E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
`
`j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m
`
`Platinum Priority – Prostate Cancer
`Editorial by Camillo Porta, Sergio Bracarda and Romano Danesi on pp. 680–681 of this issue
`
`A Randomised Phase 2 Trial of Dexamethasone Versus
`Prednisolone in Castration-resistant Prostate Cancer
`
`Ramachandran Venkitaraman a, David Lorente b, Vedang Murthy c, Karen Thomas d,
`Lydia Parker b, Ruth Ahiabor b, David Dearnaley b, Robert Huddart b, Johann De Bono b,
`Chris Parker d,*
`
`a Ipswich Hospital NHS and University Campus Suffolk, Ipswich, UK; b Institute of Cancer Research, Sutton, UK; c Advanced Centre for Treatment Research and
`Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India; d Royal Marsden Hospital, Sutton, UK
`
`Article info
`
`Abstract
`
`Article history:
`Accepted October 1, 2014
`
`Keywords:
`Prostate cancer
`Dexamethasone
`Prednisolone
`
`Please visit
`www.eu-acme.org/
`europeanurology to read and
`answer questions on-line.
`The EU-ACME credits will
`then be attributed
`automatically.
`
`Background: Prednisolone is widely used as secondary hormonal treatment for castra-
`tion-resistant prostate cancer (CRPC). We hypothesised that dexamethasone, another
`corticosteroid, is more active.
`Objective: To compare the activity of prednisolone and dexamethasone in CRPC.
`Design, setting, and participants: This single-centre, randomised, phase 2 trial was
`performed in 82 men with chemotherapy-naı¨ve CRPC enrolled from 2006 to 2010.
`Intervention: Prednisolone 5 mg twice daily versus dexamethasone 0.5 mg once daily
`versus intermittent dexamethasone 8 mg twice daily on days 1–3 every 3 wk.
`Outcome measurements and statistical analysis: The main end point was prostate-
`specific antigen (PSA) response rate. Secondary end points included time to PSA
`progression, radiologic response rate using Response Evaluation Criteria In Solid Tumors
`(RECIST), and safety.
`Results and limitations: The intermittent dexamethasone arm was dropped after no
`response was seen in seven patients. By intention to treat, confirmed PSA response was
`seen in 41% versus 22% for daily dexamethasone versus prednisolone, respectively
`( p = 0.08). In evaluable patients, the PSA response rates were 47% versus 24% for
`dexamethasone and prednisolone, respectively ( p = 0.05). Median time to PSA progres-
`sion was 9.7 mo on dexamethasone versus 5.1 mo on prednisolone (hazard ratio: 1.6;
`95% confidence interval, 0.9–2.8). In 43 patients with measurable disease, the response
`rate by RECIST was 15% and 6% for dexamethasone and prednisolone, respectively
`( p = 0.6). Of 23 patients who crossed over at PSA progression on prednisolone, 7 of the
`19 evaluable (37%) had a confirmed PSA response to dexamethasone. Clinically signifi-
`cant toxicities were rare.
`Conclusions: Dexamethasone may be more active than prednisolone in CRPC. In the
`absence of more definitive trials, dexamethasone should be used in preference to
`prednisolone.
`Patient summary: We compared two different steroids used for treating men with
`advanced prostate cancer. Our results suggest that dexamethasone may be more
`effective than prednisolone and that both are well tolerated.
`Clinical trial registry: EUDRAC 2005-006018-16
`# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`* Corresponding author. Royal Marsden Hospital, Academic Urology Unit, Downs Road, Sutton, SM2
`5PT, UK. Tel. +44 020 8661 3425; Fax: +44 020 8643 8809.
`E-mail address: chris.parker@rmh.nhs.uk (C. Parker).
`
`http://dx.doi.org/10.1016/j.eururo.2014.10.004
`0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`Amerigen Exhibit 1132
`Amerigen v. Janssen IPR2016-00286
`
`

`
`674
`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`1.
`
`Introduction
`
`Prednisolone is widely used as secondary hormonal treat-
`ment for patients with castration-resistant prostate cancer
`(CRPC) [1]. Several corticosteroids, including hydrocortisone
`and dexamethasone, have also achieved favourable symp-
`tomatic, biochemical, and radiologic responses [2–4]. It has
`been assumed that corticosteroids are active in CRPC by
`suppression of adrenal androgen production. Hence, one
`would expect any corticosteroid that suppresses adrenocor-
`ticotrophic hormone (ACTH) to be equally effective [1]. Pred-
`nisolone is also used in combination with cytotoxic
`chemotherapy and with abiraterone to ameliorate the
`toxicities of treatment in patients with metastatic CRPC [5,6].
`Prednisolone has been reported in phase 2 studies to
`produce PSA response rates of 20–25% in patients with CRPC
`[3,7]. Numerous phase 3 randomised trials of systemic
`chemotherapy or hormonal therapy in CRPC have used
`prednisolone as the control intervention [5,7,8]. In these
`trials, the PSA response rate to prednisolone has ranged
`from 16% to 24%, and the median time to PSA progression
`has ranged from 2 mo to 6 mo [6–10]. The published activity
`data for prednisolone in CRPC are summarised in Table 1
`[3,4,6–17].
`Dexamethasone has been less well studied in the
`treatment of CRPC. Phase 2 studies of low-dose, daily
`dexamethasone have reported somewhat higher PSA re-
`sponse rates of 50–60%, with median time to PSA progression
`from 7 mo to 8 mo [4,11]. The two largest studies, including a
`combined total of 237 patients treated with dexamethasone
`as a single agent, both reported PSA response rates of around
`50% [4,12]. The published activity data for low-dose, daily
`dexamethasone in CRPC are summarised in Table 1.
`Dexamethasone has also been used intermittently at
`higher doses as a premedication and as an antiemetic in
`association with cytotoxic chemotherapy for CRPC [5]. It is
`unclear whether this intermittent use of dexamethasone
`contributes to the activity of chemotherapy for CRPC.
`Current clinical data suggest that dexamethasone may
`be more active than prednisolone in the treatment of CRPC.
`
`We conducted a randomised phase 2 trial comparing
`dexamethasone and prednisolone to explore this hypothe-
`sis. We initially tested two different dose schedules for
`dexamethasone, given the important possibility that
`intermittent dexamethasone might contribute to the
`activity of chemotherapy for CRPC.
`
`2.
`
`Methods
`
`We conducted a single-centre, randomised, open-label, phase 2 trial of
`
`daily prednisolone versus daily dexamethasone versus intermittent
`
`dexamethasone in patients with CRPC. Men with either histologically
`
`proven adenocarcinoma of the prostate or sclerotic bone metastases on
`
`imaging and a presenting PSA >100 ng/ml were eligible for inclusion.
`
`All patients had a baseline PSA >5 ng/ml, castrate levels of testosterone
`
`(<2 nmol/l) on androgen deprivation therapy with luteinising hormone-
`
`releasing hormone analogues or had had bilateral orchidectomy. They
`
`had progressive disease, defined as a rising PSA using three serum PSA
`
`measurements, each obtained at least 7 d apart within 3 mo prior to the
`
`start of the trial. In accordance with the UK National Institute for Health
`
`and Clinical Excellence prostate cancer guideline, patients typically
`
`received an antiandrogen as second-line hormone therapy. Patients who
`
`were withdrawn from antiandrogen therapy also required one PSA level
`
`higher than the last prewithdrawal PSA or two consecutive increases in
`
`PSA documented after the postwithdrawal nadir 4 wk from treatment
`
`withdrawal
`
`if treated with flutamide and 6 wk if treated with
`
`bicalutamide. Patients with progression of measurable disease Response
`
`Evaluation Criteria In Solid Tumors (RECIST) or progression of bone disease
`
`were also required to fit the criteria for PSA progression. Patients were
`chemotherapy naı¨ve and had not received prior abiraterone or enzalu-
`
`tamide. Eligibility also included life expectancy 3 mo, Eastern Coopera-
`
`tive Oncology Group (ECOG) performance status 0–3, and optimal
`
`analgesia. Exclusion criteria included external beam radiotherapy,
`
`brachytherapy, or cryotherapy within 4 wk prior to the start of the study,
`
`serious or uncontrolled coexistent nonmalignant disease, active or
`
`uncontrolled infection, a history of untreated peptic ulcer disease,
`
`inability to comply with pain scores and quality of life assessments,
`
`treatment with any investigational compound within 30 d, any previous
`
`treatment with corticosteroids for prostate cancer at any time, or any of
`
`the following treatment in the past 4 wk: antiandrogens, oestrogens,
`
`radioisotopes, or chemotherapy.
`
`All patients had baseline investigations including medical history,
`
`physical examination, ECOG performance status, serum PSA (within 7 d of
`
`Table 1 – Clinical studies of corticosteroids in castration-resistant prostate cancer
`
`Study
`
`Daily dose, mg
`
`Prednisolone
`Berry et al [9]
`Tannock et al [8]
`Fossa et al [13]
`de Bono et al [6]
`Fossa et al [3]
`Sternberg et al [7]
`Sartor et al [14]
`Ryan et al [10]
`Dexamethasone
`Nishimura et al [11]
`Storlie et al [15]
`Morioka et al [16]
`Saika et al [16]
`Venkitaraman et al [4]
`Shamash et al [12]
`
`10
`10
`20
`10
`20
`20
`20
`10
`
`0.5–2
`1.5–2.25
`1.5
`1.5
`0.5
`2
`
`n
`
`60
`81
`50
`398
`101
`50
`29
`542
`
`37
`38
`27
`19
`102
`135
`
`PSA = prostate-specific antigen; TTPSA = time to prostate-specific antigen progression.
`
`PSA response rate, %
`
`Median TTPSA progression, mo
`
`24
`22
`26
`16
`21
`9
`33
`24
`
`62
`61
`59
`28
`50
`50
`
`4.1
`-
`4
`6.6
`3.4
`2.5
`2
`5.6
`
`9
`8
`5.4
`7.3
`7.4
`8.1
`
`

`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`675
`
`randomisation), serum testosterone, and routine haematology and
`
`Table 2 – Patient characteristics
`
`biochemistry tests including urea, creatinine, potassium, sodium, alkaline
`
`phosphatase, and blood glucose. Baseline imaging comprised chest
`
`radiograph, computed tomography (CT) of abdomen and pelvis, and bone
`
`scan. Quality of life and pain assessment were performed within 7 d of
`
`randomisation with the EuroQol EQ-5D questionnaire, the Brief Pain
`
`Inventory (BPI) pain questionnaire, and an analgesic score.
`
`Patients were randomised in a 1:1:1 ratio among intermittent
`
`dexamethasone (8 mg twice daily for 3 d every 3 wk), daily dexametha-
`
`sone (0.5 mg once daily), and prednisolone (5 mg twice daily), to be
`
`continued until biochemical progression or unacceptable toxicity. All
`
`study drugs were administered orally. Patients who developed PSA
`
`progression on prednisolone were offered crossover to daily dexametha-
`
`sone. Assessments during the study were performed every 6 wk and
`
`included physical examination; toxicity assessment; ECOG performance
`
`status; serum PSA; haematology and biochemistry tests; and the EuroQol
`
`questionnaire, BPI, and analgesic score (week 6,12, and 18 only). In
`
`patients with measurable disease, CT scans of abdomen and pelvis were
`
`repeated every 12 wk until 36 wk to assess response by RECIST criteria.
`
`The primary end point was PSA response, defined as a 50% decline in
`
`serum PSA, confirmed at least 4 wk later. Secondary end points included
`
`time to PSA progression, objective response rate using RECIST criteria,
`
`safety, and tolerability. In PSA nonresponders, progression was defined
`
`as a 25% increase over the nadir value (provided the rise was a minimum
`
`of 5 ng/ml) and confirmed by a second value at least 1 wk later. In PSA
`
`responders, progression was defined as a 50% increase over the nadir
`
`value (provided the rise was a minimum of 5 ng/ml) and confirmed by a
`
`second value at least 1 wk later. The local National Health Service
`
`research ethics committee approved the study protocol, and all patients
`
`gave written informed consent.
`
`2.1.
`
`Statistical methods
`
`Assuming a PSA response rate for prednisolone of 20%, the study was
`
`powered to detect a PSA response rate of 60% in each experimental arm. To
`2 test of equal proportions
`detect this difference, use of the two-sided x
`required 28 patients per group with a two-sided a of 0.025 and 80% power.
`
`We planned to recruit 36 patients per group to ensure 28 evaluable
`
`patients. Univariate analysis of predictors of PSA response was done using
`
`binary logistic regression, with a p value <0.05 considered significant.
`
`Univariate analyses of predictors of time to PSA progression were also
`
`assessed by the Cox proportional hazards model. These statistical analyses
`
`used SPSS 14 (IBM Corp, Armonk, NY, USA).
`
`Characteristics
`
`Dexamethasone
`
`Prednisolone
`
`No. of patients
`At diagnosis
`Age, yr, median (range)
`T stage, n
`T1/2
`T3/4
`Not known
`M stage, n
`M0
`M1
`Gleason score, n
`6
`7
`8–10
`Missing
`PSA, median (range)
`At randomisation
`Age, yr median (range)
`Performance status, n
`0
`1
`2
`3
`Time from first-line
`hormone therapy, mo,
`median (range)
`PSA nadir on first-line
`hormone therapy, ng/ml,
`median (range)
`Prior radical external beam
`radiation therapy to
`prostate, n
`Metastatic sites, no.
`Bone
`Lymph node
`Visceral
`None
`PSA, ng/ml, median (range)
`Haemoglobin, mg/dl,
`median (range)
`Alkaline phosphatase, U/l,
`median (range)
`Lactate dehydrogenase, U/l,
`median (range)
`Albumin, g/l, median (range)
`
`39
`
`36
`
`67 (55–82)
`
`67 (51–82)
`
`9
`18
`12
`
`19
`20
`
`7
`15
`14
`
`25
`11
`
`6
`12
`16
`5
`34 (6.2–5000)
`
`5
`12
`18
`1
`49 (5.9–4000)
`
`74 (58–87)
`
`73 (60–89)
`
`19
`12
`2
`0
`50 (7–174)
`
`20
`9
`2
`1
`39 (7–155)
`
`1.1 (0–101)
`
`0.8 (0–34)
`
`11
`
`16
`
`27
`18
`2
`5
`22.1 (6.3–881)
`13.5 (8.5–16.1)
`
`22
`14
`3
`6
`48.5 (6.2–2397)
`13.5 (8.5–16.1)
`
`77 (40–354)
`
`84 (44–969)
`
`161 (99–762)
`
`161 (125–518)
`
`37 (27–41)
`
`38 (15–43)
`
`3.
`
`Results
`
`A total of 82 patients consented and were enrolled in the
`study between April 2006 and July 2010. All patients were
`followed up until PSA progression, death, or a minimum of
`11 mo. Thirty-nine patients were randomised to dexameth-
`asone 0.5 mg daily, 36 patients to prednisolone 5 mg twice
`daily, and 7 to intermittent dexamethasone. Randomisation
`to the intermittent dexamethasone arm was stopped early
`because of lack of antitumour activity. None of the seven
`patients achieved a PSA response, at which point recruit-
`ment to that arm of the trial was stopped. All results below
`are restricted to the 75 patients randomised to the other
`two arms of the trial. The demographics of the study
`population are given in Table 2.
`In the intent-to-treat analysis, PSA responses were seen
`in 16 of 39 patients (41%) in the dexamethasone arm
`compared with 8 of 36 (22%) in the prednisolone arm
`
`( p = 0.08). In those patients evaluable for PSA response (with
`at least two on-treatment PSA levels at least 1 wk apart), the
`response rates were 47% (16 of 34) for dexamethasone and
`24% (8 of 33) for prednisolone ( p = 0.05). Figure 1 shows a
`waterfall plot illustrating the maximum decline in PSA while
`on the study drug. On univariate analysis, PSA response was
`associated with lower baseline serum PSA level ( p = 0.004)
`and lower baseline alkaline phosphatase level ( p = 0.03).
`Median time to PSA progression was 9.7 mo (95%
`confidence interval [CI], 6.3–13.1 mo) for patients random-
`ised to dexamethasone versus 5.1 mo (95% CI, 1.8–8.3 mo)
`for prednisolone (hazard ratio: 1.6; 95% CI, 0.9–2.8) (Fig. 2).
`Of the 36 patients randomised to prednisolone, 23 patients
`crossed over to dexamethasone on biochemical disease
`progression. Of these, 19 patients were evaluable for PSA
`response assessment. Seven of the 19 (37%) achieved a PSA
`response to dexamethasone after previous PSA progression
`on prednisolone.
`
`

`
`676
`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`Maximum PSA fall from baseline
`
`Maximum PSA fall from baseline to 12 wk
`
`Continuous low dose dexamethasone
`Prednisolone
`
`Continuous low dose dexamethasone
`Prednisolone
`
`(a)
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`-20%
`
`-40%
`
`-60%
`
`-80%
`
`Percent change from baseline to nadir
`
`-100%
`
`100%
`
`(b)
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`-20%
`
`-40%
`
`-60%
`
`-80%
`
`-100%
`
`Percent change from baseline to nadir
`
`Fig. 1 – Maximum prostate-specific antigen decline by study drug (a) at any time on initial study drug treatment and (b) within the first 12 wk.
`PSA = prostate-specific antigen.
`
`A total of 43 patients had measurable disease at baseline.
`The objective response rates by RECIST criteria were 15%
`(3 of 20) and 6% (1 of 18)
`for dexamethasone and
`prednisolone, respectively ( p = 0.6). Figure 3 illustrates an
`objective response to dexamethasone. This patient, with a
`pretreatment PSA of 47 ng/ml, obtained a complete response
`to dexamethasone on CT scan and an undetectable PSA of
`<0.04 ng/ml. His serum PSA remains undetectable after
`treatment with dexamethasone for 44 mo.
`Thirteen patients in each treatment group were on
`analgesia at baseline. Pain scores, analgesic use, and EQ-5D
`health scores improved during study treatment, with no
`significant difference between treatments but with a trend
`for greater improvement in pain for dexamethasone rather
`than prednisolone (Table 3). Clinically significant toxicities
`were uncommon (Table 4). No significant difference was
`seen between the two study drugs with regard to safety and
`tolerability. Fifty-one patients were normoglycaemic at
`
`baseline. Of these, 14 of 25 on dexamethasone had at least
`one glucose level >6 mmol/l versus 20 of 26 on predniso-
`lone. Three patients on prednisolone versus none on
`dexamethasone had at least one random glucose level
`>12 mmol/l.
`
`4.
`
`Discussion
`
`This study is the only completed randomised comparison of
`different corticosteroids in CRPC. The results are consistent
`with the hypothesis that dexamethasone 0.5 mg daily is
`more active than prednisolone 10 mg daily in the treatment
`of CRPC. It is noteworthy that a significant proportion of
`patients (7 of 19, 36%) achieved a PSA response to
`dexamethasone after PSA progression on prednisolone.
`The data are in keeping with the previously reported
`activity of these agents in nonrandomised clinical trials of
`prednisolone and dexamethasone in CRPC (Table 1). In an
`
`[(Fig._1)TD$FIG]
`

`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`677
`
`Fig. 2 – Time to prostate-specific antigen progression.
`PSA = prostate-specific antigen.
`
`early study of abiraterone treated without concomitant
`steroids, the addition of dexamethasone on progression
`was capable of inducing PSA responses [18]. Recently, the
`change from prednisolone to dexamethasone in patients
`progressing on abiraterone showed PSA declines and RECIST
`responses after switching steroids [19].
`The current study has several limitations. Although it is
`the only randomised trial of corticosteroids in CRPC, it is a
`relatively small phase 2 trial lacking adequate statistical
`power to prove a real difference in activity between the two
`drugs. Although dexamethasone showed activity following
`disease progression on prednisolone, we cannot exclude
`the possibility that this represents a withdrawal response
`to stopping prednisolone. Patients did not cross over from
`
`dexamethasone to prednisolone, so we cannot comment on
`the activity of prednisolone after progression on dexa-
`methasone. No correlative studies were performed, so the
`current study does not provide any mechanistic insights to
`explain how dexamethasone might be more active than
`prednisolone.
`No responses were observed in the seven patients
`randomised to intermittent dexamethasone 8 mg twice
`daily for 3 d every 3 wk. This result is similar to data from
`Weitzman et al, who reported no biochemical responses in
`12 patients treated with dexamethasone 20 mg three times
`daily for 1 d every 3 wk [20]. These observations strongly
`suggest that intermittent dexamethasone used either as
`premedication or as an antiemetic does not contribute
`
`Fig. 3 – Radiologic response to dexamethasone.
`
`[(Fig._2)TD$FIG]
`[(Fig._3)TD$FIG]
`

`
`678
`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`Table 3 – Pain scores
`
`Pain score
`
`Dexamethasone (n = 39)
`
`Prednisolone (n = 36)
`
`Mean average pain score
`Baseline
`Week 6
`Week 12
`Week 18
`Mean worst pain score
`Baseline
`Week 6
`Week 12
`Week 18
`EQ-5D overall score *
`Baseline
`Week 6
`Week 12
`Week 18
`
`1.9
`1.6
`1.3
`1.0
`
`2.4
`2.0
`1.5
`1.0
`
`59
`73
`74
`67
`
`2.2
`1.4
`2.1
`1.9
`
`2.8
`1.9
`2.6
`2.4
`
`61
`69
`67
`70
`
`Patients were asked to score pain at its worst over the past 24 h and
`average pain by circling a whole number from 0 to 10, with 0 being no pain
`and 10 being worst imaginable pain.
`* EQ-5D overall heath state, measured on a visual analogue score from 0
`(worst) to 100 (best).
`
`significantly to the activity of chemotherapy for CRPC
`[11,21].
`The mechanism of action of corticosteroids in CRPC has
`generally been linked to their inhibition of the pituitary
`production of ACTH, leading to the reduced synthesis of
`adrenal androgens [22]. The longer half-life of dexametha-
`sone could produce a more effective suppression of ACTH
`than prednisolone, leading to higher antitumoural activity.
`Dexamethasone has also been reported to have an
`antiangiogenic effect on prostate cancer cell lines, mediated
`via the glucocorticoid receptor, leading to a reduction in
`vascular endothelial growth factor and interleukin-8
`expression [23] and has been shown to reduce expression
`of the androgen receptor (AR) [24].
`Paradoxically, concomitant steroid treatment has also
`been associated with the development of resistance to
`treatment in CRPC. Subgroup analyses of
`large trials
`evaluating abiraterone and enzalutamide have reported
`worse outcomes in patients treated with corticosteroids at
`baseline [25,26]. AR mutations that are activated by
`
`Table 4 – Most common adverse events
`
`prednisolone at levels present in the blood of CRPC patients
`treated with prednisolone 5 mg twice daily have been
`identified [27,28]. More recently, a role of the glucocorticoid
`receptor (GR) as regulator of AR-driven genes in situations of
`androgen deprivation has been proposed [29]. Increased
`expression of GR in cell lines and tissue of patients treated
`with enzalutamide was associated with resistance [30]. Pred-
`nisolone 5 mg twice daily, which represents a threefold
`higher equivalent corticosteroid dose than that of dexameth-
`asone 0.5 mg once daily, could be more prone to activate a
`mutated AR or a promiscuous GR and thus induce disease
`progression. This hypothesis could also explain secondary
`responses to dexamethasone after progression to predniso-
`lone as ‘‘withdrawal responses’’ with a similar mechanism to
`that described in first-generation antiandrogens [31].
`
`5.
`
`Conclusions
`
`Taken together with the previous data on prednisolone and
`dexamethasone in CRPC, our study challenges current clinical
`practice. The justification for prednisolone as the cortico-
`steroid of choice for CRPC should now be questioned, given
`these data indicating higher antitumor activity for dexa-
`methasone. In the absence of definitive clinical trial data, we
`believe that dexamethasone 0.5 mg daily should be regarded
`as standard for patients with CRPC who require corticoster-
`oid monotherapy. Given that abiraterone, docetaxel, and
`cabazitaxel are all approved for use in CRPC in combination
`with prednisolone, future studies should explore the use of
`dexamethasone in combination with these agents.
`
`Author contributions: Chris Parker had full access to all the data in the
`
`study and takes responsibility for the integrity of the data and the
`
`accuracy of the data analysis.
`
`Study concept and design: C. Parker, De Bono, Dearnaley, Venkitaraman,
`
`Murthy.
`
`Acquisition of data: C. Parker, Dearnaley, Huddart, Venkitaraman, Murthy,
`
`Ahiabor, L. Parker.
`
`Analysis and interpretation of data: C. Parker, Dearnaley, Huddart,
`
`Thomas, Lorente, De Bono.
`
`Drafting of the manuscript: Venkitaraman, C. Parker.
`
`Critical revision of the manuscript for important intellectual content:
`
`Venkitaraman, Lorente, Murthy, Ahiabor, L. Parker, Thomas, Dearnaley,
`
`Huddart, De Bono, C. Parker.
`
`Statistical analysis: Thomas.
`
`Obtaining funding: C. Parker.
`
`Administrative, technical, or material support: None.
`
`Adverse event
`
`Dexamethasone
`(n = 39)
`
`Prednisolone
`(n = 36)
`
`Supervision: None.
`
`Other (specify): None.
`
`Grade 1/2
`
`Grade 3/4
`
`Grade 1/2
`
`Grade 3/4
`
`Diarrhoea
`Dyspepsia
`Oedema
`Fatigue
`Genitourinary
`Haematologic
`Musculoskeletal
`Neurologic
`Pain
`Respiratory
`Weight gain
`
`0
`3
`2
`5
`2
`2
`4
`5
`6
`3
`5
`
`0
`0
`0
`0
`2
`0
`1
`0
`0
`1
`0
`
`5
`4
`4
`6
`8
`2
`4
`8
`15
`6
`7
`
`0
`0
`0
`1
`3
`0
`1
`2
`1
`1
`0
`
`Financial disclosures: Chris Parker certifies that all conflicts of interest,
`
`including specific financial interests and relationships and affiliations
`
`relevant to the subject matter or materials discussed in the manuscript
`
`(eg, employment/affiliation, grants or funding, consultancies, honoraria,
`
`stock ownership or options, expert testimony, royalties, or patents filed,
`
`received, or pending), are the following: None.
`
`Funding/Support and role of the sponsor: This study was funded by the
`
`Prostate Cancer Support Organisation and supported by the National
`
`Institute for Health Research Royal Marsden and Institute for Cancer
`
`Research Biomedical Research Centre. The sponsors were involved in the
`
`design and conduct of the study.
`
`

`
`E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 6 7 3 – 6 7 9
`
`679
`
`References
`
`[16] Morioka M, Kobayashi T, Furukawa Y, et al. Prostate-specific antigen
`
`levels and prognosis in patients with hormone-refractory prostate
`
`[1] Khandwala HM, Vassilopoulou-Sellin R, Logethetis CJ, Friend KE.
`
`cancer treated with low-dose dexamethasone. Urol Int 2002;68:10–5.
`
`Corticosteroid-induced inhibition of adrenal androgen production
`
`[17] Saika T, Kusaka N, Tsushima T, et al. Okayama Urological Cancer
`
`in selected patients with prostate cancer. Endocr Pract 2001;7:
`
`Collaborating Group. Treatment of androgen-independent prostate
`
`11–5.
`
`cancer with dexamethasone: a prospective study in stage D2
`
`[2] Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L,
`
`patients. Int J Urol 2001;8:290–4.
`
`Rider W. Treatment of metastatic prostatic cancer with low-dose
`
`[18] Attard G, Reid AHM, de Bono JS. Abiraterone acetate is well toler-
`
`prednisone: evaluation of pain and quality of life as pragmatic
`
`ated without concomitant use of corticosteroids. J Clin Oncol
`
`indices of response. J Clin Oncol 1989;7:590–7.
`
`2010;28:e560–1, author reply e562.
`
`[3] Fossa˚ SD, Slee PH, Brausi M, et al. Flutamide versus prednisone in
`
`[19] Lorente D, Weatherstone K, Omlin A, et al. Tumor responses after
`
`patients with prostate cancer symptomatically progressing after
`
`steroid switch of prednisolone (P) to dexamethasone (D) in castra-
`
`androgen-ablative therapy: a phase III study of the European
`
`tion-resistant prostate cancer (CRPC) patients (pts) on abiraterone
`
`organization for research and treatment of cancer genitourinary
`
`acetate (AA) [abstract 2918]. Eur J Cancer 2013:49.
`
`group. J Clin Oncol 2001;19:62–71.
`
`[20] Weitzman AL, Shelton G, Zuech N, et al. Dexamethasone does not
`
`[4] Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP,
`
`significantly contribute to the response rate of docetaxel and estra-
`
`Parker CC. Efficacy of low-dose dexamethasone in castration-re-
`
`mustine in androgen independent prostate cancer. J Urol 2000;163:
`
`fractory prostate cancer. BJU Int 2008;101:440–3.
`
`834–7.
`
`[5] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
`
`[21] Dorff TB, Crawford ED. Management and challenges of corticoster-
`
`mitoxantrone plus prednisone for advanced prostate cancer. N Engl
`
`oid therapy in men with metastatic castrate-resistant prostate
`
`J Med 2004;351:1502–12.
`
`cancer. Ann Oncol 2013;24:31–8.
`
`[6] De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased
`
`[22] Eichholz A, Ferraldeschi R, Attard G, de Bono JS. Putting the brakes
`
`survival in metastatic prostate cancer. N Engl J Med 2011;364:
`
`on continued androgen receptor signaling in castration-resistant
`
`1995–2005.
`
`prostate cancer. Mol Cell Endocrinol 2012;360:68–75.
`
`[7] Sternberg CN, Whelan P, Hetherington J, et al. Phase III trial of
`
`[23] Yano A, Fujii Y, Iwai A, Kageyama Y, Kihara K. Glucocorticoids
`
`satraplatin, an oral platinum plus prednisone vs. prednisone alone
`
`suppress tumor angiogenesis and in vivo growth of prostate cancer
`
`in patients with hormone-refractory prostate cancer. Oncology
`
`cells. Clin Cancer Res 2006;12:3003–9.
`
`2005;68:2–9.
`
`[24] Nishimura K, Nonomura N, Satoh E, et al. Potential mechanism for
`
`[8] Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitox-
`
`the effects of dexamethasone on growth of androgen-independent
`
`antrone plus prednisone or prednisone alone for symptomatic
`
`prostate cancer. J Natl Cancer Inst 2001;93:1739–46.
`
`hormone-resistant prostate cancer: a Canadian randomized trial
`
`[25] Montgomery RB, Kheoh TS, Molina A, et al. Effect of corticosteroid
`
`with palliative end points. J Clin Oncol 1996;14:1756–64.
`
`(CS) use at baseline (CUB) on overall survival (OS) in patients (pts)
`
`[9] Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study
`
`receiving abiraterone acetate (AA): Results from a randomized
`
`of mitoxantrone plus low dose prednisone versus low dose predni-
`
`study (COU-AA-301) in metastatic castration-resistant prostate
`
`sone alone in patients with asymptomatic hormone refractory
`
`cancer (mCRPC) post-docetaxel (D) [abstract 5014]. J Clin Oncol
`
`prostate cancer. J Urol 2002;168:2439–43.
`
`2013;31(Suppl).
`
`[10] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic
`
`[26] Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid
`
`prostate cancer without previous chemotherapy. N Engl J Med
`
`use on efficacy and safety in the phase III AFFIRM study of enza-
`
`2013;368:138–48.
`
`lutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin
`
`[11] Nishimura K, Nonomura N, Yasunaga Y, et al. Low doses of oral
`
`Oncol 2013;31(Suppl).
`
`dexamethasone for hormone-refractory prostate carcinoma. Can-
`
`[27] Zhao XY, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote
`
`cer 2000;89:2570–6.
`
`androgen-independent growth of prostate cancer cells through a
`
`[12] Shamash J, Powles T, Sarker SJ, et al. A multi-centre randomised
`
`mutated androgen receptor. Nat Med 2000;6:703–6.
`
`phase III trial of dexamethasone vs dexamethasone and diethyl-
`
`[28] Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone,
`
`stilbestrol in castration-resistant prostate cancer: immediate vs
`
`eplerenone, and prednisolone with wild-type and mutant androgen
`
`deferred diethylstilbestrol. Br J Cancer 2011;104:620–8.
`[13] Fossa˚ SD, Jacobsen A-B, Ginman C, et al. Weekly docetaxel and
`
`receptor: a rationale for increasing abiraterone exposure or com-
`
`bining with MDV3100. Cancer Res 2012;72:2176–82.
`
`prednisolone versus prednisolone alone in androgen-independent
`
`[29] Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique
`
`prostate cancer: a randomized phase II study. Eur Urol 2007;52:
`
`androgen and glucocorticoid receptor binding events in prostate
`
`1691–9.
`
`cancer cells. Cancer Res 2013;73:1570–80.
`
`[14] Sartor O, Weinberger M, Moore A, Li A, Figg WD. Effect of predni-
`
`[30] Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor
`
`sone on prostate-specific antigen in patients with hormone-refrac-
`
`confers resistance to antiandrogens by bypassing androgen recep-
`
`tory prostate cancer. Urology 1998;52:252–6.
`
`tor blockade. Cell 2013;155:1309–22.
`
`[15] Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC,
`
`[31] Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal
`
`Richardson RL. Prostate specific antigen levels and clinical response
`
`alone or in combination with ketoconazole in androgen-indepen-
`
`to low dose dexamethasone for hormone-refractory metastatic
`
`dent prostate cancer patients: a phase III trial (CALGB 9583). J Clin
`
`prostate carcinoma. Cancer 1995;76:96–100.
`
`Oncol 2004;22:1025–33.