Prostate Cancer and Prostatic Diseases (2016) 00, 1 –5
`© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1365-7852/16
`
`www.nature.com/pcan
`
`ORIGINAL ARTICLE
`
`Impact of single-agent daily prednisone on outcomes in men
`with metastatic castration-resistant prostate cancer
`G Sonpavde1,6, GR Pond2,6, AJ Templeton3, ED Kwon4 and JS De Bono5
`
`BACKGROUND: Despite palliative benefits and PSA responses, the objective clinical impact of daily oral prednisone (P) for
`metastatic castration-resistant prostate cancer (mCRPC) is unknown. We performed a pooled analysis of control arms of randomized
`trials that either did or did not administer single-agent P to evaluate its impact on overall survival (OS) and toxicities.
`METHODS: Individual patient data from control arms of randomized trials of men with mCRPC who received placebo or P+placebo
`post docetaxel were eligible for analysis. The impact of P on OS and severe toxicities was investigated in Cox regression models
`adjusted for known prognostic factors. Statistical significance was defined as P o 0.05 and all tests were two sided.
`RESULTS: Data from the control arms of two randomized phase III trials were available totaling 794 men: the COU-AA-301 trial
`(n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not
`significantly associated with OS compared with placebo in a multivariable analysis (hazard ratio = 0.89 (95% confidence interval
`0.72–1.10), P = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology Group (ECOG)-performance status
`(PS) ⩾ 1, Gleason score ⩾ 8, liver metastasis, high PSA, hypoalbuminemia and elevated lactate dehydrogenase (LDH). Grade ⩾ 3
`therapy-related toxicities were significantly increased with P plus placebo compared with placebo (hazard ratio = 1.48 (95%
`confidence interval 1.03–2.13), P = 0.034). Other baseline factors significantly associated with a higher risk of grade ⩾ 3 toxicities
`were ECOG-PS ⩾ 1, hypoalbuminemia and elevated LDH. Fatigue, asthenia, anorexia and pain were not different based on P
`administration.
`CONCLUSIONS: P plus placebo was associated with higher grade ⩾ 3 toxicities but not extension of OS compared with placebo
`alone in men with mCRPC who received prior docetaxel. Except for the use of P with abiraterone to alleviate toxicities, the use of P
`should be questioned given its association with toxicities and resistance.
`
`Prostate Cancer and Prostatic Diseases advance online publication, 27 September 2016; doi:10.1038/pcan.2016.44
`
`INTRODUCTION
`Since randomized trials employed daily low-dose oral prednisone
`(P) with mitoxantrone chemotherapy to treat men with metastatic
`castration-resistant prostate cancer (mCRPC), P has been used
`subsequently in combination with taxanes.1–5 P was combined
`with abiraterone acetate to mitigate the toxicities of mineralo-
`corticoid excess.6,7 However, the impact of single-agent daily P on
`clinical outcomes remains unclear.
`Moreover, P may induce toxicities, exacerbate comorbidities,
`incite resistance pathways and attenuate the benefits of
`immunotherapy.8,9 Daily corticosteroids may cause hyperglyce-
`mia, osteoporosis, myopathy, edema, hypertension and infections
`and potentially counteract the benefits of immunotherapy. In the
`era of emerging promising immunotherapeutic agents, long-term
`therapy with corticosteroids preceding or following the immu-
`notherapeutic is not desirable. In this context, abiraterone plus P
`did not blunt the immunologic properties of sipuleucel-T in a
`randomized phase II trial, although the impact on long-term
`outcomes is unknown.10 In addition, prolonged administration of
`daily corticosteroids may promote steroid dependency, and
`withdrawal may lead to adverse effects of low cortisol such as
`fatigue and postural hypotension.11 Therefore, a reevaluation of
`the role of daily oral corticosteroids is overdue.
`
`One trial-level meta-analysis of randomized trials could not
`demonstrate a significant impact of P, mostly in combination with
`chemotherapy, on overall survival (OS) or toxicities.12 However, the
`impact of single-agent P on OS and toxicities is unknown. Indeed, a
`randomized trial comparing P with placebo is unlikely to be ever
`performed. We performed a comparative analysis of control arms
`of two randomized trials that either did or did not administer
`single-agent P to evaluate its impact on OS and severe toxicities.
`
`MATERIALS AND METHODS
`Trials and patients
`Individual patient data from the control arms of the CA184-043 and COU-
`AA-301 phase III trials were available for analysis.6,13 Both trials were
`designed for men with mCRPC with progressive disease following docetaxel.
`CA184-03 compared ipilimumab with placebo as a 90 min intravenous
`infusion every 3 weeks up to 4 doses. All patients also received a single 8 Gy
`dose of radiotherapy to a bone lesion before beginning the intravenous
`therapy. COU-AA-301 compared oral P 5 mg twice daily combined with
`either abiraterone acetate or placebo. Men in the control arm of CA184-043
`received placebo only and corticosteroids were not allowed at baseline but
`were allowed subsequently if clinically necessary (for example, for patients
`judged to have severe immune adverse events). Those in the COU-AA-301
`received daily P plus placebo. Both trials recruited men with mCRPC who
`had previously received docetaxel. Demographic data, clinical and
`
`1University of Alabama at Birmingham, Birmingham, AL, USA; 2McMaster University, Hamilton, Ontario, Canada; 3Kantonsspital St Gallen, St Gallen, Switzerland; 4Mayo Clinic,
`Rochester, MN, USA and 5The Institute of Cancer Research, London, UK. Correspondence: Dr G Sonpavde, Division of Hematology-Oncology, Department of Medicine, UAB
`Comprehensive Cancer Center, 1720 2nd Avenue South, NP2540B, Birmingham, AL 35294, USA.
`E-mail: gsonpavde@uabmc.edu
`6These two authors contributed equally to this work.
`Received 13 March 2016; revised 27 May 2016; accepted 16 June 2016
`
`Amerigen Exhibit 1133
`Amerigen v. Janssen IPR2016-00286
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`

`
`Prednisone for advanced prostate cancer
`G Sonpavde et al
`
`2
`
`Table 1. Patient characteristics and outcomes
`
`Characteristic
`
`Statistic
`
`CA184-043
`
`COU-AA-301
`
`P-value
`
`Baseline characteristics
`Age
`
`ECOG-PS
`
`Gleason score
`Baseline albumin (g dl − 1)
`Lymphocytes × 103
`μl − 1
`μl − 1
`Neutrophils × 103
`NL ratio
`
`PSA
`LDH
`Hemoglobin
`Bone metastases
`Visceral metastases
`Liver metastases
`
`Survival
`N (%) deaths
`Overall survival
`
`Mean (s.d.)
`Median (IQR)
`0
`1
`2
`N (%) 8–10
`Median (IQR)
`Median (IQR)
`Median (IQR)
`Median (IQR)
`N (%) ⩾ 5
`Median (IQR)
`N (%) 4ULN
`N (%) Anemic ( o 11 g dl − 1)
`N (%)
`N (%)
`N (%)
`
`N (%)
`Median (95% CI) months
`1 Year (95% CI) %
`2 Years (95% CI) %
`
`N
`
`400
`
`390
`
`375
`359
`349
`349
`349
`
`334
`378
`380
`400
`400
`400
`
`400
`400
`
`Result
`
`67 (8)
`68 (62–73)
`170 (44)
`220 (56)
`0 (0)
`186 (50)
`4.1 (3.9–4.3)
`1.2 (0.9–1.7)
`4.3 (3.2–5.8)
`3.6 (2.4–5.3)
`95 (27)
`177 (47–417)
`214 (57)
`111 (29)
`364 (91)
`114 (29)
`47 (12)
`
`351 (88)
`10 (8–11)
`72 (67–76)
`41 (36–46)
`
`N
`
`394
`
`381
`
`395
`393
`363
`363
`363
`
`391
`382
`376
`398
`397
`397
`
`394
`398
`
`Result
`
`69 (9)
`69 (63–75)
`137 (36)
`199 (52)
`45 (12)
`205 (52)
`4.1 (3.8–4.3)
`1.1 (0.8–1.5)
`4.4 (3.4–6.1)
`4.3 (2.8–6.6)
`138 (38)
`132 (40–474)
`165 (43)
`116 (31)
`358 (90)
`101 (25)
`30 (8)
`
`224 (57)
`11 (10–12)
`78 (73–82)
`45 (40–50)
`
`0.001
`
`0.033a
`
`0.52
`0.059
`0.003
`0.13
`o 0.001
`0.002
`0.74
`o 0.001
`0.63
`0.61
`0.34
`0.055
`
`0.35b
`0.12c
`
`Abbreviations: CI, confidence interval; ECOG-PS, Eastern Cooperative Group-Performance Status; IQR, interquartile range; LDH, lactate dehydrogenase; NL,
`neutrophil/lymphocyte; ULN, upper limit of normal. aComparison is ECOG 0 versus ECOG ⩾ 1. bLog-rank test. cWilcoxon test.
`
`laboratory prognostic factors, OS and toxicity data were collected. Toxicities
`were graded using the National Cancer Institute’s Common Terminology
`Criteria for Adverse Events (version 3.0) in both trials.
`
`Statistical methods
`2 and Wilcoxon
`The Kaplan–Meier method was used to calculate OS. The χ
`rank sum tests were used to compare baseline differences. Given longer
`follow-up in the BMS (Bristol-Myers Squibb) CA184-043 trial, both a log-rank
`and generalized Wilcoxon test were performed. The generalized Wilcoxon
`test adds weights (relative to the number of patients still at risk), thereby
`putting greater emphasis on earlier OS times. Cox proportional hazards
`regression were used to explore effect of P on OS adjusted for potential
`prognosticators. Baseline prognostic factors available from both trials and
`previously reported to be prognostic factors were used in the multivariable
`analysis including the following: age, Eastern Cooperative Oncology Group
`(ECOG)-performance status (PS), Gleason score, PSA albumin, lymphocytes,
`neutrophils, sites of metastases (bone,
`liver, visceral), hemoglobin and
`lactate dehydrogenase (LDH).14–16 Logistic regression was used to evaluate
`the association of grade ⩾ 3 adverse events overall regardless of attribution
`to therapy as well as attributed to therapy. Specific toxicities and events that
`may be alleviated by P were also examined for association of overall and
`grade ⩾ 3 events with treatment including fatigue, asthenia, anorexia and
`pain. Statistical significance was defined as a P-value of o0.05, and all tests
`were two sided.
`
`RESULTS
`Patient characteristics
`Data from all 798 patients enrolled in the control arm from either
`clinical trial were available for analysis, namely 400 from the
`placebo-alone group in CA184-043 and 398 from the P plus
`placebo group in COU-AA-301. Descriptive statistics are presented
`in Table 1, and frequently occurring grade ⩾ 3 adverse events are
`summarized in Table 2. There were statistically significant
`differences between the two trials for some baseline variables
`with higher age,
`lower LDH and poorer ECOG-PS in the COU-
`
`Table 2. Grade ⩾ 3 AEs experienced by 42.5% (10 patients)a
`
`Characteristic
`
`CA184-043
`
`COU-AA-301
`
`Anemia
`Asthenia
`Anorexia
`Arthralgia
`Back pain
`Bone pain
`Decreased appetite
`Dehydration
`Dyspnea
`Fatigue
`Musculoskeletal pain
`Nausea
`Pain
`Pain in extremity
`Pelvic pain
`Pulmonary embolism
`Spinal cord compression
`Vomiting
`At least 1 grade ⩾ 3 AE
`At least 1 grade ⩾ 3-attributable AE
`
`47 (11.8%)
`14 (3.5%)
`0
`0
`22 (5.5%)
`19 (4.8%)
`13 (3.3%)
`10 (2.5%)
`8 (2.0%)
`37 (9.3%)
`12 (3.0%)
`7 (1.8%)
`24 (6.0%)
`11 (2.8%)
`2 (0.5%)
`4 (1.0%)
`4 (1.0%)
`10 (2.5%)
`236 (59.0%)
`43 (10.8%)
`
`30 (7.5%)
`8 (2.0%)
`12 (3.0%)
`16 (4.0%)
`38 (9.5%)
`29 (7.3%)
`1 (0.3%)
`7 (1.8%)
`12 (3.0%)
`39 (9.8%)
`8 (2.0%)
`10 (2.5%)
`7 (1.8%)
`21 (5.3%)
`10 (2.5%)
`12 (3.0%)
`20 (5.0%)
`11 (2.8%)
`243 (61.1%)
`71 (17.8%)
`
`Abbreviation: AE, adverse event. aUsing National Cancer Institute’s Common
`Terminology Criteria for Adverse Events (version 3.0).
`
`AA-301 patients, and lower neutrophil/lymphocyte ratio in the
`CA184-043 patients. A total of 32/304 (10.5%) evaluable CA184-
`043 patients had a decline in PSA of ⩾ 50% compared with
`baseline, as opposed to 40/317 (12.6%) of COU-AA-301 patients
`that was not statistically significant (P = 0.45). Alternatively, no
`difference was seen in rates of PSA decline (32/400 = 8.0% versus
`if one considers all patients without
`40/398 = 10.1%, P = 0.33)
`postbaseline PSA as a failure to have a PSA response.
`
`Prostate Cancer and Prostatic Diseases (2016), 1 – 5
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`© 2016 Macmillan Publishers Limited, part of Springer Nature.
`
`

`
`Figure 1. Association of prednisone with survival.
`
`Table 3. Multivariable analysis of for association of variables with
`overall survival
`
`Factor
`
`Type
`
`Hazard ratio
`(95% CI)
`
`P-value
`
`Age
`ECOG-PS
`Gleason score
`Liver metastases
`Visceral
`metastases
`Bone metastases
`PSA
`
`LDH
`Hemoglobin
`Prednisone
`
`Yes vs no
`Log-transform, per 1
`unit increase
`Baseline albumin Per 1 g dl − 1 increase 0.50 (0.37–0.66) o 0.001
`NL ratio
`Log-transform, per 1
`1.16 (0.99–1.34)
`0.063
`unit increase
`Elevated vs normal
`o 11 vs ⩾ 11 g dl − 1
`P vs no P
`
`Per 10 years older
`⩾ 1 vs 0
`⩾ 8 vs ⩽ 7
`Yes vs no
`Yes vs no
`
`1.10 (0.97–1.24)
`1.29 (1.05–1.60)
`1.25 (1.02–1.52)
`1.50 (1.03–2.16)
`1.06 (0.82–1.37)
`
`0.13
`0.017
`0.028
`0.033
`0.65
`
`0.13
`1.35 (0.91–2.01)
`1.16 (1.09–1.23) o 0.001
`
`2.10 (1.71–2.57) o 0.001
`1.14 (0.91–1.42)
`0.27
`0.89 (0.72–1.10)
`0.27
`
`Prednisone for advanced prostate cancer
`G Sonpavde et al
`
`3
`
`Frequency of grade ⩾ 3 toxicities with placebo or daily oral
`Figure 2.
`prednisone. Using the National Cancer Institute’s Common Termi-
`nology Criteria for Adverse Events (version 3.0) in both trials. AE,
`adverse event; PE, pulmonary embolism.
`
`overall grade ⩾ 3 adverse events on univariable analysis, multi-
`variable analysis demonstrated a significantly higher risk of grade
`inspection, LDH was
`⩾ 3 toxicities (P = 0.034). Upon further
`observed as a potential confounding variable.
`In patients with
`LDH 4upper limit of normal (ULN), 81% had a grade ⩾ 3 adverse
`event in the COU-AA-301 trial compared with 69% in the CA184
`trial, whereas for those with LDH o ULN, 47% and 46% had a
`grade ⩾ 3 adverse event in COU-AA-301 and CA184, respectively.
`Similarly, P administration was
`significantly associated with
`therapy-attributed grade ⩾ 3 toxicities on multivariable analysis
`(P = 0.001) (Table 4a and b), but not univariable analysis.
`When examining fatigue, asthenia, anorexia and pain that may
`be alleviated by P, both overall and grade ⩾ 3 events were not
`multivariably associated with P, except grade ⩾ 3 anorexia.
`Although limited by small numbers, there was a statistically
`significant difference in the proportion of patients with grade ⩾ 3
`anorexia (12/398 (3.0%) with P plus placebo vs 1/400 (0.3%) with
`placebo alone, P = 0.002, multivariable odds ratio = 11.48 (95%
`confidence interval 1.34–98.03), P = 0.026).
`
`DISCUSSION
`In this large retrospective study of control arms of two phase III
`trials, P plus placebo was associated with higher grade ⩾ 3
`toxicities (both overall and those attributed to therapy) but not
`extension of OS or PSA response compared with placebo alone
`after controlling for major baseline clinical and laboratory
`prognostic factors in post-docetaxel men with mCRPC. In addition,
`events of all grades that may be alleviated by P such as fatigue,
`asthenia, anorexia and pain did not appear significantly different
`based on P administration, suggesting the lack of clear palliative
`benefit. Our study included 798 patients overall and 610 were
`evaluable for
`the multivariable analysis that evaluated the
`independent impact of single-agent P after accounting for major
`baseline prognostic factors. These results partially accord with the
`previously reported trial-level meta-analysis of randomized trials
`that did not demonstrate a significant impact of P, generally in
`combination with chemotherapy, on OS or toxicities.12
`Our study is limited by its retrospective design, and the fact that
`patients were not randomized between treatment arms. There
`
`Abbreviations: CI, confidence interval; ECOG-PS, Eastern Cooperative
`Group-Performance Status; LDH, lactate dehydrogenase; NL, neutrophil/
`lymphocyte; P, prednisone.
`
`Association of P with OS
`There was no significant difference in OS (median OS 10.0 vs
`10.9 months, P = 0.12 using Wilcoxon test) between the placebo-
`alone and placebo plus P groups. In the 610 patients with data
`available for all factors, the multivariable analysis also did not
`demonstrate a significant association (P = 0.27) between P
`administration and OS (Figure 1 and Table 3). A supportive
`analysis performed with weights applied for the number of
`patients at risk and normalized to the sample size yielded similar
`results (univariable P = 0.37 and multivariable P = 0.92). Multiple
`previously known prognostic factors were significantly associated
`with poor OS on multivariable analysis including ECOG-PS ⩾ 1,
`Gleason score ⩾ 8, liver metastasis, PSA, albumin and LDH.
`
`Association of P with toxicities
`The proportion of patients with at least one grade ⩾ 3 adverse
`2 test P = 0.56) in the
`event was similar (59.0% versus 61.1%, χ
`placebo-alone and placebo plus P groups (Table 2 and Figure 2).
`Although P administration was not significantly associated with
`
`© 2016 Macmillan Publishers Limited, part of Springer Nature.
`
`Prostate Cancer and Prostatic Diseases (2016), 1 – 5
`
`

`
`4
`
`Prednisone for advanced prostate cancer
`G Sonpavde et al
`
`Table 4. Multivariable analysis of for association of variables with all
`grade ⩾ 3 toxicities (a) and toxicities attributable to therapy (b)
`
`Factor
`
`Type
`
`Odds ratio (95%
`CI)
`
`P-value
`
`(a)
`Age
`ECOG-PS
`Gleason score
`Liver metastases
`Visceral
`metastases
`Bone
`metastases
`PSA
`
`Baseline
`albumin
`NL ratio
`
`LDH
`Hemoglobin
`Prednisone
`
`(b)
`Age
`ECOG-PS
`Gleason score
`Liver metastases
`Visceral
`metastases
`Bone
`metastases
`PSA
`
`Baseline
`albumin
`NL ratio
`
`LDH
`Hemoglobin
`Prednisone
`
`Per 10 years older
`⩾ 1 vs 0
`⩾ 8 vs ⩽ 7
`Yes vs no
`Yes vs no
`
`0.99 (0.79–1.24)
`1.52 (1.06–2.18)
`1.41 (0.99–2.01)
`1.15 (0.53–2.53)
`1.01 (0.64–1.62)
`
`0.93
`0.025
`0.059
`0.72
`0.95
`
`Yes vs no
`
`1.05 (0.57–1.95)
`
`0.88
`
`Log-transform, per 1
`unit increase
`Per 1 g dl − 1 increase 0.56 (0.33–0.96)
`
`1.10 (0.98–1.22)
`
`0.10
`
`0.036
`
`Log-transform, per 1
`unit increase
`Elevated vs normal
`o 11 vs ⩾ 11 g dl − 1
`P vs no P
`
`1.16 (0.87–1.54)
`
`0.32
`
`2.85 (1.96–4.16) o 0.001
`1.48 (0.94–2.31)
`0.088
`1.48 (1.03–2.13)
`0.034
`
`Per 10 years older
`⩾ 1 vs 0
`⩾ 8 vs ⩽ 7
`Yes vs no
`Yes vs no
`
`1.08 (0.81–1.45)
`0.83 (0.50–1.38)
`1.57 (0.97–2.53)
`1.34 (0.53–3.37)
`0.83 (0.44–1.56)
`
`0.60
`0.48
`0.065
`0.54
`0.55
`
`Yes vs no
`
`0.68 (0.30–1.52)
`
`0.34
`
`Log-transform, per 1
`unit increase
`Per 1 g dl − 1 increase 0.83 (0.42–1.63)
`
`1.15 (0.99–1.34)
`
`0.069
`
`0.59
`
`Log-transform, per 1
`unit increase
`Elevated vs normal
`o 11 vs ⩾ 11 g dl − 1
`P vs no P
`
`1.57 (1.08–2.27)
`
`0.018
`
`2.03 (1.21–3.39)
`1.11 (0.65–1.92)
`2.28 (1.37–3.77)
`
`0.007
`0.70
`0.001
`
`Abbreviations: CI, confidence interval; ECOG-PS, Eastern Cooperative
`Group-Performance Status; LDH, lactate dehydrogenase; NL, neutrophil/
`lymphocyte; P, prednisone.
`
`may be unmeasured systematic differences between these trials
`and it
`is impossible to distinguish between these potential
`differences, and differences due to treatment with P. Thus, the
`results require validation. Although the study could not identify a
`significant association of P with OS in univariable analyses, P was
`associated with higher grade ⩾ 3 toxicities in the multivariable
`analysis after controlling for major baseline prognostic factors.
`However, the results of the multivariable analysis are probably
`more relevant, as baseline clinical and tumor-related factors (for
`example, age, anemia, LDH and performance status) can affect
`both survival and toxicities.14,17 Notably, the difference in toxicities
`does not imply lack of palliative benefits from corticosteroids that
`would require the longitudinal measures of quality of life using
`validated instruments. Given higher grade ⩾ 3 toxicities with P but
`not with placebo in those with LDH 4ULN, high LDH may portend
`higher risk of toxicities from P.
`In addition, there were other
`significant differences between trials
`in terms of patients’
`characteristics. Data regarding corticosteroid use before trial and
`following start of trial therapy were not available, but may
`confound results and is another limitation. Nevertheless, most
`patients had probably been exposed to prior P, as they were all
`pretreated with docetaxel that is commonly administered in
`combination with P. Potentially, different results may have been
`
`obtained in patients not previously treated with P. The placebo
`was administered as a daily oral dose in the COU-AA-301 trial, and
`as 4 intravenous infusions given once every 3 weeks in the CA184-
`043 trial
`(nonprogressing patients could continue to receive
`infusions every 3 months till progression or toxicities). In addition,
`the CA184-03 trial administered a single 8 Gy dose of radiation to
`a bone metastasis at baseline (to enhance immune response to
`ipilimumab in the experimental arm), although this is unlikely to
`have affected either toxicities or survival
`in the placebo arm.
`However, both trials were conducted in post-docetaxel patients
`and control arms exhibited similar median OS (10–11 months) and
`progression-free survival (3–4 months).
`Although corticosteroids are associated with toxicities as
`described earlier, daily-low dose corticosteroids appear to have
`modest antitumor activity and palliative benefits at least in a subset
`of patients, and may avert adverse effects of other antitumor
`agents. However, our study did not demonstrate differences in PSA
`declines between placebo and P. There may be differences based
`on the potency of the specific corticosteroid as suggested by a
`randomized phase II trial that demonstrated higher PSA response
`rates for dexamethasone vs prednisolone (47% vs 24%).18 One
`setting where the use of daily oral corticosteroids is required is in
`combination with abiraterone, where corticosteroids inhibit miner-
`alocorticoid excess leading to adverse events.6,7 Corticosteroids
`may suppress adrenocorticotrophic hormone and downregulate
`androgens, cytokines and other growth-promoting factors.19–23 The
`anti-inflammatory and anti-angiogenic activity of P may confer
`palliative benefits in 15 to 30% of patients, as demonstrated in
`prospective trials.1,2,19–21,24,25 In pre-docetaxel patients, PSA and
`RECIST (Response Evaluation Criteria In Solid Tumors) responses
`were observed in 24% and 16% of patients
`receiving P,
`respectively.6 Similarly, in post-docetaxel patients, PSA and RECIST
`responses were seen in 10.1% and 2.8% of patients, respectively.26
`Indeed, circulating tumor cell declines have been observed in a
`small subset of patients who received P alone.27 One retrospective
`study of 200 patients with mCRPC suggested that P potentially
`extends progression-free survival
`in the context of docetaxel
`in
`patients with mCRPC (median progression-free survival 7.8 vs
`6.2 months, P = 0.03), although the benefit appeared limited to
`patients not previously exposed to corticosteroids.28 Therefore, the
`clinical relevance of favorable PSA, RECIST, progression-free survival
`and circulating tumor cell changes and palliative benefits in a small
`subset of patients needs to be placed in the context of absence of
`evidence demonstrating improved OS.
`impact of
`In contrast, other data suggest a detrimental
`corticosteroids on outcomes. Analysis of post-docetaxel men
`receiving enzalutamide demonstrated that corticosteroids at base-
`line were associated with worse survival.29 The reason for this
`observation may be resistance mechanisms induced by enzaluta-
`mide or the institution of corticosteroids in patients with more
`aggressive symptomatic disease.30 Preclinical data indicate that P
`exposure may foster resistance to androgen inhibitors by binding to
`glucocorticoid receptors.9 It is also worrisome that corticosteroids
`may exhibit agonist activity on mutant androgen receptors.31,32 In
`addition, lower testosterone appears to be associated with poorer
`survival,
`suggesting that
`lower
`testosterone mediated by
`corticosteroid-induced adrenocorticotrophic hormone suppression
`may mechanistically confer poorer outcomes.33 Conversely, in post-
`docetaxel men receiving abiraterone plus P, baseline corticosteroids
`did not exhibit an impact on survival.34
`Following the phase III
`trials using low-dose oral daily
`corticosteroids in combination with mitoxantrone,
`they were
`employed in combination with docetaxel or cabazitaxel, with the
`rationale being to maintain balance between the arms. However,
`randomized phase III trials evaluating enzalutamide, radium223,
`sipuleucel-T and ipilimumab contained control arms without
`P.8,13,35–37 We propose that with the exception of the use of P with
`abiraterone to alleviate toxicities and single-agent P as late-line
`
`Prostate Cancer and Prostatic Diseases (2016), 1 – 5
`
`© 2016 Macmillan Publishers Limited, part of Springer Nature.
`
`

`
`Prednisone for advanced prostate cancer
`G Sonpavde et al
`
`5
`
`palliative therapy in the absence of trials, its routine use should be
`restrained given absence of data demonstrating improved
`survival, and association with toxicities and resistance.
`
`CONFLICT OF INTEREST
`
`The authors declare no conflict of interest.
`
`ACKNOWLEDGEMENTS
`
`We thank Bristol Myers Squibb and Project Data Sphere for providing data.
`
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