Drugs (2016) 76:421–430
`DOI 10.1007/s40265-015-0530-7
`
`C U R R E N T O P I N I O N
`
`Managing Metastatic Castration-Resistant Prostate Cancer
`in the Pre-chemotherapy Setting: A Changing Approach
`in the Era of New Targeted Agents
`
`Zafeiris Zafeiriou1,2
`
`• Anuradha Jayaram1,2
`
`• Adam Sharp1,2
`
`• Johann S. de Bono1,2
`
`Published online: 12 February 2016
`Ó Springer International Publishing Switzerland 2016
`
`the therapeutic options for
`In recent years,
`Abstract
`treating men with metastatic castration-resistant prostate
`cancer have increased substantially. The hormonal treat-
`ments
`abiraterone
`acetate
`and
`enzalutamide,
`the
`chemotherapeutics docetaxel and cabazitaxel, the radio-
`pharmaceutical alpharadin and the immunotherapeutic
`Sipuleucel-T have entered the field. Additionally, corti-
`costeroids, which are used extensively, have documented
`activity but no documented survival benefit. Physicians
`treating patients with metastatic prostate cancer immedi-
`ately after castration resistance develops currently have at
`least four different options to choose from for the first
`treatment. These therapeutic choices and their several
`possible ways of sequential use have not yet been com-
`pared to each other head-to-head and may never be.
`Therefore, there is an unmet need to inform their use with
`prospective clinical data. Additionally, the new indications
`of docetaxel for hormone naı¨ve prostate cancer is changing
`the landscape of prostate cancer treatment and questions
`the traditional classifications
`‘pre-chemotherapy’ and
`‘post-chemotherapy’. In this work we attempt to address
`these challenges in the treatment of metastatic castration-
`resistant prostate cancer with the focus mainly on the non-
`cytotoxic agents. We try to integrate available clinical and
`preclinical
`information to suggest optimal ways of
`treatment.
`
`& Johann S. de Bono
`johann.de-Bono@icr.ac.uk
`
`1 Division of Clinical Studies, The Institute of Cancer
`Research, Downs Rd, Sutton, London, Surrey SM2 5PT, UK
`
`2 Drug Development Unit, The Royal Marsden NHS
`Foundation Trust, London, UK
`
`Key Points
`
`The use of docetaxel in the hormone-naı¨ve setting
`will change the landscape of mCRPC treatment,
`changing the ‘pre-chemotherapy’ space.
`
`Current evidence does not allow judgements on the
`superiority of any of the available agents.
`
`Validated predictive biomarkers together with new
`targeted agents may render discussion of sequencing
`of current treatments obsolete in the near future.
`
`1 Introduction: The Natural Course of the Disease
`
`Prostate cancer (PCa) is a major morbidity factor world-
`wide, representing approximately 7 % of all deaths in
`males [1]. About 30 % of newly diagnosed patients
`develop metastatic disease and up to half of these will have
`metastatic disease at presentation [2]. Metastatic PCa is the
`lethal
`form of
`the disease and presents mainly with
`osteoblastic bone metastases and nodal disease and less
`often with liver and lung metastases. It is treated with
`surgical or chemical castration, [3] to which first generation
`antiandrogens can be added with limited benefit. Castration
`results in impressive responses but
`invariably leads to
`resistance despite anorchid levels of testosterone within a
`median time of 15–25 months [4]. This state is character-
`ized as metastatic castration-resistant prostate cancer
`(mCRPC); mCRPC is a heterogeneous disease, as is evi-
`dent from multiple large phase III trials [5, 6]. Some
`
`Amerigen Exhibit 1135
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`422
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`Z. Zafeiriou et al.
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`patients survive for several years and remain asymptomatic
`or mildly symptomatic for longer periods, while others
`succumb quickly to their disease. This clinical hetero-
`geneity underlies a wide range of genomic aberrations [7].
`Before modern treatments,
`the median survival of
`patients with mCRPC was between 12 and 20 months for
`symptomatic and asymptomatic patients, respectively [8,
`9]. The only therapeutic options were secondary hormonal
`manipulations: diethylstilbestrol, ketoconazole, changing
`or withdrawing antiandrogens and monotherapy with cor-
`ticosteroids, yet without any documented survival advan-
`tage [10].
`After 2010 several new drugs appeared on the stage of
`mCRPC treatment, prolonging overall survival (OS) after
`castration resistance to approximately 3 years. Their opti-
`mal sequence and use has nevertheless not been established
`and there are several unanswered questions. In the current
`work we attempt to address these areas of controversy and
`to recommend optimal ways to use available treatments by
`integrating information from the available clinical and
`preclinical data.
`
`2 Corticosteroids: Two-faceted Drugs?
`
`Corticosteroids are easily accessible drugs and their
`application in mCRPC dates back to the 1950s [11]. They
`are able to induce prostate-specific antigen (PSA) respon-
`ses and symptomatic relief [5, 12, 13] and most mCRPC
`patients at some time point receive corticosteroids either as
`monotherapy or as an adjunct to other treatments. Dex-
`amethasone monotherapy results in higher PSA response
`rates than prednisone (40 vs. 20 %) [12], and during abi-
`raterone treatment PSA responses have been reported after
`substituting prednisone 5 mg twice daily (bid) with dex-
`amethasone 0.5 mg once daily (od) [14]. Corticosteroids
`are hypothesized to act by suppressing the adrenocorti-
`cotropic hormone (ACTH) axis and reduce androgenic
`steroids that can then activate wildtype or mutated andro-
`gen receptor (mAR). The longer half-life of dexamethasone
`compared to prednisolone may suppress ACTH more
`efficiently and may explain this steroid switch response
`rate [12]. Furthermore, glucocorticoid receptor (GR) has
`been reported to transcribe genes otherwise regulated by
`AR [15] in androgen-deprived conditions and so contribute
`to castration resistance. Therefore, dexamethasone 0.5 mg
`od, corresponding to a lower equivalent glucocorticoid
`activity compared to prednisolone 5 mg bid, may result in
`reduced GR activation [12] which hypothetically could
`result in tumour regression. Mutant forms of AR may also
`be activated by prednisolone but not by dexamethasone
`[16]; in such cases a change of prednisone to dexametha-
`sone may result in a withdrawal response [17]. Therefore,
`
`although corticosteroids are useful drugs in the treatment of
`CRPC, they should also be used with caution and discon-
`tinued if not clinically indicated as they have been reported
`to potentially drive PCa growth.
`
`3 The Advent of a New Era: New Drugs
`for Metastatic Castration-Resistant Prostate
`Cancer (mCRPC)
`
`The first drug to show improved survival of mCRPC
`patients was docetaxel [18]. Sipuleucel-T [19] and cabaz-
`itaxel [20] were subsequently approved. Then abiraterone
`acetate and enzalutamide followed, proving that mCRPC
`remains dependent on ligand-dependent activation of the
`AR pathway [21]. This can occur with AR gene amplifi-
`cation [22], use by the tumour of androgenic steroids
`generated by the adrenals or the tumour itself [23, 24], AR
`mutations rendering AR sensitive to atypical ligands [25]
`or ligand-independent AR splice-variants [26]. Radium-223
`[27] was the last drug to complete the current armamen-
`tarium for mCRPC treatment.
`
`4 Abiraterone and Enzalutamide in mCRPC
`
`Abiraterone is a CYP17 inhibitor, blocking the synthesis of
`androgens [28, 29] both extragonadally and in the tumour,
`and also acting as a potent AR inhibitor through its
`metabolites [30]. Enzalutamide binds AR at its ligand-
`binding domain and reduces AR translocation to the
`nucleus and its interaction with DNA [31]. Both drugs were
`tested initially in patients previously treated with doc-
`etaxel, ensuring patients’ prior exposure to the then avail-
`able standard treatment. Abiraterone combined with
`prednisone was tested against prednisone plus placebo in
`the COU-AA-301 trial [13] and enzalutamide against pla-
`cebo in the AFFIRM trial [32], with 30 % of the patients in
`each arm receiving steroids at baseline [33]. Abiraterone
`showed a median OS (mOS) of 15.8 months compared to
`11.2 months for placebo plus prednisone (hazard ratio
`(HR) 0.74; 95 % confidence interval (CI) 0.64–0.86) [34]
`and
`enzalutamide
`a mOS of
`18.4 months
`versus
`13.6 months for placebo (HR 0.63; 95 % CI 0.53–0.75).
`The slight differences in outcome in both the control and
`experimental arms of these trials may be interpreted as
`suggesting that one treatment
`is better than the other.
`However, this is not supported by the data. Certainly, a
`negative effect of prednisone on survival could be assumed
`based on the OS differences of the control arms, in line
`with the aforementioned preclinical data supporting the
`hypothesis that steroids can promote PCa growth. Further
`analysis is warranted to clarify this observation.
`
`

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`
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`After COU-AA-301 and AFFIRM, abiraterone and
`enzalutamide were tested in chemotherapy-naı¨ve patients.
`PREVAIL evaluated enzalutamide versus placebo in 1,717
`minimally symptomatic patients and showed in a pre-
`planned interim analysis a significantly improved mOS of
`32.4 versus 30.2 months with placebo (HR 0.71; 95 % CI
`0.60–0.84) and a much more impressive difference in
`radiological progression favouring the experimental arm
`(HR 0.19; 95 % CI 0.15–0.23) [6]. In COU-AA-302, a
`phase III trial of abiraterone and prednisone versus pred-
`nisone alone in 1,088 asymptomatic or minimally symp-
`tomatic patients, abiraterone significantly improved mOS to
`34.7 from 30.3 months with placebo (HR 0.81; 95 % CI
`0.70–0.93) [35]. Both abiraterone and enzalutamide also
`showed improvement in a number of clinically meaningful
`secondary endpoints
`such as:
`time to initiation of
`chemotherapy, time to PSA progression, time to pain pro-
`gression, time to first skeletal-related event, time to decline
`in performance status or time to decline in quality of life
`[36, 37]. Crucially, OS in both trials represented the effect
`of not only abiraterone or enzalutamide alone but also of
`post-trial treatments. Importantly, many patients initially on
`placebo were crossed over to active drug [6, 35]. Patients
`with poor prognostic factors [38] were excluded from both
`PREVAIL and COU-AA-302, and patients with an albumin
`of \30 g/L or 35 g/L, respectively, significant pain or an
`Eastern Cooperative Oncology Group Performance Status
`(ECOG PS) of more than 1 were not enrolled. In COU-AA-
`302 visceral disease was also excluded.
`Are these treatments also suitable for chemo-naı¨ve
`patients who have these poor prognostic factors? The data
`from the post-chemotherapy trials COU-AA-301 and
`AFFIRM provide some hints. They recruited patients with
`an ECOG PS of B2, visceral disease and significant pain,
`while patients with an albumin of \30 g/L and a hae-
`moglobin of \9 g/L were excluded. In the subgroup anal-
`ysis of AFFIRM the HR for death was in favour of
`enzalutamide in all subgroups although not statistically
`significant in the small subgroups that had an ECOG PS of
`2, or two or more previous chemotherapy regimens [32].
`The same holds true for COU-AA-301 and patients with an
`ECOG PS of 2. This, however, probably relates to insuffi-
`cient statistical power [34]. Therefore enzalutamide and
`abiraterone should be considered in chemo-naı¨ve patients
`with poor PS even more since they are better tolerated than
`chemotherapy.
`In both AFFIRM and COU-AA-301,
`patients with significant pain also derived a clear benefit and
`had a significantly reduced HR (0.71; 95 % CI 0.54–0.94
`and 0.78 95 % CI 0.63–0.96, respectively) [32, 34].
`Regarding patients with visceral disease, both in PRE-
`VAIL and in AFFIRM the HRs were favourable (HR 0.82;
`95 % CI 0.55–1.23 and HR 0.78; 95 % CI 0.56–1.09,
`respectively) but did not reach statistical significance [6,
`
`32], with the lack of statistical power being the most
`probable reason for this as only 214 and 278 patients,
`respectively, had liver or lung disease. In COU-AA-301
`trial the beneficial effect of abiraterone in the subset with
`visceral disease (352 patients out of 1195) reached statis-
`tical significance at the first interim analysis [13] (HR 0.70;
`95 % CI 0.52–0.94) but not at the final analysis [34], and
`was confirmed in a separate post hoc analysis [39].
`Therefore, use of abiraterone or enzalutamide for the
`treatment of patients with visceral disease in the pre-
`chemotherapy setting is supported by the data overall.
`
`5 Enzalutamide and Abiraterone versus Docetaxel
`as First Option After Castration
`
`Physicians have tended to treat patients with poor prog-
`nostic parameters with chemotherapy, considering it as
`more ‘active’ based on the fact that these patients were
`excluded from the pre-chemotherapy trials of enzalutamide
`and abiraterone. Nevertheless, looking into the docetaxel
`versus mitoxantrone trial TAX-327, it becomes evident that
`docetaxel is not an ideal option in this subset either: The
`survival curves of both arms were overlapping in the first 6
`months, indicating that patients with a life expectancy of
`\6 months did not derive significant benefit. Patients with
`pain, a Karnofsky performance status B80 % or visceral
`disease, however, still had a favourable HR compared to
`the mitoxantrone arm [40].
`In addition, there is a prevalent concept that docetaxel
`being a cytotoxic drug can act ‘faster’ compared to hor-
`monal treatments. Time to palliation of symptoms can be
`used to compare speed of effect onset. In TAX-327 patients
`with pain had a median time to pain response of 27 days
`[41], whereas it was 5.6 months in COU-AA-301 [37]. The
`true meaning of such post hoc comparisons is uncertain.
`Further studies are needed to elucidate how to best
`sequence these drugs.
`Emerging data from the CHAARTED trial in patients
`with non-castrate metastatic prostate cancer
`(nCMPC)
`comparing docetaxel together with androgen deprivation
`therapy (ADT) versus ADT alone and the STAMPEDE
`trial comparing standard of care versus standard of care
`plus docetaxel in hormone-sensitive locally advanced and
`metastatic PCa suggest
`that patients treated early with
`docetaxel derive significant survival benefit [42, 43]. A
`smaller trial, GETUG-AFU 15, however, did not show any
`OS survival benefit from adding docetaxel to castration in
`this population [44]. In CHAARTED the mOS for the
`experimental arm was 57.6 months versus 44 months for
`the control arm, with a HR of 0.61 (95 % CI 0.47–0.80)
`and an absolute gain of 13.6 months of mOS. In STAM-
`PEDE the mOS for the ADT plus docetaxel arm was
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`77 months compared to 67 for the control arm (HR 0.76;
`95 % CI 0.63–0.91). The reported benefits in absolute OS
`were impressive, surpassing any previous experience in
`mCRPC, but the HRs were not much different from what
`was previously described for AFFIRM (0.63), PREVAIL
`(0.70), COU-AA-301 (0.74), COU-AA-302 (0.52) and
`TAX-327 (0.76). It therefore seems reasonable to suggest
`that the reason for this big difference in absolute OS is that
`the improved HR for death is acting over a longer period of
`time, from castration to even beyond discontinuation of
`docetaxel, resulting in an increased cumulative absolute
`survival benefit. It remains to be seen whether the use of
`abiraterone and/or enzalutamide for hormone-sensitive
`metastatic disease can generate this degree of benefit.
`Extrapolating this hypothesis, it could be assumed that
`initiating treatment with docetaxel immediately after cas-
`tration resistance arises and reserving abiraterone or
`enzalutamide for later use might result in longer OS rather
`than following the opposite approach. Nevertheless, a ret-
`rospective series reporting on 198 patients, compared OS
`from the time point of first treatment initiation after the
`development of castration resistance to death in patients
`who received after castration resistance abiraterone first
`and then docetaxel versus patients who received first doc-
`etaxel and subsequently abiraterone. This study reported a
`trend in favour of abiraterone being administered first but
`this did not reach statistical significance [45]. Another
`retrospective study exploring the same question in 58
`patients also could not find a difference [46]. These studies
`are limited by their retrospective nature, but indicate that
`the above-described hypothesis might not be correct. A
`retrospective trial is needed to provide robust evidence.
`
`6 Sequencing Enzalutamide and Abiraterone
`
`It was thought initially that using abiraterone and enzalu-
`tamide sequentially might offer benefit as they act at dif-
`ferent sites in the AR pathway. Several retrospective
`studies show only limited activity of enzalutamide post
`abiraterone with [50 % PSA responses ranging between
`12 and 28 % and mPFS of approximately 3–4 months
`(Table 1). Nevertheless, patients who do experience a PSA
`response also have improved OS [47]. Abiraterone post
`enzalutamide was investigated in fewer studies with
`response rates varying between 10 and 18 % and a short
`time to progression [71, 72]. In view of this limited
`activity, sequential treatment should not be considered as a
`standard option in mCRPC, as delaying another active
`treatment might prove detrimental, especially in rapidly
`progressing patients. Recent work has also suggested that
`patients with CTCs expressing the AR splice variant AR-
`v7, a ligand-independent splice variant lacking the ligand
`
`binding domain, are unlikely to respond to subsequent
`treatment with abiraterone or enzalutamide; patients with
`CTCs not expressing AR-v7 had a PSA response rate of
`50 % with enzalutamide and 68 % with abiraterone [48].
`This finding certainly needs to be verified in larger studies,
`but use of such predictive biomarkers to identify respon-
`ders will enable informed sequential treatment with abi-
`raterone or enzalutamide and provide for some patients
`extra months of life of good quality. Trials regarding
`sequential use and combinations of abiraterone and enza-
`lutamide are ongoing (NCT02125357, NCT02116582 and
`NCT02268175), but if ligand-independent AR splice vari-
`ants are confirmed to be a major factor for resistance to
`these drugs, we should not anticipate major improvements
`of OS in unselected patients with sequential or combined
`strategies.
`
`7 Toxicity and Choice of Drug
`
`Enzalutamide and abiraterone appear largely equivalent in
`activity but their different toxicity profiles may guide the
`physician’s choice. Abiraterone is infrequently associated
`with hyperaldosteronism due to an excess of mineralocor-
`ticoids. This is usually mitigated by suppressing the ACTH
`axis by coadministration of corticosteroids or through the
`use of mineralocorticoid receptor antagonists like epler-
`enone. Spironolactone should be avoided since this can
`activate wildtype AR signalling [49]. Patients receiving
`abiraterone can therefore be exposed to the side effects of
`protracted corticosteroid use such as osteoporosis, glau-
`coma, diabetes, insulin tolerance or Cushing’s syndrome
`[50–52]. Enzalutamide is associated with fatigue, head-
`ache, diarrhoea, musculoskeletal pain and cognitive
`impairment, and has been described to cause convulsions
`as a dose-limiting toxicity in phase I trials and in \1 % of
`patients in phase III trials [32, 53]. Isolated cases of pos-
`terior reversible encephalopathy have also been described
`in association with enzalutamide [54]. Based on the side-
`effect profile, patients with uncontrolled hypertension,
`diabetes or contraindications to steroids should be dis-
`couraged from using abiraterone. On the other hand
`enzalutamide should be avoided in patients with conditions
`predisposing to seizures or central nervous
`system
`disorders.
`
`8 Other Treatment Options: Alpharadin
`and Sipuleucel-T
`
`treatment options have gained regulatory
`Two other
`approval: Radium-223 and Sipuleucel-T. 223RaCl2 is a
`calcium mimetic selectively deposited in bone stroma,
`
`

`
`Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting
`
`425
`
`Table 1 Studies evaluating sequential treatment with enzalutamide and abiraterone
`
`n
`
`Prior
`docetaxel
`
`Endpoint
`
`Response
`rate (%)
`
`mPFS
`
`Enzalutamide post abiraterone
`
`Schrader et al. [64]
`
`Bianchini et al. [65]
`
`Thomsen et al. [66]
`
`Badrising et al. [67]
`
`Azad et al. [68]
`
`35
`
`39
`
`24
`
`61
`
`68
`
`47
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`No
`
`[50 % PSA decline
`
`C30 % decline in PSA
`confirmed after C4 weeks
`
`C50 % decline in PSA
`confirmed after C4 weeks
`
`[30 % PSA decline
`
`C30 % decline in PSA
`confirmed after C4 weeks
`
`C50 % decline in PSA
`confirmed after C4 weeks
`
`C50 % decline in PSA
`confirmed after C3 weeks
`
`C50 % decline in PSA
`confirmed after C3 weeks
`
`C50 % decline in PSA
`
`29
`
`41
`
`13
`
`46
`
`46
`
`21
`
`22
`
`25
`
`34
`
`NA
`
`2.8 mo (PSA, radiological
`or clinical)
`
`NA
`
`12 wks (radiological)
`
`4.6 mo (radiological or
`clinical)
`
`6.6 mo (radiological or
`clinical)
`
`Suzman et al. [69]
`
`30
`
`Brasso et al. [47]
`
`137
`
`Yes
`
`Cheng et al. [70]
`
`79
`
`No
`
`165
`
`Yes
`
`Schmid et al. [73]
`
`35
`
`Abiraterone post enzalutamide
`
`Noonan et al. [71]
`
`Loriot et al. [72]
`
`30
`
`38
`
`Yes
`
`Yes
`
`Yes
`
`Unconfirmed [30 % PSA
`decline
`
`Unconfirmed [50 % PSA
`decline
`
`C30 % PSA decline
`
`C50 % PSA decline
`
`C30 % PSA decline
`
`C50 % PSA decline
`
`C50 % PSA decline
`
`C30 % PSA decline
`
`C50 % decline in PSA
`confirmed after C4 weeks
`
`C30 % PSA decline
`
`38
`
`18
`
`28
`
`18
`
`24
`
`17
`
`10
`
`10
`
`8
`
`18
`
`4.7 mo (radiolological or
`clinical)
`
`3.1 mo (radiological)
`
`4.0 mo (PSA only)
`
`2.8 mo (PSA only)
`
`3.1 mo (radiological)
`
`15.4 wks (PSA, radiological
`or clinical)
`
`2.7 mo (PSA, radiological
`or clinical)
`
`PSA prostate-specific antigen, NA not available, mo months
`
`where it emits a particles. These induce DNA double-
`strand breaks [55, 56] but have a short penetration range
`(\100 lm; 2–10 cell diameters) and cause minimal effects
`in the surrounding bone marrow [55, 57]. ALSYMPCA
`compared six injections of 223RACl2 every 4 weeks to
`placebo in 922 symptomatic patients with mCRPC without
`visceral metastases, who may not have had prior docetaxel
`but had at least two bone metastases on bone scan; nodal
`disease had to be no larger than 3 cm in short axis [58].
`The study showed a significantly improved mOS of 14
`versus 11.2 months in the placebo arm [27]. Skeletal-re-
`lated events (SREs) were lower and time to first SRE was
`significantly delayed in the 223RACl2 arm. The toxicity
`profile of 223RACl2 was favourable, with low rates of grade
`3 and 4 neutropenia, thrombocytopenia and diarrhoea.
`
`Because 223Ra is acting over a short distance it might
`have more impact when employed at an earlier stage when
`the disease is less likely to have extraosseous metastatic
`sites or to have developed soft tissue emanating from the
`bone lesions; indeed, trials testing this in asymptomatic
`patients are already recruiting (NCT02043678), but from
`the subset analysis of ALSYMPCA the opposite seems to
`hold: Patients with less than six metastatic sites in the
`bones seem to derive less benefit [27].
`Sipuleucel-T consists of peripheral blood mononuclear
`cells obtained through leukapheresis from each patient and
`cultured in vitro for 2–3 days with a fusion protein of pro-
`static acid phosphatase (PAP) and granulocyte–macrophage
`colony-stimulating factor, supposed to be inducing an
`immune response to PAP-expressing PCa cells once the cells
`
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`are re-infused [59]. It was approved by the US Food and Drug
`Administration (FDA) based on the IMPACT trial [50],
`which randomised 512 mainly chemotherapy-naı¨ve patients
`with asymptomatic or minimally symptomatic mCRPC and
`no visceral metastases to leukapheresis and subsequently to
`three bi-weekly infusions of either the processed cells or to
`reinfusion of part of the leukapheresed cells after processing
`and removal of the majority of them for future use. It
`demonstrated a statistically significant improvement in OS
`by 4.1 months but without any difference in time to objective
`disease progression and hardly any PSA responses. Usually
`clinical benefit is associated with some degree of PSA or
`radiological response [60], but immunotherapy does not
`necessarily follow the pattern of classical treatments [61].
`Concerns have been raised whether the observed difference
`in OS reflects a true survival benefit as patients [65 years
`had a substantially decreased OS in the control arm, poten-
`tially related to a detrimental effect of the leukapheresis
`procedures in elderly patients. This probably created the
`false impression of survival benefit when compared to the
`experimental arm [62]. Patients aged\65 years did not seem
`to have obtained any benefit. Therefore, currently there are
`insufficient data to recommend treatment with Sipuleucel-T.
`In any case, the complex administration and treatment costs
`have limited its clinical utilization, and in Europe autho-
`rization was withdrawn upon request of the company.
`
`9 Future Options
`
`Several trials are currently testing new and older agents in
`different settings. Abiraterone, enzalutamide and ARN-509,
`another second generation antiandrogen with an identical
`mechanism of action to enzalutamide [63], are being tested
`in a variety of sequences and combinations even with cyto-
`toxic, immunotherapeutic (PROSTVAC, NCT01867333) or
`targeted agents. These trials may provide further clues to the
`optimum sequence and timing of these treatments and also
`new predictive biomarkers to allow informed selection of
`patients. The era of molecularly stratified therapy is also
`being inaugurated by the results of next-generation
`sequencing of mCRPC tissue: 90 % harbour potentially
`actionable mutations and 30 % have mutations in genes
`involved in DNA repair pathways including BRCA2 and
`ATM [7]. Mutations in these genes were found to be enriched
`in the responders of a cohort treated with olaparib [64],
`confirming that even in mCRPC PARP (poly ADP ribose
`polymerase) inhibition and defects in homologous recom-
`bination are synthetically lethal [65, 66].
`
`10 Conclusions
`
`The treatment of mCRPC is changing rapidly but many
`questions remain regarding the optimal sequencing of the
`available drugs. In the chemotherapy-naı¨ve setting both
`abiraterone and enzalutamide appear equivalent, and are
`now established first options for minimally symptomatic or
`asymptomatic patients. Extrapolating data available from
`post-chemotherapy trials, we believe that both have effi-
`cacy in chemotherapy-naı¨ve patients with poorer prog-
`nostic features including the presence of visceral disease.
`Further trials dedicated to this group are warranted since
`chemotherapy for these patients may not impart major
`benefit. Sequential or combination use of the next gener-
`ation hormonal agents abiraterone and enzalutamide cannot
`currently be recommended. Prospective trials are warranted
`to further
`inform these decisions. Recent findings in
`metastatic hormone-naı¨ve patients are likely to shift the use
`of chemotherapy to earlier stages of the disease. The use of
`Sipuleucel-T remains controversial and cannot be currently
`recommended. Alpharadin should probably be best given
`earlier in the course of the disease, before patients develop
`extraosseous disease, although this is also clearly effective
`in later stages of the disease. The repertoire of treatments
`for mCRPC is continuing to expand and new agents such as
`the PARP inhibitor olaparib are inaugurating the era of
`targeted treatments. New effective treatments in the near
`future, along with validated predictive biomarkers, will
`probably render discussions of sequencing of the existing
`ones obsolete.
`
`Acknowledgements Professor de Bono’s team acknowledges sup-
`port from Cancer Research UK, Prostate Cancer UK, Movember,
`Department of Defense, a Stand Up To Cancer—Prostate Cancer
`Foundation ‘Prostate Cancer Dream Team’ Translational Cancer
`Research Grant, an Experimental Cancer Medicine Center grant and
`the National Institute for Health Research Biomedical Research
`Center.
`
`Compliance with Ethical Standards
`
`JdB is an employee of the ICR which has a
`Conflict of interest
`commercial interest in abiraterone acetate, PARP inhibitors in BRCA
`cancers, Pi3K and AKT inhibitors. JbB has served as a consultant for
`AstraZeneca, Astellas, Genentech, GSK, Janssen, Sanofi Aventis. ZZ,
`AJ and AS declare that they have no conflicts of interest.
`
`Appendix
`
`See Table.
`
`

`
`Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting
`
`427
`
`Clinical trials
`
`NCT Number Official Title
`
`NCT00638690 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus
`Prednisone in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Failed Docetaxel-
`Based Chemotherapy
`
`NCT00887198 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus
`Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration Resistant
`Prostate Cancer
`
`NCT00974311 A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of
`Oral MDV3100 in Patients With Progressive Castration Resistant Prostate Cancer Previously Treated
`With Docetaxel-Based Chemotherapy
`
`NCT01212991 A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of
`Oral MDV3100 in Chemotherapy- Naı¨ve Patients With Progressive Metastatic Prostate Cancer Who
`Have Failed Androgen Deprivation Therapy
`
`Trial Name
`
`COU-AA-301
`
`COU-AA-302
`
`AFFIRM
`
`PREVAIL
`
`NCT00309985 Chemo-Hormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate
`Cancer
`
`CHAARTED
`
`NCT00268476 Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy - Androgen
`Suppression-Based Therapy Alone or Combined With Zoledronic Acid, Docetaxel, Prednisolone,
`Celecoxib, Abiraterone, Enzalutamide and/or Radiotherapy in Treating Patients With Locally Advanced
`or Metastatic Prostate Cancer
`
`STAMPEDE
`
`NCT00104715 Randomized Phase III Trial Comparing an Association of Hormonal Treatment and Docetaxel Versus
`Hormonal Treatment Alone in Metastatic Prostate Cancers
`
`GETUG-AFU 15
`
`Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer
`
`NCT00699751 A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment
`of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases
`
`NCT00065442 A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Immunotherapy With Autologous
`Antigen Presenting Cells Loading With PA2024 (Provenge(R), APC8015) in Men With Metastatic
`Androgen Independent Prostatic Adenocarcinoma
`
`TAX-327
`
`ALSYMPCA
`
`IMPACT
`
`NCT01682772 A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer
`
`TOPARP
`
`NCT02125357 A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic
`Castration Resistant Prostate Cancer
`
`NCT02116582 A Multicenter, Single Arm Study of Enzalutamide in Patients With Progressive Metastatic Castration
`Resistant Prostate Cancer Previously Treated With Abiraterone Acetate
`
`NCT02268175 A Phase II Randomized Study of Enzalutamide ? Leuprolide Versus Enzalutamide ? Leuprolide ?
`Abiraterone Acetate ? Prednisone as Neoadjuvant Therapy for High-Risk Prostate Cancer Undergoing
`Prostatectomy
`
`NCT02043678 A Phase III Randomized, Double-Blind, Placebo-Controlled Trial of Radium-223 Dichloride in
`Combination With Abiraterone Acetate and Prednisone/Prednisolone in the Treatment of Asymptomatic
`or Mildly Symptomatic Chemotherapy-Naı¨ve Subjects With Bone Predominant Metastatic Castration
`Resistant Prostate Cancer
`
`NCT01867333 A Randomized Phase II Trial Combining Vaccine Therapy With PROSTVAC /TRICOM and Enzalutamide
`vs. Enzalutamide Alone in Men With Metastatic Castration Resistant Prostate Cancer
`
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