`
`British Journal of Cancer (2014) 111, 2248–2253 | doi: 10.1038/bjc.2014.531
`
`Keywords: castration-resistant prostate cancer; prednisolone; glucocorticoid receptor; steroid switch; abiraterone;
`hormone therapy; dexamethasone; androgen receptor
`
`Tumour responses following a steroid switch
`from prednisone to dexamethasone in
`castration-resistant prostate cancer patients
`progressing on abiraterone
`D Lorente1, A Omlin1,2, R Ferraldeschi1, C Pezaro1, R Perez1, J Mateo1, A Altavilla1, Z Zafeirou1, N Tunariu1,
`C Parker3, D Dearnaley3, S Gillessen2, J de Bono*,1 and G Attard1
`1Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The
`Institute of Cancer Research, Downs Road, Sutton SM2 5PT, Surrey, UK; 2Kantonsspital St. Gallen, Department of Oncology and
`Haematology, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland and 3Academic Urology Unit, The Royal Marsden NHS
`Foundation Trust, Downs Road, Sutton SM2 5PT, Surrey, UK
`
`Background: Abiraterone is a CYP17A1 inhibitor that improves survival in castration-resistant prostate cancer (CRPC). Abiraterone
`is licensed in combination with prednisone 5 mg twice daily to prevent a syndrome of secondary mineralocorticoid excess. We
`hypothesised that a ‘steroid switch’
`from prednisone to dexamethasone would induce secondary responses in patients
`progressing on abiraterone and prednisone 5 mg b.i.d.
`
`Methods: We performed a ‘steroid switch’ in patients with CRPC at PSA progression on abiraterone and prednisolone. Patients
`were monitored for secondary declines in PSA, radiological tumour regression and toxicity.
`
`Results: A retrospective analysis of 30 CRPC patients who underwent a steroid switch from prednisolone to dexamethasone while
`on abiraterone was performed. A total of six patients (20%) had a X50% PSA decline that was confirmed by a second PSA level at
`least 3 weeks later. In all, 11 patients (39.2%) had a confirmed X30% PSA decline. Median time to PSA progression on abiraterone
`and dexamethasone was 11.7 weeks (95% CI: 8.6–14.8 weeks) in the whole cohort and 27.6 weeks (95% CI: 14.5–40.7 weeks) in
`patients who achieved a confirmed 50% PSA decline. Nine patients had RECIST evaluable disease: two of these patients had
`RECIST partial response, six patients had stable disease and one patient had progressive disease at the first imaging assessment.
`Treatment was well tolerated, with no grade 3 and grade 4 adverse events. One patient had to be reverted to prednisolone
`because of grade 2 hypotension.
`
`Conclusions: Durable PSA responses occur in up to 40% of patients following a ‘steroid switch’ for PSA progression on
`abiraterone and prednisone. Studies are ongoing to elucidate the mechanisms underlying this response.
`
`two novel hormonal agents have received
`In recent years,
`regulatory approval for the treatment of castration-resistant
`prostate cancer (CRPC). Both abiraterone, a CYP17A1 inhibitor
`that suppresses androgen and oestrogen synthesis, and enzalu-
`tamide, a potent next-generation antiandrogen, have been
`
`randomised,
`in large,
`survival
`shown to improve overall
`placebo-controlled phase III trials (de Bono et al, 2011; Scher
`et al, 2012). Abiraterone was evaluated in phase III trials and is
`licensed for administration in combination with prednisone
`(administered as the active metabolite prednisolone in the UK)
`
`*Correspondence: Professor J de Bono; E-mail: Johann.DeBono@icr.ac.uk
`
`Received 30 May 2014; revised 2 September 2014; accepted 10 September 2014; published online 14 October 2014
`
`& 2014 Cancer Research UK. All rights reserved 0007 – 0920/14
`
`Amerigen Exhibit 1129
`Amerigen v. Janssen
`IPR2016-00286
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`
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`Tumour responses following steroid switch in CRPC
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`BRITISH JOURNAL OF CANCER
`
`Table 1. Overall clinical characteristics at steroid switch: median (range)
`
`Responders (PSA decline X50%) Nonresponders (PSA decline o50%)
`8
`22
`
`65 years (61–82)
`
`69.6 years (51.2–80)
`
`N
`
`Age
`
`ECOG PS
`0
`1
`2
`Haemoglobin (g dl 1)
`Alk Phos (IU l 1)
`LDH (IU l 1)
`Albumin (g dl 1)
`PSA (ng ml 1)
`
`Metastases
`B only
`B þ LN
`B þ V
`B þ LN þ V
`LN only
`
`Previous bicalutamide
`Yes
`No
`
`Previous Dex monotherapy
`Yes
`No
`
`Overall
`30
`
`68.9 years
`
`8 (26.7%)
`19 (63.3%)
`3 (10%)
`
`12.6 (7.9–15.2)
`
`140.5 (48–2238)
`
`172.5 (107–631)
`
`36 (25–42)
`
`199.5 (9.7–2689)
`
`12 (40%)
`12 (40%)
`1 (3.3%)
`3 (10%)
`2 (6.6%)
`
`23 (76.7%)
`7 (23.3%)
`
`9 (30%)
`21 (70%)
`
`4 (50)
`3 (37.5)
`1 (12.5)
`
`12.6 (7.9–14.4)
`
`100 (53–2238)
`
`214 (169–546)
`
`36 (25–42)
`
`331.5 (9.7–2689)
`
`4 (50)
`2 (25)
`1 (12.5)
`0
`1 (12.5)
`
`6 (75)
`2 (25)
`
`4 (50)
`4 (50)
`
`4 (18.2)
`16 (72.9)
`2 (9.1)
`
`12.6 (10.9–15.2)
`
`158 (48–630)
`
`170 (107–631)
`
`37 (33–42)
`
`164 (11–523)
`
`8 (36.4)
`10 (45.5)
`0
`3 (13.6)
`1 (4.5)
`
`17 (80)
`5 (20)
`
`5 (22.7)
`17 (77.3)
`
`6.6 m (2–29)
`
`4 (18.2)
`17 (77.3)
`1 (4.5)
`
`Median time on previous Dex
`
`6.6 m (2–55.2)
`
`10.1 m (3.5–55.2)
`
`Previous CT lines
`0
`1
`2
`
`4 (13.3%)
`24 (80%)
`2 (6.6%)
`
`0
`7 (87.5)
`1 (12.5)
`
`Median Time on AA þ P
`
`6.36 m (2.7–28.7)
`
`6.8 m (4.8–28.7)
`
`5.4 m (2.7–16.7)
`
`Median % PSA decline on AA þ P
`
`71.5% (99% to þ 65%)
`
`78.2% (99% to þ 65%)
`
`66.6% (97% to þ 63%)
`
`Abbreviations: AA ¼ Abiraterone; Alk Phos ¼ Alkaline Phosphatase; B ¼ bone; CAB ¼ combined androgen blockade; CT ¼ chemotherapy; Dex ¼ Dexamethasone; LDH ¼ Lactate
`dehydrogenase; LN ¼ lymph nodes; m ¼ months; NR ¼ not reached; P ¼ prednisolone; PS ¼ performance status; PSA ¼ prostate-specific antigen; V ¼ visceral; yr ¼ years.
`
`secondary
`to prevent a syndrome of
`5 mg twice daily,
`mineralocorticoid excess caused by a loss of negative feedback
`of adrenocorticotropic hormone (Attard et al, 2008).
`We have previously reported a randomised phase II trial of
`dexamethasone 0.5 mg daily vs prednisolone 5 mg b.i.d. in CRPC
`patients, in which the confirmed X50 PSA decline rates were 31%
`for dexamethasone and 17% for prednisolone (Venkitaraman et al,
`2013). Moreover, in our previously reported phase I/II trial of
`abiraterone initially administered without concomitant corticos-
`teroids to 54 patients, the addition of dexamethasone 0.5 mg once
`daily at PSA progression on abiraterone without steroids resulted
`in secondary PSA declines in 25% of patients (Attard et al, 2009),
`regardless of prior progression on the same dose and regimen of
`single agent dexamethasone. We hypothesised that changing
`prednisolone for dexamethasone (a term we designated ‘steroid
`switch’) would be associated with tumour responses and could
`re-induce sensitivity to abiraterone.
`
`PATIENTS AND METHODS
`
`Patient characteristics. We performed a retrospective analysis of
`CRPC patients in whom a steroid switch from prednisolone to
`dexamethasone was performed between January 2011 and
`December 2013 at the Royal Marsden NHS Foundation Trust
`and the Kantonsspital St. Gallen. All patients were experiencing
`PSA progression according to Prostate Cancer Working Group 2
`
`Table 2. Treatment received after discontinuation of
`abiraterone and dexamethasone
`Cabazitaxel
`
`9 (30%)
`
`Docetaxel
`
`Enzalutamide
`
`Carboplatin
`
`PARP inhibitor
`
`Diethylstilboestrol
`
`Best supportive care
`
`3 (10%)
`
`2 (6.7%)
`
`1 (3.3%)
`
`1 (3.3%)
`
`1 (3.3%)
`
`6 (20%)
`
`criteria (PSAWG2) (Scher et al, 2008); in addition, radiological
`progression was observed in three patients before switching
`steroids. All patients were clinically stable. IRB approval to report
`these data was obtained from the Committee for Clinical Research
`at the Royal Marsden and Ethical Committee of the Kantonsspital
`St Gallen. The date of cut-off was the 4th of January 2014.
`A descriptive analysis of clinical characteristics, PSA declines
`and previous treatments was performed. Imaging assessments were
`performed as per local guidelines, every 3–6 months. Treatment
`with abiraterone and dexamethasone was discontinued at the time
`of clinical or radiological progression. Patients who received doses
`of dexamethasone 41 mg once daily for more than 4 weeks were
`excluded from the analysis.
`In accordance with PSAWG2 criteria (Scher et al, 2008), a PSA
`decline was defined as confirmed if it presisted in a second reading at
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`www.bjcancer.com | DOI:10.1038/bjc.2014.531
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`BRITISH JOURNAL OF CANCER
`
`Tumour responses following steroid switch in CRPC
`
`least 3 weeks later. PSA progression was defined as a 25% rise above
`the nadir, confirmed by a second reading at least 3 weeks later (Scher
`et al, 2008). Time to PSA progression was defined as the time from
`
`switch to the first PSA value fulfilling progression criteria. Radiological
`responses were defined as per RECIST (Response Evaluation Criteria
`In Solid Tumours) version 1.1 (Eisenhauer et al, 2009).
`
`40%
`
`20%
`
`0%
`
`–20%
`
`–40%
`
`–60%
`
`–80%
`
`–100%
`
`40%
`
`20%
`
`0%
`
`–20%
`
`–40%
`
`–60%
`
`–80%
`
`–100%
`
`Prior single agent dexamethasone
`No prior single agent dexamethasone
`
`Figure 1. Waterfall graph representing PSA declines on steroid switch.
`(A) PSA declines at 12 weeks. (B) Maximum PSA declines. Striped
`bars represent patients with prior single agent dexamethasone;
`nonstriped bars represent patients with no prior single agent
`dexamethasone. PSA increases have been capped at þ 50%.
`
`Statistical analyses. Statistical analyses were performed with IBM
`SPSS Statistics version 20. Time on treatment with abiraterone and
`dexamethasone (after steroid switch), time to PSA progression and
`time to PSA nadir were calculated using the Kaplan–Meier method.
`
`RESULTS
`
`Patient characteristics. We performed a steroid switch on
`standard doses of abiraterone from prednisolone/prednisone
`5 mg twice daily to dexamethasone 0.5–1 mg once daily at PSA
`progression in 30 patients. A total of 26 patients had a switch from
`10 mg prednisolone/prednisone to 0.5 mg dexamethasone. One
`patient had an initial dose of 1.5 mg once daily, which was
`successfully tapered to 0.5 mg over the first 3 weeks. One patient
`received dexamethasone 2 mg once daily initially, which was
`tapered to 1 mg once daily over 3 weeks; the remaining two
`patients received dexamethasone 1 mg once daily, with no dose
`modifications. Clinical characteristics of patients at the time of
`steroid switch are summarised in Table 1.
`At
`the time of data cut-off, 23 patients had discontinued
`treatment and 7 patients still continued on treatment with
`abiraterone and dexamethasone. Treatments administered after
`discontinuation of abiraterone are summarised in Table 2.
`Nine patients
`(30%) had received previous
`single agent
`dexamethasone; all of
`these patients had documented disease
`progression on dexamethasone, which consisted in PSA progres-
`sion in five patients and PSA and radiological progression in four
`patients. Patients had received abiraterone and prednisolone/
`prednisone for a median of 27.73 weeks (range: 11.7–124.4) before
`replacing prednisolone/prednisone 5 mg twice daily with dexa-
`methasone 0.5–1 mg once daily.
`
`treatment. Treatment with
`Duration of
`and
`abiraterone
`dexamethasone was maintained for a median of 20.6 weeks
`
`Table 3. Clinical characteristics of patients with a confirmed X50% PSA decrease
`
`Max. PSA decline (%)
`Dose of daily Dex (mg)
`
`95.6%
`0.5
`
`84.5%
`0.5
`
`79.4%
`0.5
`
`78.6%
`0.5
`
`77.2%
`1a
`
`57%
`0.5
`
`Clinical characteristics at steroid switch
`Age (years)
`ECOG PS on Switch
`Hb (g dl 1)
`Alk Phos (IU l 1)
`LDH (IU l 1)
`Albumin (g dl 1)
`Metastases
`
`Response to steroid switch
`Baseline PSA before switch (ng ml 1)
`PSA nadir on switch
`Duration of treatment Abi þ Dex (m)
`Time to PSA nadir on Abi þ Dex (m)
`Time to PSA Progression on Abi þ Dex (m)
`
`Treatment before switch
`Duration of treatment AA þ Pred (m)
`Max. PSA decline on AA þ Pred
`Previous single agent Dex (m)
`Time from previous single agent Dex (m)
`Max. PSA decline on Previous single agent Dex
`Previous CT lines
`
`73.1
`1
`10
`2238
`418
`36
`Bone
`
`1084
`48
`12.2 (Ong)
`3.6
`8.7
`
`4.8
`78%
`Yes (59.9)
`28.1
`97%
`1
`
`81.8
`0
`12.4
`100
`214
`42
`Bone, LN
`
`2689
`418
`6.5 (Ong)
`4.7
`3.6
`
`4.8
`27%
`Yes (15.3)
`15.6
`27%
`1
`
`61
`1
`14.4
`57
`171
`37
`LN
`
`9.7
`1.9
`5.7
`1.8
`3.6
`
`22.1
`99%
`No
`—
`—
`1
`
`62.5
`1
`13.7
`85
`169
`34
`Bone, LN
`
`210
`45
`13.9
`6.2
`8.7
`
`14.9
`38%
`Yes (3.5)
`45.8
`38%
`1
`
`63.6
`0
`12.8
`NA
`NA
`NA
`Bone
`
`37.7
`8.5
`5.5 (Ong)
`4.5
`6.4
`
`6.7
`84%
`No
`—
`—
`1
`
`73
`0
`13.6
`53
`242
`36
`LN, Pulm
`
`15
`6.5
`5.8
`1.5
`4.9
`
`6.4
`48%
`Yes (4.9)
`6.4
`71%
`2
`
`Abbreviations: Alk Phos ¼ Alkaline Phosphatase; CT ¼ chemotherapy; Dex ¼ dexamethasone; Hb ¼ haemoglobin; LDH ¼ Lactate dehydrogenase; LN ¼ lymph nodes; m ¼ months; NR ¼ not
`reached; Ong ¼ ongoing; PSA ¼ prostate-specific antigen; Pulm ¼ pulmonary metastases; yr ¼ years.
`a
`Intially on Dexamethasone 2 mg OD, tapered to 1 mg over 2 weeks and kept on 1 mg OD throughout the study.
`
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`Ongoing
`
`Discontinued
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`Time (weeks)
`
`19-Jul-2012
`
`22-Feb-2013
`
`0
`
`–20
`
`–40
`
`–60
`
`–80
`
`–100
`
`% Decline from baseline
`
`2500
`
`Baseline Abi-Pred: 2052 ng ml –1
`23-May-2012
`
`Switch to Abi-Dex: 1084 ng ml –1
`17-Oct-2012
`
`10-Dec-2012: 66 ng ml –1
`
`07-Jan-2013: 60 ng ml –1
`
`Nadir Abi-Dex: 48 ng ml –1
`o4-Feb-2013
`
`PSA progression Abi-Dex: 76 ng ml –1
`08-Jul-2013
`
`09-Sep-2013: 162 ng ml –1
`
`Nadir Abi-Pred: 448 ng ml –1
`20-Aug-2012
`
`0 1-Jul-2 0 1 2
`
`0 1-O ct-2 0 1 2
`
`0 1-Ja n-2 0 1 3
`
`0 1-A pr-2 0 1 3
`
`0 1-Jul-2 0 1 3
`
`0 1-O ct-2 0 1 3
`
`Date
`
`2000
`
`1500
`
`1000
`
`PSA (ng ml–1)
`
`500
`
`0
`
`Started Abi-Pred: 28-Apr-2011. PSA 218 ng ml –1
`
`300.00
`
`Started Abi-Dex: 28-Apr-2011. PSA 210 ng ml –1
`
`Nadir Abi-Dex: 45 ng ml –1
`01-Feb-2013
`
`Prog Abi-Dex: 64 ng ml –1
`17-Apr-2013
`
`200.00
`
`PSA (ng ml–1)
`
`100.00
`
`0.00
`
`130
`
`120
`
`110
`
`100
`
`90
`
`80
`
`PSA (ng ml–1)
`
`Nadir Abi-Pred: 11-May-2011. PSA 136 ng ml –1
`
`Stopped Abi-Dex: 136 ng ml –1
`18-Sep-2013
`
`01.7.2011 01.1.2012 01.7.2012 01.1.2013 01.7.2013
`
`Date
`
`Switch to Abi-Dex: 130 ng ml –1
`17-Jul-2013
`
`Last PSA: 130 ng ml –1
`11-Dec-2013
`
`Baseline Abi-Pred:
`108 ng ml –1
`17-Apr-2013
`
`Sclerotic changes in bone metastases
`associated with a 77% PSA decline
`
`Baseline: 15-Apr-2013
`
`Steroid switch: 12-Jul-2013
`
`Nadir Abi Pred: 86 ng ml –1 15-May-2013
`
`Nadir Abi-Dex: 91 ng ml –1
`24-Sep-2013
`
`12 weeks post-switch: 14-Oct-2013
`
`PSA progression Abi-Dex:
`91 ng ml –1 24-Sep-2013
`
`26-Jul-2013 02-Sep-2013 14-Oct-2013 11-Dec-2013
`17-Apr-2013
`15-May-2013
`24-Sep-2013
`16-Agu-2013
`12-Nov-2013
`
`Date
`
`Figure 2. Top left: evolution of PSA values in a patient with a 95.6% PSA decline. Top right: evolution of PSA values (%) in patients with a X 50%
`PSA decline. Middle: increased bone lesion sclerosis during treatment in a patient with a 77% PSA decline. Bottom: RECIST PR in supraclavicular
`lymph nodes in a patient with a 30% PSA decline.
`
`(95% CI: 16.2–24.9). A total of 23 patients had discontinued
`treatment and 7 patients continued on treatment at data censoring.
`Of these, 13 patients (56.5%) discontinued treatment owing to
`
`radiological progression, 7 (30.4%) owing to clinical progression
`and 3 (13%) owing to PSA progression exclusively before being
`enroled in subsequent clinical trials.
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`Tumour responses following steroid switch in CRPC
`
`One patient stopped treatment because of radiological progres-
`sion with new liver lesions on the CT scan performed owing to
`clinical worsening (increased fatigue and pain) 4 weeks after the
`steroid switch despite a 55% decline in PSA levels. Upon
`discontinuation of abiraterone, this patient went on to receive
`cabazitaxel chemotherapy.
`
`PSA declines. Declines in PSA 450% that were confirmed by at
`least one PSA value 4 weeks later were observed in six patients.
`Two patients had unconfirmed maximal PSA declines of 66% and
`55%, respectively. PSA declines at 12 weeks and maximum PSA
`declines are represented in Figure 1. The clinical characteristics of
`the six patients with a confirmed PSA decline X50% are
`summarised in Table 3. Four of
`these patients remained on
`treatment at the time of data cut-off. Eleven patients (39%) had
`confirmed PSA declines X30%. Baseline PSA at steroid switch
`ranged from 9.7 to 2689 ng ml 1. Median time to PSA nadir in
`patients with a confirmed 50% PSA decline was 7.7 weeks (95% CI:
`0–20.8 weeks). Median time to PSA progression on abiraterone
`and dexamethasone was 11.7 weeks (95% CI: 8.6–14.8 weeks) in
`the whole cohort and 27.6 weeks (95% CI: 14.5–40.7 weeks) in
`patients who achieved a confirmed 50% PSA decline. The change
`in PSA values relative to baseline is represented in Figure 2. Three
`of seven patients with serum LDH above normal limits at steroid
`switch experienced a post-switch normalisation; all three patients
`had a 50% PSA decline.
`Of the six patients with confirmed 50% PSA declines, four had
`received previous treatment with single agent dexamethasone, for a
`duration ranging between 15.2 and 259.6 weeks. Five patients had
`received prior bicalutamide. Four patients had received prior
`docetaxel, one patient was chemotherapy naı¨ve and one patient
`had received docetaxel and mitoxantrone. Response to previous
`treatment with abiraterone and prednisolone/prednisone ranged
`from a 27% to a 99% PSA decline.
`
`Radiological response. Overall, 20 patients had a CT scan
`performed within 4 weeks before the steroid switch that was used
`as a baseline for response assessment. Nine patients had RECIST
`evaluable disease. One patient, with baseline bone metastasis and a
`histologically proven adrenal metastasis, showed a RECIST partial
`response after 12 weeks of treatment and a 77% confirmed PSA
`decline. A second RECIST partial response in supraclavicular and
`retroperitoneal nodes was observed after 12 weeks in a patient with
`baseline lymph node disease only in conjunction with a confirmed
`30% PSA decline (Figure 2). Five patients with RECIST evaluable
`disease had stable disease on imaging assessment, with maximal
`PSA declines ranging from 80% to 15%. Two of these patients
`showed no change in the size of the lymph nodes, but a significant
`increase in sclerosis of the bone lesions was observed (Figure 2).
`
`Safety. Treatment was well tolerated with no grade 3 toxicities (see
`Table 4). No dose reductions of abiraterone were required. One
`patient, who was normotensive on abiraterone and prednisolone
`5 mg b.i.d. and had not been on antihypertensives, experienced
`grade 2 postural hypotension after steroid switch that mandated
`re-initiation of prednisolone 5 mg b.i.d. before final discontinua-
`tion of abiraterone. Postural hypotension resolved after restarting
`prednisolone 5 mg twice daily instead of dexamethasone 0.5 mg
`once daily. Conversely, grade 1 and grade 2 hypertension was
`present
`in six patients (21%),
`four of whom had also had
`hypertension of an equal grade on abiraterone and prednisolone
`5 mg twice daily that persisted despite institution of antihyperten-
`sive medication. Two patients (7.1%) presented with grade 1
`hypokalaemia, one of whom had also previously suffered two
`episodes of grade 1 hypokalaemia on abiraterone and prednisolone
`5 mg twice daily. Two patients (7.1%) presented with self-limiting
`grade 1 to grade 2 transaminase elevation that resolved after 4
`weeks. One patient experienced grade 1 hyponatraemia that lasted
`
`Table 4. Toxicity before and after steroid switch
`
`Grade 1-2 Toxicity
`Hypertension
`
`Hypokalaemia
`
`Transaminase elevation
`Othera
`a
`
`Pre-switch
`11 (39.3%)
`
`8 (28.6%)
`
`2 (7.1%)
`
`1 (3.6%)
`
`Post-switch
`7 (29%)
`
`2 (7.1%)
`
`1 (3.6%)
`
`2 (7.1%)
`
`Other: One patient experienced grade 1 hyponatraemia that lasted for 4 cycles while on
`abiraterone þ prednisolone, which reappeared after steroid switch for 1 cycle and was
`spontaneously recovered. One patient experienced grade 2 postural hypotension after
`steroid switch.
`
`for four cycles while on abiraterone and prednisolone, and
`persisted for two cycles after steroid switch. No new episodes of
`fluid retention or other adverse events were observed.
`
`DISCUSSION
`
`This is the first report of multiple durable PSA declines in patients
`treated with abiraterone after a steroid switch from prednisolone
`5 mg b.i.d.
`to dexamethasone 0.5–1 mg once daily. In seven
`patients, maximum PSA declines on abiraterone and dexametha-
`sone were at least 25% othose achieved on abiraterone and
`prednisolone, and eight patients had a longer treatment duration
`on abiraterone and dexamethasone than on abiraterone and
`prednisolone (Figure 1). This hypothesis-generating report should
`now lead to prospective evaluation of changes in steroid dose while
`continuing and after discontinuing abiraterone.
`Radiological responses in soft tissue and/or nodal disease were
`observed in two out of nine patients. Increased sclerosis on CT
`with no change in the size of bone metastases was also observed in
`three patients who also had PSA declines. There are currently no
`established objective criteria to evaluate response in bone
`metastatic disease on CT scans; preliminary data suggest that an
`increase in bone lesion sclerosis may be associated with therapeutic
`response, as suggested by the correlation between reduction in
`FDG uptake and increased CT density (measured in Hounsfield
`units) of bone metastases from prostate cancer (Beheshti et al,
`2008; Costelloe et al, 2010).
`Conversion to dexamethasone was well tolerated and was not
`associated with adrenocortical
`insufficiency or side effects of
`mineralocorticoid excess. Dexamethasone has been reported to
`cause orthostatic hypotension when given as a treatment of
`secondary mineralocorticoid excess in a phase I trial of abiraterone
`without concomitant steroids (Ryan et al, 2010). A currently
`ongoing phase II clinical trial (NCT01867710) is evaluating the
`safety profile of abiraterone given with different steroid regimens
`(prednisolone 5 mg twice daily, prednisolone 2.5 mg twice daily,
`prednisolone 5 mg once daily and dexamethasone 0.5 mg once
`daily) to chemotherapy-naı¨ve metastatic CRPC patients. Moreover,
`abiraterone
`activity could be
`enhanced if
`combined with
`eplerenone instead of prednisolone, which, as previously reported,
`is feasible (Attard et al, 2008, 2009).
`Several hypotheses could be considered to explain the observed
`effect. Possible mechanisms of resistance that would be reversed by
`‘steroid switch’ are as follows:
`
`(1) Activation of the glucocorticoid receptor leads to resistance, as
`recently published for enzalutamide (Arora et al, 2013), which
`is reversed owing to the lower equivalent dose of dexametha-
`sone compared with prednisolone. Reduced activation of the
`glucocorticoid receptor by doses of dexamethasone with a
`lower equivalent glucocorticoid activity induces less activation
`of the GR. In all, 90% of the patients in our study ultimately
`received 0.5 mg dexamethasone daily, which represents a
`67% reduction in glucocorticoid activity compared with
`
`2252
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`www.bjcancer.com | DOI:10.1038/bjc.2014.531
`
`
`
`Tumour responses following steroid switch in CRPC
`
`BRITISH JOURNAL OF CANCER
`
`prednisolone 5 mg twice daily. The remaining three patients
`(10%) received a dose of dexamethasone 1 mg once daily,
`representing a 33% reduction in glucocorticoid activity; only one
`of
`the patients receiving dexamethasone 1 mg once daily
`achieved a 450% PSA decline.
`(2) Resistance occurs secondary to emergence of AR somatic point
`mutations that are activated by prednisolone but not by
`dexamethasone.
`(3) Resistance occurs secondary to activation of the mineralocor-
`ticoid receptor, for which dexamethasone has a lower affinity
`(Lan et al, 1982).
`(4) Other factors that may also contribute to the superior activity of
`dexamethasone in CRPC, including when administered as a
`single agent.
`
`We acknowledge the lack of a control group in which
`abiraterone was discontinued at the time of steroid switch as a
`major limitation of the study. The possibility of the observed
`responses being related to the activity of dexamethasone as a single
`agent can therefore not be excluded. However, the similar response
`rate in patients regardless of progression on prior single agent
`dexamethasone suggests that an alternative mechanism is respon-
`sible for the observed responses.
`In conclusion, performing a steroid switch in patients with a
`rising PSA while on abiraterone can delay the development of
`resistance, and it can induce radiological responses in selected
`patients. Prospective clinical
`trials with integrated biomarker
`studies are now required to further evaluate the extent of benefit
`and the biological mechanisms underlying our observations.
`
`ACKNOWLEDGEMENTS
`
`D Lorente is recipient of a 2-year bursary from the Spanish Society
`of Medical Oncology – ‘Beca SEOM Para la Investigacio´n Trasla-
`cional en el Extranjero’. A Omlin is
`the recipient of a
`2-year bursary from the Swiss Cancer League (No. BIL KLS-
`02592-02-2010). R Ferraldeschi
`is supported by the Wellcome
`Trust. Z Zafeirou is the recipient of a grant from the Hellenic
`Society of Medical Oncology. G Attard is supported by a Cancer
`Research UK Clinician Scientist Fellowship. G Attard and J de
`Bono have received support from Prostate Cancer UK and the
`Prostate Cancer Foundation.
`
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