Long-term androgen deprivation plus radical radiotherapy are now a standard of care for high-risk and locally advanced prostate cancer. Because of these two trials, hormone therapy as the sole modality of treatment is not recommended for men with localised or locally advanced disease.

Androgen deprivation is of proven value as an adjuvant to external-beam radiotherapy for higher-risk disease (table 1).103 For example, in a randomised trial of 415 patients with locally advanced disease, the addition of 3 years of androgen deprivation improved 10 year overall

survival after radiotherapy from 40% to 58% (HR 0·60, 95% CI 0·45–0·80; p=0·0004).104 Adjuvant androgen deprivation has not been shown to improve survival in low-risk disease,105 which is unsurprising given its excellent prognosis even without treatment. The optimum duration of adjuvant androgen deprivation is uncertain. TROG 96.01 compared none versus 3 months versus 6 months of neoadjuvant androgen deprivation in 818 men undergoing radiotherapy for localised and locally advanced disease.101 The use of 6 months, not 3 months, neoadjuvant androgen-deprivation signifi cantly improved overall mortality (from 43% to 29% at 10 years, HR 0·63, 0·48–0·83; p=0·0008), and 6 months should be considered the minimum duration of adjuvant treatment. EORTC 22961 randomised 970 men between 6 months and 3 years of adjuvant treatment.106 Overall mortality at 5 years was 19% and 15% (HR 1·42, 95% CI 1·09–1·85), respectively. This survival benefi t comes at the cost of a substantial prolongation of treatment-related morbidity.107

Management of metastatic diseaseFirst-line hormone treatmentDisease in many patients recurs after local therapy with a rising PSA; the optimum timing to start systemic treatment initiation is not clear. The best treatment of the prostatic primary in patients with metastatic disease at diagnosis is also unclear.108 Suppression of testicular androgens by castration (medical or surgical) is the mainstay of treatment for metastatic disease; single-agent antiandrogens such as bicalutamide have been used to initially minimise sexual dysfunction despite their inferior antitumour activity. Combination of cyproterone, fl utamide, and nilutamide with castration results in little benefi t,109 with a shorter survival for patients treated with cyproterone. Studies are now continuing to assess next-generation hormone treatments (eg, abiraterone acetate) as fi rst-line therapy, with or without chemical castration. Docetaxel might also have a role in this setting: one study showed no survival benefi t110 but another larger study (CHAARTED) has suggested a very signifi cant improve-ment in survival.

M0 diseaseMany patients develop progressive disease after castration with a rising PSA; frequently without radiological evidence of metastases. This is referred to as M0 castration-resistant prostate cancer, although these observations might be due to imaging limitations; whole-body diff usion-weighted MRI identifi es bone metastases missed by bone and CT scan (appendix).111 Little evidence exists to help treatment selection for M0 castration-resistant prostate cancer with a rising PSA. Biochemical response rates to hormonal drugs range from 30% to 80% and multinational phase 3 studies continue to assess next-generation hormone therapies in M0 patients with time to metastases as a primary endpoint. However, concerns remain about the validity of this endpoint.

Patients Comparison Overall survival outcome

HR (95% CI) p value

Trials of radical prostatectomy versus observation

SPCG496 695 Radical prostatectomy vs watchful waiting

67% vs 60% at 12 years

0·82 (0·65–1·03) 0·09

PIVOT97 731 Radical prostatectomy vs watchful waiting


0·88 (0·71–1·08) ··

Trials of hormone therapy with or without radical radiotherapy

SPCG-798 875 Hormone therapy plus EBRT vs hormone therapy


·· 0·004

NCIC PR399 1205 Hormone therapy plus EBRT vs hormone therapy


0·77 (0·61–0·98) 0·033

Trials of radical radiotherapy with or without adjuvant hormone therapy

EORTC 22863100 415 EBRT plus 3 years of hormone therapy vs EBRT


0·60 (0·45–0·80) 0·0004

RTOG 8531 977 EBRT plus lifelong hormone therapy vs EBRT


·· 0·002

TROG 9601101 537 EBRT plus 6 months of hormone therapy vs EBRT

70·8% vs 57·5% at 10 years

0·63 (0·48–0·83) 0·0008

EBRT=external-beam radiation therapy.

Table 1: Infl uential phase 3 trials for localised prostate cancer

See Online for appendix

Seminar


Treatment of metastatic castration-resistant prostate cancerSeveral treatment options are available for men with progressing metastatic castration-resistant prostate cancer. Abiraterone with prednisone is approved on the basis of COU-302 study data.112 The similar PREVAIL trial confi rmed the effi cacy of enzalutamide in chemotherapy-naive M1 castration-resistant prostate cancer.113 Availability of these next-generation therapies should decrease the use of the less eff ective ketoconazole and oestrogens. Single-drug steroids in the form of prednisolone 5 mg twice a day or dexamethasone 0·5 mg once a day (which has less mineralocorticoid receptor agonist activity, a longer half-life, and a higher biochemical response rate), remain popular treatment options but the absence of a proven survival benefi t limits their use. The potential long-term detrimental eff ects of steroids should also detract from their continued use at progression. There is no evidence base to guide the sequence of taxanes compared with next-generation hormone therapies; until clinical trials address the optimum sequence for the administration of these drugs, for most men, treatment choice will be based on the better toxicity profi les of the newer hormone treatments.

Several cytotoxics have been assessed in patients with prostate cancer but so far the only cytotoxics to show a survival advantage are docetaxel and cabazitaxel. Mitoxantrone was approved based on improved palliation, but is no longer commonly used. In the TAX-327 phase 3 study, docetaxel 75 mg/m² given once every 3 weeks improved overall survival compared with mitoxantrone 12 mg/m² every 3 weeks or docetaxel 30 mg/m² given every week for fi ve of every 6 weeks.114 The TAX327 study recruited 1006 chemotherapy-naive patients with metastatic castration-resistant prostate cancer and led to about a 3 month improvement in median survival as compared to treatment with mitroxantrone. The SWOG 9916 study also showed a survival benefi t for docetaxel (60 mg/m² every 3 weeks) and estramustine compared with mitoxantrone, but the estramustine seemed to only add toxic eff ects. Adverse events were more common in the groups treated with docetaxel but overall this treatment was well tolerated. Pharmacokinetic studies now report that in castrated men, docetaxel exposure might be decreased.115 Docetaxel retreatment for taxane-sensitive disease remains of unproven benefi t. Cabazitaxel is a second-generation semi-synthetic taxane generated to be active in docetaxel resistant or refractory models. The TROPIC study randomly assigned 755 patients with metastatic castration-resistant prostate cancer who had previously received docetaxel to either 12 mg/m² of mitoxantrone or 25 mg/m² of cabazitaxel intravenously every 3 weeks.116 The median survival was 15·1 months (95% CI 14·1–16·3) in the cabazitaxel group and 12·7 months (11·6–13·7) in the mitoxantrone group, with an HR for mortality of 0·70 (95% CI 0·59–0·83,

p<0·0001). Subgroup analyses have reported that cabazitaxel is eff ective in patients refractory and resistant to docetaxel. Studies indicate that the taxanes inhibit tubulin-dependent androgen receptor nuclear shuttling117 which could contribute to cross-resistance between taxanes and endocrine treatments, although this remains unclear118 because cabazitaxel also retains anti-tumour activity against abiraterone-resistant and enzalutamide-resistant disease.119

Ketoconazole is a non-specifi c, weak, CYP inhibitor, which is used to inhibit androgen synthesis with some antitumour activity.120 Abiraterone is a potent CYP17A1 inhibitor; when given to men receiving castration treatment, it inhibits androgenic steroid synthesis.121

CYP171A1 blockade results in a compensatory rise in adrenocorticotropic hormone, leading to increased weak glucocorticoids upstream of CYP17A1 that prevent adrenocortical insuffi ciency.121–123 Abiraterone is given with prednisone or prednisolone 5 mg twice a day to suppress adreno corticotropic-hormone-generated mineralocorticoid excess. Findings of two large randomised trials (COU-AA-301 and COU-AA-302) confi rmed that abiraterone was effi cacious in docetaxel-treated and chemotherapy-naive patients, leading to regulatory approval in 2011.112,124 Investigators for COU-AA-301 treated 1195 patients who had received up to two lines of chemotherapy including docetaxel; median overall survival in the abiraterone group was 15·8 months compared with 11·2 months in the placebo group.125 Abiraterone and prednisone signifi cantly delayed pain progression and skeletal-related events, improving fatigue, quality of life, and pain control when compared with prednisone alone, which also had antitumour activity.126,127 A second randomised trial (COU-AA-302) enrolled 1088 chemotherapy-naive men with metastatic castration-resistant prostate cancer and a rising PSA but minimal symptoms.112 At a pre-planned interim analysis after 433 deaths and a median follow-up of 22·2 months, radiological progression-free survival for abiraterone and prednisone was signifi cantly improved compared with placebo and prednisone.112 At the fi nal analysis, overall survival was also confi rmed to be signifi cantly increased (HR 0·81 [95% CI 0·70–0·93]; p=0·0033).128 Abiraterone improved all the secondary endpoints of the study. The mechanisms underlying resistance to abiraterone remain unclear. Researchers have reported residual ligands might reactivate androgen receptor signalling129 and in-vivo xenografts have shown increased CYP17A1 expression at progression on abiraterone.130,131

Enzalutamide is a potent next-generation anti androgen drug, selected for clinical development after showing activity in bicalutamide-resistant mice overexpressing androgen receptor or with a mutant androgen receptor.132 Shown to be highly active in early clinical trials, a phase 3 study randomly assigned men with metastatic castration-resistant prostate cancer who had previously received docetaxel chemotherapy to either enzalutamide 160 mg

Seminar


per day (n=800) or placebo (n=399).133 Findings showed a median of 4·8 months improvement in overall survival (HR 0·631; p<0·0001) in favour of enzalutamide. Based on these data, enzalutamide was approved for the treatment of metastatic castration-resistant prostate cancer after docetaxel. The PREVAIL prechemotherapy enzalutamide trial also reported a very signifi cant decrease in the risk of radiological progression (progression-free survival 0·19; 95% CI 0·15–0·23; p<0·001) and a signifi cant improvement in overall survival (HR 0·71; 95% CI 0·60–0·84; p<0·001).134 These fi nding have led to the extension of enzalutamide’s license to chemotherapy-naive patients. The emergence of mutant androgen receptors activated by enzalutamide135 or the outcompeting of enzalutamide by increased androgens129 are postulated to be mechanisms of resistance, as is signalling by other nuclear steroid receptors such as the glucocorticoid receptor.136 Preliminary data suggest that response rates to abiraterone after enzalutamide and conversely enzalutamide after abiraterone are low137–139 and no robust criteria exist clinically to select one drug rather than the other. The presence of androgen receptor splice variants without the ligand-binding domain has been associated with resistance to abiraterone and enzalutamide and could be one explanation for this signifi cant cross-resistance.140 Clinical trials that assess the combination of CYP17A1 inhibition with androgen receptor antagonism are continuing, with drugs given both at start of castration treatment (NCT00268476) and in patients with castration-resistant prostate cancer (NCT01949337).

Bone-targeting treatmentBone metastases develop in most men with metastatic castration-resistant prostate cancer and lead to complications (skeletal-related events) such as bone pain needing radiotherapy, pathological fracture, spinal cord

compression, and the need for orthopaedic surgery. Two drugs have been approved for prevention of skeletal-related events. Zoledronic acid is a bis phosphonate that inhibits osteoclast-mediated bone resorption. In a randomised trial of 422 patients with zoledronic acid and bone metastases, zoledronic acid at 8 mg or 4 mg every 3 weeks was compared with placebo.141 The group given 8 mg did not have signifi cantly better outcomes than those given placebo and had more renal toxic eff ects. In the group given 4 mg, the proportion of patients that had skeletal-related events was reduced from 44% to 33% (p=0·021), although overall survival was not improved in either group. Denosumab is a human monoclonal antibody against RANKL (TNFSF11) that inhibits osteoclast function. In a randomised trial of 1904 patients with metastatic castration-resistant prostate cancer, denosumab was superior to zoledronate with regard to time to fi rst skeletal-related event (median 20·7 months vs 17·1 months; HR 0·82, 95% CI 0·71–0·95; p=0·008).142 Denosumab was associated with a higher rate of osteonecrosis of the jaw (2% vs 1% of patients) and hypocalcaemia (13% vs 6%) than was zoledronate, with no diff erence in overall survival. Moreover, zoledronate is given intravenously, denosumab subcutaneously, making denosumab more practical. However, the poor eff ect on survival for both of these drugs raises concerns about their cost-eff ectiveness (table 2); less frequent administration might improve this fi gure, al-though might generate less benefi t. Moreover, their pivotal trials were accrued before the approval of abiraterone, enzalutamide, and radium-223, all of which reduce risk of skeletal-related events. The absolute benefi t of zoledronic acid and denosumab might therefore now be smaller.

Radium-223 is an α-emitting bone-targeted radioisotope that prevents skeletal-related events and improves overall survival and quality of life for men with metastatic castration-resistant prostate cancer and bone metastases. After intravenous injection, radium-223 localises to bone

Pivotal trial Gain in median survival (months)

Approximate cost of treatment per month

Independent estimates of cost per QALY

Comment

Docetaxel (fi rst-line chemotherapy)

TAX-327114,143 2·9 £310* Not available Now available as generic drug

Cabazitaxel (second-line chemotherapy)

TROPIC116 2·4 £3670* £82 950146 Rejected for funding by NICE

Sipuleucil-T IMPACT144 4·1 £60 000†‡ Not available ··

Abiraterone (after docetaxel) COU-AA-301126 3·9 £2630* £46 800–50 000147 Accepted for funding by NICE

Enzalutamide (after docetaxel) AFFIRM133 4·8 £4800† Not available ··

Radium-223 (after docetaxel) ALSYMPCA145 2·8 Price not yet available Not available ··

Zoledronic acid Saad et al (2002)141 0 £450* £100 000 148 ··

Denosumab Fizazi et al (2011)142 0 £350* £650 000149§ ··

QALY=quality-adjusted life-years. NICE=National Institute for Health and Care Excellence. *Cost to the pharmacy at Princess Margaret Cancer Centre (PMCC, for available drugs, August, 2013), for a man of 1·75 m², using the dose and schedule evaluated in the pivotal trials, with cost converted to British pounds. †Based on US prices (not available at PMCC). ‡Price is for a course of sipuleucil-T (three infusions given at 2 week intervals). §This estimate was based in geographic regions (no longer true at PMCC) where the price of denosumab exceeded that of zoledronic acid.

Table 2: Cost of treatments for advanced castration-resistant prostate cancer

Seminar


metastases by virtue of its chemical similarity to calcium and decays with a half-life of 11 days, emitting α particles that are highly cytotoxic with a very short penetration range (100 μm). In a randomised placebo-controlled trial of 921 men with metastatic castration-resistant prostate cancer, radium-223 improved overall survival (median 14·9 months vs 11·3 months with placebo; HR 0·70, 95% CI 0·58–0·83; p<0·001), delayed time to fi rst skeletal-related events (median 9·8 vs 15·6 months; HR 0·666, 95% CI 0·52–0·83; p<0·001) and improved quality of life.145 Radium-223 was well tolerated with mild nausea and diarrhoea and a low risk of myelosuppression (eg, grade 3 or 4 thrombocytopenia in 6% vs 2% in placebo). Radium-223 has now received regulatory approval. Future trials aim to optimise the radium-223 dosing schedule and assess its use earlier in the disease and in combination with other drugs.

ImmunotherapyImmune-based approaches involve diverse ways to generate CD8 (killer) lymphocytes that lyse tumour cells.146–149 Sipuleucel-T is an active cellular immunotherapy composed of autologous peripheral-blood mononuclear cells including antigen-presenting cells that have been activated ex vivo with a recombinant fusion prostate cancer antigen (PSA). Three infusions are given over 6 weeks. Manufacture is done separately for each patient, and is costly, needing leukapheresis and personalised generation of each infusion product. Sipuleucel-T is well tolerated but can cause fl u-like syndromes and myalgia; it has little eff ect on PSA or disease progression rate. Nonetheless, a phase 3 trial of 512 patients reported a 4·1 month survival advantage for sipuleucel-T versus placebo in men with metastatic castration-resistant prostate cancer.144 A critical appraisal of these data has raised concerns that they could potentially be explained by a worse outcome in placebo group patients due to the control leukapheresis product being stored at a lower temperature than the drug.150 ProstVac VF is an engineered poxvirus-based vaccine targeting PSA using vaccinia-virus based priming followed by a series of fowl-pox-based boosts. It is well tolerated and has shown promise in a randomised phase 2 study;151 results of a randomised phase 3 trial (NCT01322490) are awaited. The CTLA4 immune checkpoint targeting antibody ipilumimab was not shown to be of signifi cant clinical benefi t in patients with late-stage metastatic castration-resistant prostate cancer in a phase 3 trial (NCT00861614), but trials are awaited for patients with earlier stage disease who have lower volume disease and are less immunocompromised (NCT01057810).

ConclusionsUnderstanding of prostate cancer genetics and molecular pathogenesis has improved substantially, with several new drugs to improve the treatment and outcome of metastatic castration-resistant prostate cancer. However,

controversies about the screening of men for prostate cancer and the treatment of localised disease remain. These have been challenging to address because of contradictory results and the diffi culties, including very long lead-time, of doing clinical trials in these groups. The clinical relevance of genetic testing to identify men at high risk of disease and of molecular subtyping of prostate cancer are as yet uncertain. Although the cost of docetaxel has recently decreased substantially since generic drugs became available, all the newer drugs for treatment of advanced prostate cancer are expensive and will probably remain so while under patent. Moreover, little information has been reported about the activity of newer drugs when used sequentially. Overtreatment of indolent disease, inadequate screening schedules, low cure rates, and invariable drug resistance remain crucial issues that require prioritisation. Continuing clinical and translational research will be key to improvements in and personalisation of the management of prostate cancer.ContributorsRAE wrote the section about causative mechanisms. FS wrote the section on screening and diagnosis. SAT wrote the section on carcinogenesis and molecular subclassifi cation. CP wrote the section about treatment of localised disease.JSdB, CP, GA, IT, and CGD cowrote the section on management of metastatic disease, while GA provided overall structure and editing for the Seminar. JSdB provided overall structure and the search strategy. All authors provided fi nal review and approval for the Seminar and had input into responding to the reviewers’ comments.

Declaration of interestsGA and JSdB are employees of The Institute of Cancer Research (ICR) based at Sutton and Fulham, which has a commercial interest in abiraterone acetate and inhibitors of PI3K/AKT signalling. GA has received consulting fees and travel support from Janssen-Cilag, Veridex, Roche-Ventana, Astellas, Novartis, and Millennium Pharmaceuticals; speaker’s fees from Janssen, Ipsen, Takeda, and Sanofi -Aventis; and grant support from AstraZeneca and Genentech. GA is on the ICR Rewards to Inventors list for abiraterone acetate. RAE has received educational grants from Vista Diagnostics, Janssen, Illumina, and GenProbe (formerly Tepnel) and honoraria from Succinct Communications. SAT is a coinventor on a patent issued to the University of Michigan on ETS fusion genes in prostate cancer. The diagnostic fi eld of use has been licensed to Gen-Probe, who has sublicensed certain rights to Ventana Medical Systems, and SAT receives distributions from licensing agreements through the University of Michigan. SAT is a coinventor on a patent fi led by the University of Michigan on SPINK1 in prostate cancer. The diagnostic fi eld of use has been licensed to Gen-Probe, who has sublicensed certain rights to Ventana Medical Systems, and SAT receives distributions from licensing agreements through the University of Michigan. SAT is a consultant and has received honoraria from Ventana Medical Systems. CGD has interests in Medimmune and has received consulting fees from Bristol-Myers Squibb, Costimm, Dendreon, Pfi zer, Roche, and Compugen. JSdB has received consulting fees from Ortho Biotech Oncology Research and Development; consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfi zer, Roche, Sanofi -Aventis, Supergen, and Takeda; and grant support from AstraZeneca and Genentech. CP has received honoraria from Bayer, BN ImmunoTherapeutics, Janssen, Sanofi -Aventis, and Takeda.

AcknowledgmentsGA and JSdB are supported by the Prostate Cancer Foundation, Prostate Cancer UK (PCUK), and Movember. JSdB is also funded by the Department of Defence and Cancer Research UK. GA is also funded by a Cancer Research UK (CRUK) Clinician Scientist Fellowship. RAE is supported by CRUK, PCUK, The Ronald and Rita McAulay Foundation,

Seminar


and the European Union Seventh Framework Programme. SAT was supported by a Career Development Award from the University of Michigan Prostate Cancer Specialised Programmes of Research Excellence and has been supported by the Prostate Cancer Foundation and SU2C. CGD is supported by National Institutes of Health R01 CA127153, 1P50CA58236–15, the Patrick C Walsh Fund, the OneInSix Foundation, the Koch Foundation, and the Prostate Cancer Foundation. We were supported by Experimental Cancer Medicine Centre and National Institute for Health Research (NIHR) funding to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. We thank Nina Tunariu, consultant radiologist at the Royal Marsden NHS Foundation Trust, for providing MRI images.

References1 Cancer Research UK. Cancer risk. July 27, 2011. http://www.

cancerresearchuk.org/cancer-info/cancerstats/incidence/risk/ (accessed Nov 21, 2012).

2 Marugame T, Katanoda K. International comparisons of cumulative risk of breast and prostate cancer, from cancer incidence in fi ve continents Vol VIII. Jpn J Clin Oncol 2006; 36: 399–400.

3 Lee J, Demissie K, Lu SE, Rhoads GG. Cancer incidence among Korean-American immigrants in the United States and native Koreans in South Korea. Cancer Contr 2007; 14: 78–85.

4 Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplifi cation of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995; 9: 401–06.

5 Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10: 33–39.

6 Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995; 332: 1393–98.

7 Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006; 66: 2815–25.

8 Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008; 68: 6407–15.

9 Hu R, Lu C, Mostaghel EA, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 2012; 72: 3457–62.

10 Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-defi cient prostate cancer. Cancer Cell 2011; 19: 575–86.

11 Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in fi rst-degree relatives of cancer probands. J Natl Cancer Inst 1994; 86: 1600–08.

12 Schaid DJ. The complex genetic epidemiology of prostate cancer. Hum Mol Genet 2004; 13 (suppl 1): R103–21.

13 Johns LE, Houlston RS. A systematic review and meta-analysis of familial prostate cancer risk. BJU Int 2003; 91: 789–94.

14 Hemminki K, Vaittinen P. Familial breast cancer in the family-cancer database. Int J Cancer 1998; 77: 386–91.

15 Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78–85.

16 Grönberg H, Damber L, Damber JE. Studies of genetic factors in prostate cancer in a twin population. J Urol 1994; 152: 1484–87.

17 Zeigler-Johnson CM, Rennert H, Mittal RD, et al. Evaluation of prostate cancer characteristics in four populations worldwide. Can J Urol 2008; 15: 4056–64.

18 Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992; 89: 3367–71.

19 MacInnis RJ, Antoniou AC, Eeles RA, et al. Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies. Genet Epidemiol 2010; 34: 42–50.

20 Schaid DJ. Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet 1998; 63: 935–41.

21 Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 141–49.

22 Eeles R, Goh C, Castro E, et al. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 2014; 11: 18–31.

23 Freedman ML, Monteiro AN, Gayther SA, et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 2011; 43: 513–18.

24 Ahmadiyeh N, Pomerantz MM, Grisanzio C, et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specifi c long-range interaction with MYC. Proc Natl Acad Sci USA 2010; 107: 9742–46.

25 Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310–16.

26 Thompson D, Easton D, and the Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001; 68: 410–19.

27 Kote-Jarai Z, Leongamornlert D, Saunders E, et al, for the UKGPCS Collaborators. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer 2011; 105: 1230–34.

28 Leongamornlert D, Mahmud N, Tymrakiewicz M, et al, for the UKGPCS Collaborators. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 2012; 106: 1697–701.

29 Cybulski C, Huzarski T, Górski B, et al. A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res 2004; 64: 2677–79.

30 Cybulski C, Wokołorczyk D, Huzarski T, et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet 2006; 43: 863–66.

31 Erkko H, Xia B, Nikkilä J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 2007; 446: 316–19.

32 Hebbring SJ, Fredriksson H, White KA, et al. Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15: 935–38.

33 Kote-Jarai Z, Jugurnauth S, Mulholland S, et al, for the UKGPCS Collaborators and the British Association of Urological Surgeons’ Section of Oncology. A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer. Br J Cancer 2009; 100: 426–30.

34 Mitra A, Fisher C, Foster CS, et al, for the IMPACT and EMBRACE Collaborators. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 2008; 98: 502–07.

35 Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013; 31: 1748–57.

36 Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917–21.

37 Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010; 28: 2512–19.

38 Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specifi c antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ 2013; 346: f2023.

39 Etzioni R, Gulati R. Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence. Med Care 2013; 51: 304–06.

40 Heijnsdijk EA, Wever EM, Auvinen A, et al. Quality-of-life eff ects of prostate-specifi c antigen screening. N Engl J Med 2012; 367: 595–605.

41 Schröder FH, Hugosson J, Roobol MJ, et al, for the ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320–28.

42 Schröder FH, Hugosson J, Roobol MJ, et al, for the ERSPC Investigators. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981–90.

43 Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ 2010; 341: c4543.

44 Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database Syst Rev 2013; 1: CD004720.

45 Andriole GL, Crawford ED, Grubb RL 3rd, et al, for the PLCO Project Team. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: 125–32.

Seminar


46 Grubb RL 3rd, Pinsky PF, Greenlee RT, et al. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on fi ndings from the initial four rounds of screening in a randomized trial. BJU Int 2008; 102: 1524–30.

47 Pinsky PF, Blacka A, Kramer BS, Miller A, Prorok PC, Berg C. Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clin Trials 2010; 7: 303–11.

48 Roobol MJ, Steyerberg EW, Kranse R, et al. A risk-based strategy improves prostate-specifi c antigen-driven detection of prostate cancer. Eur Urol 2010; 57: 79–85.

49 Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specifi c gene, highly overexpressed in prostate cancer. Cancer Res 1999; 59: 5975–79.

50 Roobol MJ, Schröder FH, van Leeuwen P, et al. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specifi c antigen in prescreened men: exploring the value of PCA3 for a fi rst-line diagnostic test. Eur Urol 2010; 58: 475–81.

51 Hambrock T, Hoeks C, Hulsbergen-van de Kaa C, et al. Prospective assessment of prostate cancer aggressiveness using 3-T diff usion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol 2012; 61: 177–84.

52 Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell 2013; 153: 666–77.

53 Lin C, Yang L, Tanasa B, et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specifi c translocations in cancer. Cell 2009; 139: 1069–83.

54 Mani R-S, Chinnaiyan AM. Triggers for genomic rearrangements: insights into genomic, cellular and environmental infl uences. Nat Rev Genet 2010; 11: 819–29.

55 Carver BS, Tran J, Gopalan A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009; 41: 619–24.

56 King JC, Xu J, Wongvipat J, et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet 2009; 41: 524–26.

57 Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifi es recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 2012; 44: 685–89.

58 Berger MF, Lawrence MS, Demichelis F, et al. The genomic complexity of primary human prostate cancer. Nature 2011; 470: 214–20.

59 Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–43.

60 Lindberg J, Mills IG, Klevebring D, et al. The mitochondrial and autosomal mutation landscapes of prostate cancer. Eur Urol 2013; 63: 702–08.

61 Beltran H, Rubin MA. New strategies in prostate cancer: translating genomics into the clinic. Clin Cancer Res 2013; 19: 517–23.

62 Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profi ling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

63 Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–48.

64 Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 2007; 448: 595–99.

65 Clark J, Attard G, Jhavar S, et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene 2008; 27: 1993–2003.

66 Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol 2011; 29: 3659–68.

67 Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON. Identifi cation of a cell of origin for human prostate cancer. Science 2010; 329: 568–71.

68 Stoyanova T, Cooper AR, Drake JM, et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci USA 2013; 110: 20111–16.

69 Wang X, Kruithof-de Julio M, Economides KD, et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 2009; 461: 495–500.

70 Wang ZA, Mitrofanova A, Bergren SK, et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 2013; 15: 274–83.

71 Choi W, Porten S, Kim S, et al. Identifi cation of distinct basal and luminal subtypes of muscle-invasive bladder cancer with diff erent sensitivities to frontline chemotherapy. Cancer Cell 2014; 25: 152–65.

72 Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer refl ect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111: 3110–15.

73 Börno ST, Fischer A, Kerick M, et al. Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov 2012; 2: 1024–35.

74 Huang S, Gulzar ZG, Salari K, Lapointe J, Brooks JD, Pollack JR. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene 2012; 31: 4164–70.

75 Liu W, Lindberg J, Sui G, et al. Identifi cation of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene 2012; 31: 3939–48.

76 Mao X, Yu Y, Boyd LK, et al. Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis. Cancer Res 2010; 70: 5207–12.

77 Bhalla R, Kunju LP, Tomlins SA, et al. Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma. Mod Pathol 2013; 26: 835–48.

78 Rosen P, Sesterhenn IA, Brassell SA, McLeod DG, Srivastava S, Dobi A. Clinical potential of the ERG oncoprotein in prostate cancer. Nat Rev Urol 2012.

79 Young A, Palanisamy N, Siddiqui J, et al. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. Am J Clin Pathol 2012; 138: 685–96.

80 Epstein JI, Egevad L, Humphrey PA, Montironi R, for the Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol 2014; 38: e6–19.

81 Lindberg J, Klevebring D, Liu W, et al. Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins. Eur Urol 2013; 63: 347–53.

82 Cheng L, Song SY, Pretlow TG, et al. Evidence of independent origin of multiple tumors from patients with prostate cancer. J Natl Cancer Inst 1998; 90: 233–37.

83 Aryee MJ, Liu W, Engelmann JC, et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci Transl Med 2013; 5: 169ra10.

84 Liu W, Laitinen S, Khan S, et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 2009; 15: 559–65.

85 Sboner A, Demichelis F, Calza S, et al. Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med Genomics 2010; 3: 8.

86 Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res 2009; 69: 2912–18.

87 Mendiratta P, Mostaghel E, Guinney J, et al. Genomic strategy for targeting therapy in castration-resistant prostate cancer. J Clin Oncol 2009; 27: 2022–29.

88 Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov 2012; 2: 995–1003.

89 Beltran H, Yelensky R, Frampton GM, et al. Targeted next-generation sequencing of advanced prostate cancer identifi es potential therapeutic targets and disease heterogeneity. Eur Urol 2013; 63: 920–26.

90 Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identifi cation of new drug targets. Cancer Discov 2011; 1: 487–95.

91 Lapuk AV, Wu C, Wyatt AW, et al. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J Pathol 2012; 227: 286–97.

Seminar


92 Mosquera JM, Beltran H, Park K, et al. Concurrent AURKA and MYCN gene amplifi cations are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 2013; 15: 1–10.

93 Parker C. Active surveillance: towards a new paradigm in the management of early prostate cancer. Lancet Oncol 2004; 5: 101–06.

94 Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010; 28: 126–31.

95 Selvadurai ED, Singhera M, Thomas K, et al. Medium-term outcomes of active surveillance for localised prostate cancer. Eur Urol 2013; 64: 981–87.

96 Bill-Axelson A, Holmberg L, Ruutu M, et al, for the SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17.

97 Wilt TJ, Brawer MK, Jones KM, et al, for the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–13.

98 Widmark A, Klepp O, Solberg A, et al, for the Scandinavian Prostate Cancer Group Study 7 and the Swedish Association for Urological Oncology 3. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009; 373: 301–08.

99 Warde P, Mason M, Ding K, et al, for the NCIC CTG PR.3/MRC UK PR07 investigators. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011; 378: 2104–11.

100 Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008; 26: 2497–504.

101 Denham JW, Steigler A, Lamb DS, et al. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 2011; 12: 451–59.

102 Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–42.

103 Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006; 4: CD006019.

104 Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010; 11: 1066–73.

105 Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011; 365: 107–18.

106 Bolla M, de Reijke TM, Van Tienhoven G, et al, for the EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009; 360: 2516–27.

107 Wilke DR, Krahn M, Tomlinson G, Bezjak A, Rutledge R, Warde P. Sex or survival: short-term versus long-term androgen deprivation in patients with locally advanced prostate cancer treated with radiotherapy. Cancer 2010; 116: 1909–17.

108 Sydes MR, Parmar MKB, Mason MD, et al. Flexible trial design in practice—stopping arms for lack-of-benefi t and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 2012; 13: 168.

109 Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000; 355: 1491–98.

110 Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–58.

111 Lecouvet FE, El Mouedden J, Collette L, et al. Can whole-body magnetic resonance imaging with diff usion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Eur Urol 2012; 62: 68–75.

112 Ryan CJ, Smith MR, de Bono JS, et al, for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–48.

113 Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33.

114 Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12.

115 Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol 2010; 28: 4562–67.

116 de Bono JS, Oudard S, Ozguroglu M, et al, for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–54.

117 Gan L, Chen S, Wang Y, et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res 2009; 69: 8386–94.

118 Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943–47.

119 Pezaro CJ, Omlin AG, Altavilla A, et al. Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur Urol 2014; 66: 459–65.

120 Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004; 22: 1025–33.

121 Attard G, Reid AHM, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confi rms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008; 26: 4563–71.

122 Attard G, Reid AHM, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27: 3742–48.

123 Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 2010; 28: 1481–88.

124 de Bono JS, Logothetis CJ, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

125 Fizazi K, Scher HI, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: fi nal overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983–92.

126 Logothetis CJ, Basch E, Molina A, et al. Eff ect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012; 13: 1210–17.

127 Sternberg CN, Molina A, North S, et al. Eff ect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Ann Oncol 2013; 24: 1017–25.

128 Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): fi nal overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152–60.

129 Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012; 72: 2176–82.

130 Cai C, Chen S, Ng P, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 2011; 71: 6503–13.

131 Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011; 17: 5913–25.

Seminar


132 Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: 787–90.

133 Scher HI, Fizazi K, Saad F, et al, for the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–97.

134 Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33.

135 Balbas MD, Evans MJ, Hosfi eld DJ, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2013; 2: e00499.

136 Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013; 155: 1309–22.

137 Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802–07.

138 Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013; 24: 1807–12.

139 Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer 2014; 50: 78–84.

140 Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38.

141 Saad F, Gleason DM, Murray R, et al, and the Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–68.

142 Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813–22.

143 Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 26: 242–45.

144 Kantoff PW, Higano CS, Shore ND, et al, for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22.

145 Parker C, Nilsson S, Heinrich D, et al, and the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23.

146 Kearns B, Lloyd Jones M, Stevenson M, Littlewood C. Cabazitaxel for the second-line treatment of metastatic hormone-refractory prostate cancer: a NICE single technology appraisal. Pharmacoeconomics 2013; 31: 479–88.

147 Dyer M, Rinaldi F, George E, Adler AI. NICE guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. Lancet Oncol 2012; 13: 762–63.

148 McKeage K, Plosker GL. Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases. Pharmacoeconomics 2008; 26: 251–68.

149 Snedecor SJ, Carter JA, Kaura S, Botteman MF. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a cost-eff ectiveness analysis. J Med Econ 2013; 16: 19–29.

150 Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst 2012; 104: 273–79.

151 Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28: 1099–105.

seminar prostate cancer -...

Documents