URO ONCO

Welcome, this website is intended for all international healthcare professionals in uro-oncology. By clicking the link below you are declaring and confirming that you are a healthcare professional.

You are here

A Randomised Phase 2 Trial of Dexamethasone Versus Prednisolone in Castration-resistant Prostate Cancer

European Urology 2015 Apr;67(4):673-9

Comment from Henk van der Poel: Continuous but not intermittent dexamethasone was superior to prednisolone in men with prechemotherapy CRPC. With double the PSA response rate and almost double the time to PSA progression for dexamethasone daily, but RECIST responses were less than 15% for both regiments.

Abstract

Background

Prednisolone is widely used as secondary hormonal treatment for castration-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-naïve 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 progression 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 significant 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

Take Home Message

Dexamethasone 0.5 mg daily should be standard for patients with castration-resistant prostate cancer who require corticosteroid monotherapy. Given that abiraterone, docetaxel, and cabazitaxel are all approved in combination with prednisolone, future studies should explore the use of dexamethasone in combination with these agents.

Keywords: Prostate cancer, Dexamethasone, Prednisolone.

1. Introduction

Prednisolone is widely used as secondary hormonal treatment for patients with castration-resistant prostate cancer (CRPC) [1] . Several corticosteroids, including hydrocortisone and dexamethasone, have also achieved favourable symptomatic, biochemical, and radiologic responses[2], [3], and [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 adrenocorticotrophic hormone (ACTH) to be equally effective [1] . Prednisolone is also used in combination with cytotoxic chemotherapy and with abiraterone to ameliorate the toxicities of treatment in patients with metastatic CRPC[5] and [6].

Prednisolone has been reported in phase 2 studies to produce PSA response rates of 20–25% in patients with CRPC[3] and [7]. Numerous phase 3 randomised trials of systemic chemotherapy or hormonal therapy in CRPC have used prednisolone as the control intervention[5], [7], and [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], [7], [8], [9], and [10]. The published activity data for prednisolone in CRPC are summarised in Table 1 [3], [4], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], and [17].

Table 1 Clinical studies of corticosteroids in castration-resistant prostate cancer

Study Daily dose, mg n PSA response rate, % Median TTPSA progression, mo
Prednisolone
 Berry et al [9] 10 60 24 4.1
 Tannock et al [8] 10 81 22 -
 Fossa et al [13] 20 50 26 4
 de Bono et al [6] 10 398 16 6.6
 Fossa et al [3] 20 101 21 3.4
 Sternberg et al [7] 20 50 9 2.5
 Sartor et al [14] 20 29 33 2
 Ryan et al [10] 10 542 24 5.6
Dexamethasone
 Nishimura et al [11] 0.5–2 37 62 9
 Storlie et al [15] 1.5–2.25 38 61 8
 Morioka et al [16] 1.5 27 59 5.4
 Saika et al [16] 1.5 19 28 7.3
 Venkitaraman et al [4] 0.5 102 50 7.4
 Shamash et al [12] 2 135 50 8.1

PSA = prostate-specific antigen; TTPSA = time to prostate-specific antigen progression.

Dexamethasone has been less well studied in the treatment of CRPC. Phase 2 studies of low-dose, daily dexamethasone have reported somewhat higher PSA response rates of 50–60%, with median time to PSA progression from 7 mo to 8 mo[4] and [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] and [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 hypothesis. 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 naïve and had not received prior abiraterone or enzalutamide. Eligibility also included life expectancy ≥3 mo, Eastern Cooperative 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 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 dexamethasone (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 dexamethasone. 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 χ2test of equal proportions required 28 patients per group with a two-sided α 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 apvalue <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 dexamethasone 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 recruitment 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 .

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)

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).

gr1

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.

Median time to PSA progression was 9.7 mo (95% confidence interval [CI], 6.3–13.1 mo) for patients randomised 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 ).

gr2

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

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.

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.

gr3

Fig. 3 Radiologic response to dexamethasone.

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 prednisolone. Three patients on prednisolone versus none on dexamethasone had at least one random glucose level >12 mmol/l.

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

* EQ-5D overall heath state, measured on a visual analogue score from 0 (worst) to 100 (best).

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.

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

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 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 dexamethasone. 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 significantly to the activity of chemotherapy for CRPC[11] and [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 dexamethasone 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] and [26]. AR mutations that are activated by prednisolone at levels present in the blood of CRPC patients treated with prednisolone 5 mg twice daily have been identified[27] and [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] . Prednisolone 5 mg twice daily, which represents a threefold higher equivalent corticosteroid dose than that of dexamethasone 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 prednisolone 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 corticosteroid of choice for CRPC should now be questioned, given these data indicating higher antitumor activity for dexamethasone. 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 corticosteroid 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.

References

  • [1] H.M. Khandwala, R. Vassilopoulou-Sellin, C.J. Logethetis, K.E. Friend. Corticosteroid-induced inhibition of adrenal androgen production in selected patients with prostate cancer. Endocr Pract. 2001;7:11-15
  • [2] I. Tannock, M. Gospodarowicz, W. Meakin, T. Panzarella, L. Stewart, W. Rider. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989;7:590-597
  • [3] S.D. Fosså, P.H. Slee, M. Brausi, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001;19:62-71
  • [4] R. Venkitaraman, K. Thomas, R.A. Huddart, A. Horwich, D.P. Dearnaley, C.C. Parker. Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU Int. 2008;101:440-443
  • [5] I.F. Tannock, R. de Wit, W.R. Berry, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512 Crossref
  • [6] J.S. De Bono, C.J. Logothetis, A. Molina, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005 Crossref
  • [7] C.N. Sternberg, P. Whelan, J. Hetherington, et al. Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer. Oncology. 2005;68:2-9 Crossref
  • [8] I.F. Tannock, D. Osoba, M.R. Stockler, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756-1764
  • [9] W. Berry, S. Dakhil, M. Modiano, M. Gregurich, L. Asmar. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002;168:2439-2443
  • [10] C.J. Ryan, M.R. Smith, J.S. de Bono, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148 Crossref
  • [11] K. Nishimura, N. Nonomura, Y. Yasunaga, et al. Low doses of oral dexamethasone for hormone-refractory prostate carcinoma. Cancer. 2000;89:2570-2576 Crossref
  • [12] J. Shamash, T. Powles, S.J. Sarker, et al. A multi-centre randomised phase III trial of dexamethasone vs dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred diethylstilbestrol. Br J Cancer. 2011;104:620-628 Crossref
  • [13] S.D. Fosså, A.-B. Jacobsen, C. Ginman, et al. Weekly docetaxel and prednisolone versus prednisolone alone in androgen-independent prostate cancer: a randomized phase II study. Eur Urol. 2007;52:1691-1699
  • [14] O. Sartor, M. Weinberger, A. Moore, A. Li, W.D. Figg. Effect of prednisone on prostate-specific antigen in patients with hormone-refractory prostate cancer. Urology. 1998;52:252-256 Crossref
  • [15] J.A. Storlie, J.C. Buckner, G.A. Wiseman, P.A. Burch, L.C. Hartmann, R.L. Richardson. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer. 1995;76:96-100 Crossref
  • [16] M. Morioka, T. Kobayashi, Y. Furukawa, et al. Prostate-specific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexamethasone. Urol Int. 2002;68:10-15 Crossref
  • [17] T. Saika, N. Kusaka, T. Tsushima, et al. Okayama Urological Cancer Collaborating Group. Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients. Int J Urol. 2001;8:290-294 Crossref
  • [18] G. Attard, A.H.M. Reid, J.S. de Bono. Abiraterone acetate is well tolerated without concomitant use of corticosteroids. J Clin Oncol. 2010;28:e560-e561 author reply e562 Crossref
  • [19] D. Lorente, K. Weatherstone, A. Omlin, et al. Tumor responses after steroid switch of prednisolone (P) to dexamethasone (D) in castration-resistant prostate cancer (CRPC) patients (pts) on abiraterone acetate (AA) [abstract 2918]. Eur J Cancer. 2013;:49
  • [20] A.L. Weitzman, G. Shelton, N. Zuech, et al. Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. J Urol. 2000;163:834-837 Crossref
  • [21] T.B. Dorff, E.D. Crawford. Management and challenges of corticosteroid therapy in men with metastatic castrate-resistant prostate cancer. Ann Oncol. 2013;24:31-38 Crossref
  • [22] A. Eichholz, R. Ferraldeschi, G. Attard, J.S. de Bono. Putting the brakes on continued androgen receptor signaling in castration-resistant prostate cancer. Mol Cell Endocrinol. 2012;360:68-75 Crossref
  • [23] A. Yano, Y. Fujii, A. Iwai, Y. Kageyama, K. Kihara. Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res. 2006;12:3003-3009 Crossref
  • [24] K. Nishimura, N. Nonomura, E. Satoh, et al. Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst. 2001;93:1739-1746 Crossref
  • [25] R.B. Montgomery, T.S. Kheoh, A. Molina, et al. Effect of corticosteroid (CS) use at baseline (CUB) on overall survival (OS) in patients (pts) receiving abiraterone acetate (AA): Results from a randomized study (COU-AA-301) in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel (D) [abstract 5014]. J Clin Oncol. 2013;31(Suppl)
  • [26] H.I. Scher, K. Fizazi, F. Saad, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin Oncol. 2013;31(Suppl)
  • [27] X.Y. Zhao, P.J. Malloy, A.V. Krishnan, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6:703-706
  • [28] J. Richards, A.C. Lim, C.W. Hay, 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;72:2176-2182
  • [29] B. Sahu, M. Laakso, P. Pihlajamaa, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res. 2013;73:1570-1580 Crossref
  • [30] V.K. Arora, E. Schenkein, R. Murali, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309-1322 Crossref
  • [31] E.J. Small, S. Halabi, N.A. Dawson, 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;22:1025-1033 Crossref

Footnotes

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

lowast Corresponding author. Royal Marsden Hospital, Academic Urology Unit, Downs Road, Sutton, SM2 5PT, UK. Tel. +44 020 8661 3425; Fax: +44 020 8643 8809.