Genitourinary Cancer
`
`Use of Prednisone With Abiraterone Acetate in Metastatic
`Castration-Resistant Prostate Cancer
`RICHARD J. AUCHUS,a MARGARET K. YU,b SUZANNE NGUYEN,c SUNEEL D. MUNDLEc,d
`aDepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA; bJanssen Research & Development,
`Los Angeles, California, USA; cJanssen Scientific Affairs LLC, Johnson & Johnson, Horsham, Pennsylvania, USA; dDepartment of
`Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
`Disclosures of potential conflicts of interest may be found at the end of this article.
`Key Words. Adrenal cortex hormones x 17-(3-Pyridyl)-5,16-androstadien-3b-acetate x Steroid 17-a-hydroxylase x Prednisone x
`Prostatic neoplasms
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`ABSTRACT
`
`Abiraterone acetate, a prodrug of the CYP17A1 inhibitor
`abiraterone that blocks androgen biosynthesis, is approved for
`treatment of patients with metastatic castration-resistant
`prostate cancer (mCRPC) in combination with prednisone or
`prednisolone 5 mg twice daily.This review evaluatesthe basis for
`the effects of prednisone on mineralocorticoid-related adverse
`events that arise because of CYP17A1 inhibition with abirater-
`one. Coadministration with the recommended dose of gluco-
`corticoid compensates for abiraterone-induced reductions in
`serum cortisol and blocks the compensatory increase in adreno-
`corticotropic hormone seen with abiraterone. Consequently,
`5 mg prednisone twice daily serves as a glucocorticoid replace-
`ment therapy when coadministered with abiraterone acetate,
`analogous to use of glucocorticoid replacement therapy for
`certain endocrine disorders. We searched PubMed to identify
`safety concerns regarding glucocorticoid use, placing a focus
`
`on longitudinal studies in autoimmune and inflammatory
`diseases and cancer. In general, glucocorticoid-related adverse
`events, including bone loss, immunosuppression, hyperglyce-
`mia, mood and cognitive alterations, and myopathy, appear
`dose related and tend to occur at doses and/or treatment
`durations greater than the low dose of glucocorticoid approved
`in combination with abiraterone acetate for the treatment of
`mCRPC. Although glucocorticoids are often used to manage
`tumor-related symptoms or to prevent treatment-related
`toxicity, available evidence suggests that prednisone and
`dexamethasone might also offer modest therapeutic benefit in
`mCRPC. Given recent improvements in survival achieved for
`mCRPC with novel agents in combination with prednisone,
`the risks of these recommended glucocorticoid doses must
`be balanced with the benefits shown for these regimens.
`The Oncologist 2014;19:1231–1240
`
`Implications for Practice: Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone, suppresses testosterone and
`cortisol production in patients with metastatic castration-resistant prostate cancer (mCRPC), but cortisol precursors with min-
`eralocorticoid activity rise during abiraterone acetate monotherapy. Low-dose prednisone (5 mg twice daily) coadministration
`serves as glucocorticoid replacement therapy, lowers adrenocorticotropic hormone, and reduces the incidence and severity of
`mineralocorticoid-related adverse events. In contrast, pharmacologic glucocorticoid doses used to treat other malignancies and
`autoimmune disorders are typically $20 mg/day prednisone equivalence, and these higher doses are associated with an adverse
`safety profile. The safety profile of low-dose glucocorticoid use in mCRPC deserves further study.
`
`INTRODUCTION
`
`The progression of metastatic castration-resistant prostate
`cancer (mCRPC) despite androgen deprivation therapy and
`castrate testosterone levels frequently reflects the continued
`production of androgens in the adrenal glands and within
`prostate tumor tissue [1, 2]. Abiraterone acetate is the prodrug
`of abiraterone, which blocks androgen biosynthesis via in-
`hibition of steroid 17-hydroxylase/17,20-lyase (cytochrome
`P450c17 [CYP17A1]) [3]. Abiraterone acetate in combination
`with prednisone or prednisolone at a low dose of 5 mg twice
`
`daily has been shown to improve survival of mCRPC patients
`previously treated with docetaxel and those who had not
`received prior chemotherapy [4, 5]. The administration of
`abiraterone acetate with glucocorticoids is necessary to
`manage adverse events related to mineralocorticoid excess,
`such as hypokalemia, hypertension, and fluid retention, which
`can occur as a result of CYP17A1 inhibition [6–8]. This review
`evaluates the basis for the remedial effects of low-dose
`prednisone to prevent mineralocorticoid excess-related
`
`Correspondence: Richard J. Auchus, M.D., Ph.D., University of Michigan, Department of Internal Medicine; Division of Metabolism,
`Endocrinology, and Diabetes, 5560 MSRB II, Ann Arbor, Michigan 48109-5678, USA. Telephone: 734-615-9497; E-Mail: rauchus@med.umich.
`edu Received April 24, 2014; accepted for publication September 25, 2014; first published online in The Oncologist Express on October 31,
`2014. ©AlphaMed Press 1083-7159/2014/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2014-0167
`
`The Oncologist 2014;19:1231–1240 www.TheOncologist.com
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`©AlphaMed Press 2014
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`Use of Prednisone With Abiraterone Acetate
`
`adverse events anticipated with abiraterone acetate therapy
`and assesses safety concerns about glucocorticoid therapy
`based on longitudinal studies conducted in autoimmune and
`inflammatory diseases and cancer.
`
`MATERIALS AND METHODS
`We searched PubMed using the terms corticosteroids, gluco-
`corticoids, steroids, abiraterone, prostate cancer, and metastatic
`castrate-resistant prostate cancer for clinical trials, reviews, and
`case reports published in English without filtering for dates.
`Information selected for this article was obtained from pre-
`clinical investigations, early clinical trials, and phase III studies
`that served as the basis for approval of prednisone with
`abiraterone acetate in patients progressing after docetaxel
`and without prior chemotherapy. A focus was placed on the
`glucocorticoid literature with filters of clinical trial, review, case
`reports, and English describing longitudinal follow-up of the
`prolonged therapeutic use of prednisone and its association
`with autoimmune and inflammatory disease, malignant dis-
`ease, bone abnormalities, hyperglycemia and diabetes, mood
`and cognitive function, fatigue, and myopathy. Also included
`were the effects of prednisone on immune function and the
`therapeutic benefits and disadvantages of prednisone co-
`administration in prostate cancer. Data from recent congress
`presentations and publications known to the authors in-
`dependent of this literature search were also incorporated.
`We did not include in vitro data showing glucocorticoid
`receptor stimulation of cancer growth or genes overlapping
`with androgen receptor targets in CRPC because this
`mechanism of driving disease progression has not been
`established beyond preclinical models. AFFIRM data show-
`ing increased risk of death and progression with baseline
`glucocorticoid use independent of other prognostic factors
`also were not included [9] because prognostic models from the
`COU-AA-301 trial did not validate this result. The latter
`information is the subject of a separate line of investigation
`which was published separately [10].
`
`IMPACT OF BLOCKING CYP17A1 ON SYNTHESIS OF ADRENAL
`STEROIDS BEYOND ANDROGENS
`Abiraterone is a potent, selective, and irreversible inhibitor of
`CYP17A1, a microsomal enzyme with 17a-hydroxylase and
`C17,20-lyase activities that are required for androgen bio-
`synthesis via both classic and backdoor pathways (Fig. 1) [3,
`12]. Whereas androgen biosynthesis requires both of these
`CYP17A1 activities, cortisol biosynthesis requires only the 17a-
`hydroxylase activity of CYP17A1. The efficacy of abiraterone
`in blocking androgen biosynthesis is shown by substantial
`reductions in serum androgen levels (Fig. 2) [8, 13]. Use of
`abiraterone to inhibit androgen synthesis, however, is asso-
`ciated with several undesired physiologic changes, including a
`decrease in cortisol levels and a compensatory increase in
`adrenocorticotropic hormone (ACTH) [8, 13, 14]. This rise in
`ACTH leads to accumulation of steroids with mineralocorticoid
`properties upstream of CYP17A1 in the cortisol biosynthetic
`pathway (Fig. 3) and, ultimately, to mineralocorticoid-related
`adverse events, including hypertension, hypokalemia, and fluid
`retention [12].
`
`©AlphaMed Press 2014
`
`Cortisol levels follow a circadian rhythm in which levels
`are lowest at midnight, begin rising around 2–4 AM, peak
`after waking, and then slowly return to their nadir [14].
`Serum cortisol is regulated by its negative feedback on the
`hypothalamic-pituitary axis: low cortisol stimulates release
`of corticotropin-releasing hormone from the paraventricular
`nucleus of the hypothalamus, which triggers ACTH release
`from the anterior pituitary and, in turn, cortisol production in
`the adrenal cortex. Healthy adults have a morning serum
`cortisol level in the range of 5–23 mg/dL (138–635 nmol/L)
`and midnight serum cortisol ,5 mg/dL (,138 nmol/L). In
`studies of mCRPC patients, abiraterone reduced serum
`cortisol to near the lower limit of the normal range [8] and
`increased ACTH from a median of 17 pg/mL (range: ,9–50
`pg/mL) to a median of 124 pg/mL (range: 46–370 pg/mL) [13].
`When coadministered with abiraterone acetate, low-dose
`prednisone or prednisolone substitutes for cortisol, com-
`pensating for the abiraterone-induced reduction in serum
`cortisol (Fig. 4) [5, 15, 16]. Following this principle, the potent
`glucocorticoid dexamethasone normalizes the abiraterone-
`induced rise in ACTH (Fig. 5) [13]. Prednisolone or its
`precursor prednisone is approximately four times more
`potent as a glucocorticoid compared with cortisol [18].
`Treatment of 15 mCRPC patients with abiraterone acetate
`plus 10 mg prednisolone resulted in median prednisolone
`plasma concentrations of 152 nM—equivalent to 608 nM
`cortisol—thus providing physiologic glucocorticoid replace-
`ment (Fig. 4) [16]. At this dose, the mineralocorticoid activity of
`prednisolone is minimal [19].
`Glucocorticoid replacement therapy, as defined in this
`paper, has been shown to effectively reduce the incidence of
`mineralocorticoid-related adverse events in patients with
`mCRPC treated with abiraterone acetate (discussed below)
`[4, 6]. Similarly, subjects with congenital CYP17A1 deficiency
`produce excessive mineralocorticoids and develop hyperten-
`sion and hypokalemia [20], which can be mitigated by glu-
`cocorticoid replacementtherapy, includinglow-dose prednisone
`or prednisolone [21]. The use of glucocorticoid replacement
`to correct treatment-related steroid imbalances is similar to
`the use of glucocorticoid replacement therapy for other forms
`of acute or chronic adrenal insufficiency [22]. In these settings,
`the main goal is to mimic normal cortisol production to restore
`normal physiology while minimizing adverse effects. The
`choice of glucocorticoid, its dose, and the treatment duration
`are important considerations for achieving these goals [23].
`Currently, abiraterone acetate is approved only for use in
`combination with the prednisone or prednisolone dose given
`orally (5 mg) in the morning and evening. Other regimens and
`alternative glucocorticoids might be equivalent or superior
`cotherapies for specific patients, but different regimens have
`not been compared directly. There is an ongoing phase III
`trial of abiraterone acetate with 5 mg/day of prednisone or
`prednisolone in newly diagnosed patients with metastatic,
`hormone-na¨ıve prostate cancer (ClinicalTrials.gov identifier
`NCT01715285). In the phase I and II trials, abiraterone acetate
`was administered without any glucocorticoid, and hyperten-
`sion and hypokalemia were successfully managed with
`the mineralocorticoid receptor antagonist eplerenone at an
`average dose of 50 mg/day, often with addition of dexameth-
`asone 0.5 mg/day on progression [13].
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`Figure 1. Abiraterone inhibits CYP17A1, which acts at two key synthetic steps in androgen biosynthesis. Precursors upstream of CYP17A1-
`catalyzed steps accumulate, resulting in mineralocorticoid excess [11].
`Abbreviations: DHEA[-S], dehydroepiandrosterone [sulfate]; DHT, dihydrotestosterone.
`
`Figure 2. Abiraterone acetate reduces serum androgens and serum cortisol as a result of blocking CYP17A1. Shown are the changes in
`mean steroid levels from baseline to day 28 in patients with metastatic castration-resistant prostate cancer who received abiraterone
`acetate at doses of 250, 500, 750, or 1,000 mg daily [8].
`Abbreviation: DHEA-S, dehydroepiandrosterone sulfate.
`
`PHARMACOLOGIC EFFECTS OF LONG-TERM
`GLUCOCORTICOID THERAPY
`It is well recognized that glucocorticoids produce a variety of
`adverse events when used for prolonged periods to treat
`various autoimmune and inflammatory diseases, such as rheu-
`matoid arthritis, Crohn’s disease, and asthma, and various
`cancers [23–26]. Glucocorticoid-related adverse events in-
`clude altered bone metabolism,
`immunosuppression,
`in-
`creased risk of hyperglycemia and diabetes, adverse impact
`on mood and cognitive function, and muscle weakness. In
`general, these glucocorticoid-related adverse events are
`related primarily to the cumulative dose over a prolonged
`treatment period or to use of high doses during short-term
`exposure.
`
`Glucocorticoids may induce bone mineral loss and increase
`risk of osteoporosis and fracture after extensive exposure. In
`rheumatoid arthritis, glucocorticoids increase risk of these
`bone abnormalities beyond the risk associated with the
`disease itself [26, 27]. In the British General Practice Research
`Database, for example, the relative risk of hip fracture was two
`times higher among patients with versus without rheumatoid
`arthritis, with the relative risk increasing to 3.4-fold among
`those patients with rheumatoid arthritis receiving oral
`glucocorticoids [26]. Based on studies in rheumatoid arthritis
`and asthma, risk for bone mineral density reduction and/or
`osteoporosis is significant with high-dose glucocorticoids
`(.15 mg/day) and with glucocorticoid treatment at 7.5 mg/
`day for longer periods (.6 months) [28]. In addition, the
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`Figure 3. Abiraterone increases steroids with mineralocorticoid activity upstream of CYP17A1. Shown are median serum levels of
`corticosterone and deoxycorticosterone over time in patients with metastatic castration-resistant prostate cancer who received abiraterone
`acetate at doses of 250 to 2,000 mg daily. The right panel shows mean corticosterone levels at day 28 by abiraterone acetate dose [12].
`
`frequency of short-course oral glucocorticoid bursts has been
`associated with reductions in bone mineral density and in-
`creased risk of osteopenia in longitudinal studies in asthmatic
`children treated for 3 years with a total follow-up of 7 years
`and in adults with mean treatment for 7.7 years with additional
`follow-up for a median of 4 years [29, 30].
`For patients who have a set of autosomal recessive di-
`seases known as congenital adrenal hyperplasia (CAH), long-
`term disease management using glucocorticoid therapy often
`negatively affects bone health and quality of life [31].The most
`common form of CAH is 21-hydroxylase deficiency (21OHD),
`which is characterized by cortisol and aldosterone deficiency;
`furthermore, the accumulating cortisol precursors are shunted
`to other biosynthetic pathways, leading to adrenal androgen
`excess [31]. These patients receive long-term glucocorticoid
`and mineralocorticoid therapy, not only to replace the cortisol
`and aldosterone deficiency but also to suppress ACTH and thus
`adrenal androgen production.These regimens typically consist
`of supraphysiologic divided doses of hydrocortisone or sub-
`stitution with prednisone/prednisolone or dexamethasone.
`A reduction in bone mineral density and a threefold increase
`in osteopenia or osteoporosis was seen in adult male patients
`with 21OHD aged .30 years versus age-matched controls,
`with long-acting glucocorticoids more negatively affecting
`bone health compared with short-acting glucocorticoids [32].
`In this study, the majority of patients with 21OHD had normal
`bone density, and the prevalence of diabetes mellitus was
`not increased. As for asthma and inflammatory diseases, bone
`loss in CAH patients is attributed specifically to a lifetime
`of prolonged exposure to supraphysiologic glucocorticoids
`necessary to control androgen excess. Optimized glucocorti-
`coid therapy plus vitamin D and calcium supplementation
`mitigate these consequences [31, 33]. In the mCRPC setting,
`long-term glucocorticoid therapy warrants caution and
`continuous monitoring, especially in frail elderly men who
`may have significant comorbidities and prior cumulative
`steroid exposure that may adversely affect their bone health.
`Very frail patients with poor performance scores and short life
`expectancies are excluded from most clinical trials, so ex-
`trapolation of published studies to these populations should
`be done with caution.
`Glucocorticoids produce a number of metabolic effects,
`most importantly hyperglycemia and increased riskof diabetes
`mellitus. In a cohort of patients with rheumatic disease, the
`
`©AlphaMed Press 2014
`
`development of diabetes was significantly correlated with the
`cumulative prednisone dose over the course of treatment [34].
`The mean cumulative dose for patients with steroid-induced
`hyperglycemia was 26.6 g compared with 11.6 g for those
`without steroid-induced hyperglycemia [34]. Given the limited
`life expectancy of mCRPC patients, the anticipated steroid
`exposure at a dose of 10 mg/day would be lower than these
`levels (,4 g over 1 year). Moreover, the incidence of post-
`transplant diabetes among renal transplant recipients main-
`tained on prednisone 5–7.5 mg/day during a median 5-year
`follow-up was 15%, which was significantly higher than the
`incidence among those who did not have glucocorticoid
`maintenance (5%) [35].
`Glucocorticoids exert negative effects on mood and cog-
`nitive function that, again, correlate with the dose and/or
`length of treatment [36]. In a cohort of 27 children (aged 8–16
`years) with severe asthma treated with prednisolone for ,14
`days, those given high doses (mean: 62 mg/day) had increased
`symptoms of anxiety and depression compared with those
`receiving low doses (mean: 3 mg/day) [36, 37]. In a cohort of 20
`adults with asthma or rheumatic disease receiving prednisone
`at a mean dose of 19 mg/day for a mean duration of 128
`months, 12 (60%) met diagnostic criteria for a prednisone-
`induced mood disorder, most frequently depression, at some
`point during treatment [38]. Changes in cognition are often
`observed during glucocorticoid therapy, most commonly de-
`creases in declarative (verbal) memory [36]. In the afore-
`mentioned study in children with severe asthma, greater
`decreases in declarative memory were reported with high
`versus low glucocorticoid doses [36, 37]. Patients with asthma
`often receive multiple medications in addition to glucocorti-
`coids, and that might also contribute to effects on cognitive
`function.
`Minimal data are available for glucocorticoid-induced my-
`opathy in prostate cancer, but generally a low incidence is ob-
`served. Severe fatigue, myopathy, or muscle weakness were
`not reported in a phase III trial of low-dose prednisone with or
`without mitoxantrone in patients with asymptomatic CRPC
`[39]. In the TAX 327 study, in which low-dose prednisone was
`administered with either docetaxel or mitoxantrone, severe
`fatigue was reported in 5% of patients, yet myopathy was not
`reported [40]. Similarly, grade 3 fatigue was reported in 8% of
`men with mCRPC after chemotherapy who received thalido-
`mide plus oral dexamethasone [41]. In the COU-AA-302 trial of
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`Figure 5. Dexamethasone (0.5 mg/day) suppresses abiraterone-
`mediated increases in adrenocorticotropic hormone (ACTH).
`Abiraterone acetate treatment (n 5 26) was associated with
`a significant increase in median plasma ACTH levels from 17 pg/mL
`to 124 pg/mL (660% increase).This rise in ACTH was suppressed to
`below the lower limit of sensitivity (10 pg/mL) afteradministration
`of oral dexamethasone 0.5 mg/day for ,14 days. Normal ACTH
`levels in adults (mean 6 SE): 28.7 6 12 [13, 17].
`Abbreviations: ACTH, adrenocorticotropic hormone; LLOS,
`lower limit of sensitivity; Rx, treatment.
`
`for prostate cancer (e.g., prednisone 10 mg/day). In vitro,
`glucocorticoids stimulate macrophage function at low con-
`centrations (e.g., 0.1 nM), including expression of proinflam-
`matory cytokines and chemokines and production of nitric
`oxide, whereas they suppress these functions at high con-
`centrations (e.g., 1 mM) [45]. In an animal model, prednisone
`did not affect the oxidative burst mediated by complement
`receptors during neutrophil phagocytosis, even when admin-
`istered for 7–15 days at a dose equivalent to 90 mg/day in
`humans [46].
`The systemic exposure attained with the recommended
`low-dose glucocorticoids is below the amount shown to inhibit
`immune cell proliferation in response to antigens. Pediatric pa-
`tients treated with prednisone (2 mg/kg per day for 5 days,
`or #0.5 mg/kg perday for.6 months) forchronic inflammatory
`disorders, including juvenile idiopathic arthritis, systemic lupus
`erythematosus, or asthma, showed an appropriate immune
`response when immunized with influenza vaccine, successfully
`demonstrating a protective antibody titer against influenza A
`and B antigens [47, 48]. In addition, no flu-like symptoms were
`noted in any of the children during the 6-month evaluation
`period following vaccination [47]. Similarly, prednisone treat-
`ment did not influence the immunogenicity of an influenza
`vaccine in adults with rheumatoid arthritis [49], although
`a recent report indicated that prednisone doses $10 mg/day
`were associated with lower antibody responses in patients
`with systemic lupus erythematosus [50].
`
`The systemic exposure attained with the recom-
`mended low-dose glucocorticoids is below the
`amount shown to inhibit immune cell proliferation in
`response to antigens.
`
`The effect of low-dose glucocorticoids on immune re-
`sponses to personalized peptide vaccination was evaluated in
`a study of 11 mCRPC patients [51]. Most patients, particularly
`
`Figure 4. Low-dose prednisolone yields the equivalent of phy-
`siologic cortisol levels. Daily prednisolone (10 mg/day) with abi-
`raterone acetate (1,000 mg/day) in 15 castration-resistant
`prostate cancer patients led to median prednisolone concen-
`trations of 152 nmol/L (solid line). Given an ∼4:1 relative potency
`of prednisolone:hydrocortisone, 152 3 4 is equivalent to 608
`nmol/L cortisol, which is within physiologic concentrations [16].
`Dotted line is 10 nmol/L.
`
`chemotherapy-na¨ıve mCRPC patients [42], muscle weakness
`was infrequently reported in 0.6% of patients in the abiraterone
`acetate-plus-prednisone arm and in 1.1% of patients in the
`prednisone-alone arm (data on file, Janssen Research & Devel-
`opment, 2012). In other disorders, glucocorticoid-induced my-
`opathy has been associated primarily with high-dose steroid
`treatment, a sedentary lifestyle, and the use of fluorinated
`steroids (e.g., triamcinolone, dexamethasone) rather than non-
`fluorinated steroids (e.g., hydrocortisone, prednisone) [43, 44].
`The glucocorticoid-induced myopathy is fully yet slowly revers-
`ible when the dose is reduced below 30 mg/day of hydrocorti-
`sone or its equivalent, with a rehabilitative conditioning
`program appearing to be the most effective treatment [44].
`Taken together, these findings indicate that the incidence
`of glucocorticoid-induced adverse events—including bone
`loss, diabetes, central nervous system effects, and myopathy—
`are related to dose and choice of glucocorticoid, and these
`consequences tend to occur at doses much higher than those
`used in mCRPC [23]. When interpreting potential adverse
`effects of glucocorticoids in an elderly population of men with
`prostate cancer, the patients’ comorbidities, family history,
`and prior glucocorticoid and medication exposure should be
`taken into account.
`
`EFFECT OF PREDNISONE ON IMMUNE FUNCTION
`Glucocorticoids have been commonly used in cancer treatment,
`although their immunosuppressive properties have always
`been of specific concern [23]; nevertheless, the immunosup-
`pressive properties may be seen at doses of glucocorticoids
`above those recommended in approved therapeutic regimens
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`Figure 6.
`Incidence of mineralocorticoid-related adverse events in metastatic castration-resistant prostate cancer patients treated with
`abiraterone acetate plus prednisone compared with placebo plus prednisone in the COU-AA-301 and COU-AA-302 phase III randomized
`controlled studies [5, 15].
`
`when treated concurrently with dexamethasone (1 mg/day)
`or prednisolone (10 mg/day), were able to generate peptide-
`specific immunoglobulin-G antibodies and cytotoxic T-cell
`responses. These findings suggest that low-dose glucocorti-
`coids in this study did not suppress immune responses to
`tumor-specific peptides. Moreover, recent data suggest that
`immune responses to sipuleucel-T were successfully produced
`in men with mCRPC when administered concurrently with
`or prior to treatment with abiraterone acetate plus prednisone
`[52]. Thus, although the immunosuppressive effects of glu-
`cocorticoids have the potential to interfere with treatment
`effects of immunotherapeutic agents, low doses of glucocorti-
`coids do not appear to reduce immune responses to vac-
`cination substantially. Nevertheless, it is essential to consider
`the patient population (e.g., age, frailty, previous treatments)
`when interpreting the effects of glucocorticoids on immune
`function.
`
`SAFETY PROFILE OF ABIRATERONE ACETATE
`COADMINISTERED WITH PREDNISONE
`Abiraterone acetate (1,000 mg) coadministered with pred-
`nisone (5 mg twice daily) was compared with placebo plus
`prednisone in patients with mCRPC in two phase III, multi-
`national, double-blind, randomized, placebo-controlled tri-
`als. Study COU-AA-301 comprised 1,195 patients with mCRPC
`who had progressed after docetaxel treatment [4], and study
`COU-AA-302 involved 1,088 patients with mCRPC who had
`not received chemotherapy and who did not have clinically
`significant cancer-related symptoms (i.e., asymptomatic or
`minimally symptomatic patients) [5]. Both studies evaluated
`treatment effects on survival and disease progression,
`showing clinically meaningful and significant benefits in
`favor of abiraterone acetate plus prednisone [5, 15]. On the
`basis of the results from these studies, abiraterone acetate
`in combination with prednisone was approved for the
`treatment of patients with mCRPC.
`COU-AA-301 and COU-AA-302 also thoroughly assessed
`safety and tolerability, and these studies demonstrated that
`the safety profile of abiraterone acetate plus prednisone was
`
`©AlphaMed Press 2014
`
`comparable to that observed in earlier clinical studies [6, 8]. In
`both studies, adverse events associated with mineralocorti-
`coid activity were more common for abiraterone acetate plus
`prednisone than for prednisone alone (Fig. 6) [4, 5], but their
`incidence was largely abrogated by low-dose prednisone when
`compared with earlier studies of abiraterone acetate mono-
`therapy [8, 12, 53]. Notably, the majority of mineralocorticoid-
`related adverse events were grade 1 or 2 in severity. With
`coadministration of abiraterone acetate and prednisone in
`COU-AA-301, the incidence of mineralocorticoid excess-
`related severe adverse events,
`including hypertension
`(1.3% vs. 0.3%), hypokalemia (4.4% vs. 0.8%), and fluid
`retention or edema (2.5% vs. 1.0%), was low and manageable
`[15].The incidence of these severe adverse events in COU-AA-
`302 was also low, and the difference between treatment arms
`was even less apparent (hypertension, 3.9% vs. 3.0%;
`hypokalemia, 2.4% vs. 1.9%; fluid retention or edema, 0.7%
`vs. 1.7%) [5].
`The discontinuation rate for abiraterone acetate and
`prednisone in COU-AA-301 and COU-AA-302 was low, and side
`effects were easily manageable and reversible, despite the
`advanced age and advanced disease states of the study pop-
`ulations [5, 15]. Exposure to prednisone across treatment
`groups was relatively short, with a median of 7.4 months (range:
`0.2–25.6 months) in COU-AA-301 [15]. In COU-AA-302, no
`glucocorticoid-related adverse events greater than those in
`COU-AA-301 were observed despite a longer median duration
`(13.8 months) of abiraterone acetate-prednisone cotreatment
`[15, 42]. In the latter study, no new safety signals were observed
`in the subset of patients who received abiraterone acetate
`plus prednisone or prednisone alone for $24 months, with
`cumulative incidence rates of selected adverse events in-
`cluding fatigue, hypertension, osteoporosis, and hyperglycemia
`remaining similar between treatment groups [42]. Rates
`of infection were comparable in both groups during long-
`term treatment. Taken together, results from COU-AA-301
`and COU-AA-302 provide proof of principle that low-dose
`prednisone can be delivered safely without any consistent
`additional serious adverse effects while adequately managing
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`Auchus, Yu, Nguyen et al.
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`
`Table 1. Mineralocorticoid-related adverse events in abiraterone acetate-treated patients in the COU-AA-302 and COU-AA-301
`registrational trials with coadministered prednisone (North American sites) versus prednisolone (European Union sites).
`
`COU-AA-302
`
`COU-AA-301
`
`AA plus
`prednisone
`(n 5 354)
`
`Prednisone
`(n 5 345)
`
`AA plus
`prednisolone
`(n 5 188)
`
`Prednisolone
`(n 5 195)
`
`AA plus
`prednisone
`(n 5 334)
`
`Prednisone
`(n 5 159)
`
`AA plus
`prednisolone
`(n 5 457)
`
`Prednisolone
`(n 5 235)
`
`118 (33.3)
`
`99 (28.7)
`
`40 (21.3)
`
`31 (15.9)
`
`112 (33.5)
`
`34 (21.4)
`
`148 (32.4)
`
`60 (25.5)
`
`67 (18.9)
`79 (22.3)
`
`45 (13)
`37 (10.7)
`
`26 (13.8)
`39 (20.7)
`
`24 (12.3)
`36 (18.5)
`
`56 (16.8)
`40 (12.0)
`
`15 (9.4)
`14 (8.8)
`
`87 (19.0)
`48 (10.5)
`
`21 (8.9)
`11 (4.7)
`
`114 (32.2)
`
`93 (27)
`
`39 (20.7)
`
`28 (14.4)
`
`102 (30.5)
`
`34 (21.4)
`
`138 (30.2)
`
`55 (23.4)
`
`57 (16.1)
`63 (17.8)
`
`39 (11.3)
`27 (7.8)
`
`22 (11.7)
`32 (17)
`
`20 (10.3)
`29 (14.9)
`
`37 (11.1)
`36 (10.8)
`
`14 (8.8)
`13 (8.2)
`
`71 (15.5)
`42 (9.2)
`
`19 (8.1)
`18 (7.7)
`
`4 (1.1)
`
`6 (1.7)
`
`1 (0.5)
`
`3 (1.5)
`
`10 (3)
`
`0 (0)
`
`10 (2.2)
`
`4 (1.7)
`
`10 (2.8)
`16 (4.5)
`
`6 (1.7)
`10 (2.9)
`
`4 (2.1)
`7 (3.7)
`
`4 (2.1)
`7 (3.6)
`
`19 (5.7)
`4 (1.2)
`
`1 (0.6)
`1 (0.6)
`
`16 (3.5)
`6 (1.3)
`
`2 (0.9)
`0 (0)
`
`Adverse
`event
`
`All grades, n (%)
`Fluid retention/
`edema
`Hypokalemia
`Hypertension
`Grades 1 and 2, n (%)
`Fluid retention/
`edema
`Hypokalemia
`Hypertension
`Grades 3 and 4, n (%)
`Fluid retention/
`edema
`Hypokalemia
`Hypertension
`
`Abbreviation: AA, abiraterone acetate.
`
`mineralocorticoid-related adverse events resulting from
`CYP17A1 inhibition by abiraterone.
`
`THERAPEUTIC OR ADJUNCTIVE USE OF GLUCOCORTICOIDS
`IN MCRPC
`Glucocorticoids are often given to cancer patients to manage
`tumor-related symptoms, such as bone pain or weight loss,
`and to alleviate toxic effects associated with specific cancer
`treatments, such as nausea, vomiting, edema, and hyper-
`sensitivity reactions related to chemotherapy [23]. Gluco-
`corticoids are also used in specific situations, such as pain
`palliation and to reduce swelling from cord compression or
`radiation of brain metastases. Tumor-related cachexia was
`infrequent in the abiraterone acetate studies. Although
`megestrol acetate is better tolerated than dexamethasone
`[54], megestrol acetate at high doses acts as a glucocorticoid
`receptor modulator and causes adrenal axis suppression
`[54], which necessitates glucocorticoid treatment if patients
`undergo a stress-related condition, including trauma, in-
`fection, or surgery. Glucocorticoids are a viable and less
`expensive alternative to megestrol acetate for tumor-related
`cachexia in those with a history of thromboembolic com-
`plications or other contraindication.
`Low-dose glucocorticoids migh