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

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Platinum Priority – Prostate CancerEditorial 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

Article history:

Accepted October 1, 2014

Keywords:

Prostate cancer

Dexamethasone

Prednisolone

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Abstract

Background: Prednisolone is widely used as secondary hormonal treatment for castra-tion-resistant prostate cancer (CRPC). We hypothesised that dexamethasone, anothercorticosteroid, 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 wasperformed in 82 men with chemotherapy-naıve CRPC enrolled from 2006 to 2010.Intervention: Prednisolone 5 mg twice daily versus dexamethasone 0.5 mg once dailyversus 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 PSAprogression, radiologic response rate using Response Evaluation Criteria In Solid Tumors(RECIST), and safety.Results and limitations: The intermittent dexamethasone arm was dropped after noresponse was seen in seven patients. By intention to treat, confirmed PSA response wasseen in 41% versus 22% for daily dexamethasone versus prednisolone, respectively( p = 0.08). In evaluable patients, the PSA response rates were 47% versus 24% fordexamethasone 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 responserate 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 the19 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 theabsence of more definitive trials, dexamethasone should be used in preference toprednisolone.Patient summary: We compared two different steroids used for treating men withadvanced prostate cancer. Our results suggest that dexamethasone may be moreeffective 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.

. Royal Marsden Hospital, Academic Urology Unit, Downs Road, Sutton, SM2661 3425; Fax: +44 020 8643 8809.

* Corresponding author5PT, UK. Tel. +44 020 8

E-mail address: chris.parke

http://dx.doi.org/10.1016/j.eururo.2014.10.0040302-2838/# 2014 European Association of Urology. Published by Elsevier

r@rmh.nhs.uk (C. Parker).

B.V. All rights reserved.

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 9674

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.

Table 1 – Clinical studies of corticosteroids in castration-resistant pro

Study Daily dose, mg n

Prednisolone

Berry et al [9] 10 60

Tannock et al [8] 10 81

Fossa et al [13] 20 50

de Bono et al [6] 10 398

Fossa et al [3] 20 101

Sternberg et al [7] 20 50

Sartor et al [14] 20 29

Ryan et al [10] 10 542

Dexamethasone

Nishimura et al [11] 0.5–2 37

Storlie et al [15] 1.5–2.25 38

Morioka et al [16] 1.5 27

Saika et al [16] 1.5 19

Venkitaraman et al [4] 0.5 102

Shamash et al [12] 2 135

PSA = prostate-specific antigen; TTPSA = time to prostate-specific antigen progres

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 naıve 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

state cancer

PSA response rate, % Median TTPSA progression, mo

24 4.1

22 -

26 4

16 6.6

21 3.4

9 2.5

33 2

24 5.6

62 9

61 8

59 5.4

28 7.3

50 7.4

50 8.1

sion.

Table 2 – Patient characteristics

Characteristics Dexamethasone Prednisolone

No. of patients 39 36

At diagnosis

Age, yr, median (range) 67 (55–82) 67 (51–82)

T stage, n

T1/2 9 7

T3/4 18 15

Not known 12 14

M stage, n

M0 19 25

M1 20 11

Gleason score, n

6 6 5

7 12 12

8–10 16 18

Missing 5 1

PSA, median (range) 34 (6.2–5000) 49 (5.9–4000)

At randomisation

Age, yr median (range) 74 (58–87) 73 (60–89)

Performance status, n

0 19 20

1 12 9

2 2 2

3 0 1

Time from first-line

hormone therapy, mo,

median (range)

50 (7–174) 39 (7–155)

PSA nadir on first-line

hormone therapy, ng/ml,

median (range)

1.1 (0–101) 0.8 (0–34)

Prior radical external beam

radiation therapy to

prostate, n

11 16

Metastatic sites, no.

Bone 27 22

Lymph node 18 14

Visceral 2 3

None 5 6

PSA, ng/ml, median (range) 22.1 (6.3–881) 48.5 (6.2–2397)

Haemoglobin, mg/dl,

median (range)

13.5 (8.5–16.1) 13.5 (8.5–16.1)

Alkaline phosphatase, U/l,

median (range)

77 (40–354) 84 (44–969)

Lactate dehydrogenase, U/l,

median (range)

161 (99–762) 161 (125–518)

Albumin, g/l, median (range) 37 (27–41) 38 (15–43)

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

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

detect this difference, use of the two-sided x2 test of equal proportions

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).

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.

[(Fig._1)TD$FIG]

100%(a)

(b)

80%

60%

40%

20%

0%

-20%

-40%

-60%

-80%

-100%

100%

80%

60%

40%

20%

0%

-20%

-40%

-60%

-80%

-100%

Per

cent

cha

nge

from

bas

elin

e to

nad

irP

erce

nt c

hang

e fro

m b

asel

ine

to n

adir

Continuous low dose dexamethasone

Continuous low dose dexamethasonePrednisolone

Prednisolone

Maximum PSA fall from baseline

Maximum PSA fall from baseline to 12 wk

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.

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 9676

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._2)TD$FIG]

Fig. 2 – Time to prostate-specific antigen progression.PSA = prostate-specific antigen.

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

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

[(Fig._3)TD$FIG]

Fig. 3 – Radiologic respon

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

se to dexamethasone.

Table 3 – Pain scores

Pain score Dexamethasone (n = 39) Prednisolone (n = 36)

Mean average pain score

Baseline 1.9 2.2

Week 6 1.6 1.4

Week 12 1.3 2.1

Week 18 1.0 1.9

Mean worst pain score

Baseline 2.4 2.8

Week 6 2.0 1.9

Week 12 1.5 2.6

Week 18 1.0 2.4

EQ-5D overall score *

Baseline 59 61

Week 6 73 69

Week 12 74 67

Week 18 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).

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 9678

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

Adverse event Dexamethasone(n = 39)

Prednisolone(n = 36)

Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4

Diarrhoea 0 0 5 0

Dyspepsia 3 0 4 0

Oedema 2 0 4 0

Fatigue 5 0 6 1

Genitourinary 2 2 8 3

Haematologic 2 0 2 0

Musculoskeletal 4 1 4 1

Neurologic 5 0 8 2

Pain 6 0 15 1

Respiratory 3 1 6 1

Weight gain 5 0 7 0

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.

Supervision: None.

Other (specify): None.

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

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