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`Use of Prednisone With Abiraterone Acetate in Metastatic
`
`Castration-Resistant Prostate Cancer
`
`RiCHARD J. Aucuusf‘ MARGARET K. W," Suzanne Neuven,‘ SUNEEL D. MuNoLE°"’
`“Department of Internai Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA; blanssen Research & Development,
`Los Angeles, Caiifornia, USA; fianssen Scientific Affairs LLC, Johnson & Johnson, Horsham, Pennsyivania, USA; ‘Department of
`Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
`Disclosures ofpotential conflicts of interest may be found at the end of this article.
`
`Keywords. Aclrenalcortex hormones} 17-{3-Pyridyl)-5,16-androstaciien-313-acetate - Steroid 17-or-hydroxyiase -_ Prednisone -
`Prostatic neopiasrns
`
`{
`
`ABSTRACT '_
`Abiraterone acetate, a prodrug of the CYPIYA1 inhibitor
`abiraterone that blocks androgen biosynthesis, is approved for
`treatment of patients with metastatic castration—resistant
`prostate cancer (mCRPC) in combination with prednisone or
`prednisoloneSmgtwicedaélyfihis review evaluatesthe basisfor
`the effects of precinisone on mineralocorticoidwrelated 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
`serumcortisol and blocksthecompensatoryincrease 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
`
`__,._.,,,,.,.,_.,,.s,ssse_u_s_uc
`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 tow dose of giecocorticoid approved
`in combination with abiraterone acetate for the treatment of
`
`mCRPC. Although glococorticoids are often used to manage
`tumor-related symptoms or to prevent treatment-related
`toxicity, available evidence suggests that prednisone and
`dexamethasonemightalsooffermodesttherapeutic benefitin
`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 baianced with the benefits shown for these regimens.
`The Oncologist 2014;19:1231-1240
`
`
`
`iN'rRoDiicT1oN
`
`The progression of metastatic castration—resistant prostate
`cancer (mCRPC) despite androgen deprivation therapy and
`castrate testosterone levels frequently reflects the continued
`production of anclrogens in the adrenal glands and within
`prostate tumor tissue [1, 21. Abiraterone acetate is the prodrug
`of abiraterone, which blocks androgen biosynthesis via in-
`hibition of steroid 1?-hydroxylase/17,20-lyase {cytochrome
`P4S0c17 [CYP17A1]) [3}. Abiraterone acetate in combination
`with prednisone or prednisolone at a low dose of 5 mg twice
`
`daiiy has been shown to improve survival of mCRPC patients
`previously treated with docetaxel and those who had not
`received prior chemotherapy [4, S}. The administration of
`abiraterone acetate with glucocorticoids is necessary to
`manage adverse events reiatect to mineralocorticoid excess,
`such as hypokalemia, hypertension, and fluid retention, which
`can occur as a result of CYP17A1 inhibition E6‘-81. 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 ll, Ann Arbor, Michigan 481095678, LiSA.Telephone: 734-615-9497; E—Mai!: rauchus@rned.ur'nich.
`
`edu Received April 24, 201:1;acceptedforpublication September25, 2014;firstpublishedonlinein TheOncologistExpress onOctober 31,
`
`2014. ©A|phaMed Press 1083-7159/2014/520.00/0 http://dx.doi.org/10.1634/theonco|ogist.20i4—O167
`
`The Oncologist 2014;19:1231—~1240 www.TheOncologist.com
`
`©AiphaMed Press 2014
`
`1
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`1232
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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 Msmoos
`
`We searched PubMed using the terms corticosteroids, gluco-
`corticaids, steroids, abiraterone, prostate cancer, and metastatic
`castrateresistont 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 Ill 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 con
`administration in prostate cancer. Data from recent congress
`presentations and publications known to the authors in-
`dependent ofthis 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. AFFERM 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}.
`
`lMPA(2'I‘ or BL()CKiNG {.‘YP1'7A]l on SYNTHESIS OF ADRENAL
`STEROIDS BEYOND ANDROGENS
`
`Abiraterone is a potent, selective, and irreversible inhibitor of
`CYP17A1, a microsomal enzyme with 17o:-hydroxylase and
`C3_7_2g'fY35E activities that are required for androgen blo-
`synthesis via both classic and backdoor pathways (Fig. 1) [3,
`12]. whereas androgen biosynthesis requires both of these
`CYP17A1 activities, cortisol biosynthesis requires onlythe 17a-
`hydroxylase activity of CYP17A1. The efficacy of abiraterone
`in blocking androgen blosynthesis 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 rnineralocorticoid—re|ated
`adverse events, including hypertension, hypokalemia, and fluid
`retention [12].
`
`©A|phaMed 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
`hypothalamiopituitary axis: low cortisol stimulates release
`of corticotropin-releasing hormone from the paraventricuiar
`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 #3/dl. {138~—635 nmol/L)
`and midnight serum cortisol <5 HE/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 PB/rnLl [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) i5, 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 nlvl
`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 replacement therapy, including |ow~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 isto mimic normal cortisol production to restore
`normal physiology while minimizing adverse effects. The
`choice of glucocorticoid, its close, 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 Ill
`trial of abiraterone acetate with 5 mg/day of prednisone or
`prednisolone in newly diagnosed patients with metastatic,
`hormone-naive prostate cancer (Clinica|Tria|s.gov identifier
`NCT0171S285). in the phase l and II trials, abiraterone acetate
`was administered without any glucocorticoid, and hyperten-
`sion and hypokalernia 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].
`
`Oiibologist“
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`Auchus, Yu, Nguyen at al.
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`Figure 1. Abiraterone inhibits CYP17A1, which acts attwo key synthetic steps in androgen biosynthesis. Precursors upstream of CYP17A1«
`catalyzed steps accumulate, resulting in rnineralocorticoid excess [11].
`Abbreviations: DH EA[—S], dehydroepiandrosterone {sulfate}; DHT, dihycirotestosterone.
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`Figure 2. Abiraterone acetate reduces serum and rogens 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 castratiomresistant prostate cancer who received abiraterone
`acetate at doses of 250, 500, 750, or 1,000 mg daily {8].
`Abbreviation: DH EA—S, dehyciroepiandrosterone sulfate.
`
`PIiARMACOl.0GlC EFFECTS or Lone-TERM
`GLUCOCURTICOED 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]. Glucocorticoidrelated 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 ioss 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
`giuccicorticoids [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 giucocorticoid treatment at 7.5 mg]
`day for longer periods (>6 months) [28].
`In addition, the
`
`www.TheOncoiogist.com
`
`©AEphaMed Press 2014
`
`

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`Use of Prednisone With Abiraterone Acetate
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`Figure 3. Abiraterone increases steroids with mineraiocorticoid activity upstream of CYP17A1. Shown are median serum levels of
`corticosterone and deoxycorticosterone over time in patients with metastatic castration-resistant prostate cancerwho received abiraterone
`acetate at doses of 250 to 2,000 mg daiiy. 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 autosomai 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-hydroxyiase deficiency (210HD),
`which is characterized by cortisol and aldosterone deficiency;
`fu rthermore,the accumulating cortisol precursors are shunted
`to other biosynthetic pathways, leading to adrenal androgen
`excess [31]. These patients receive long—terrn 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 typicaily 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 maiority of patients with 21OHD had normal
`bone density, and the prevaience of diabetes meliitus was
`not increased. As for asthma and inflammatory diseases, bone
`toss in CAH patients is attributed specificaily to a lifetime
`of prolonged exposure to supraphysiologic giucocorticoids
`necessary to control androgen excess. Optimized glucocorti-
`cold therapy plus vitamin D and calcium supplementation
`mitigate these consequences [31, 331. in the mCRPC setting,
`long-term glucocorticoid therapy warrants caution and
`continuous monitoring, especially in frail elderly men who
`may have significant comorbidlties 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 shouid
`be done with caution.
`
`Glucocorticoids produce a number of metabolic effects,
`most importantly hyperglycemia and increased risk ofdiabetes
`mellitus. in a cohort of patients with rheumatic disease, the
`
`©AlphaMed Press 2014
`
`development of diabetes was significantly correlated with the
`cumulative prednisone dose overthe 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
`iength 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 deciarative {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-
`colds, and that might also contribute to effects on cognitive
`function.
`
`Minimal data are avaiiable 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 Ill 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
`
`T e
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`hcologisi“
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`

`Auchus, Yu, Nguyen et al.
`
`1235
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`Figure 4. Low-dose prednisoione 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 prednisoione concen-
`trations of 152 nmolfL (solid line). Given an ~4:1 relative potency
`of prednisolonemydrocortisone, 152 X 4 is equivalent to 608
`nmol/L cortisoi, which is within physiologic concentrations E16}.
`Dotted line is 10 nmol/L.
`
`chemotherapy—nai've 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 fiuorinated
`steroids (e.g., triamcinolone, dexarnethasone] rather than non-
`fluorinated steroids (e.g., hydrocortisone, prednisone) [43, 44].
`The glucocorticoiddnduced rnyopathy is fully yet slowly revers-
`ible when the close is reduced beiow 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 myopathyw
`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 giucocorticoids in an elderly population of men with
`prostate cancer, the patients’ comorbidities, family history,
`and prior giucocorticoid and medication exposure shouid be
`ta ken into account.
`
`EFFECT or PREDNISONE on iMMUNE FUNCTION
`
`Glucocorticoids have been commonly used in cancertreatment,
`although their immunosuppressive properties have aiways
`been of specific concern [Z3]; nevertheless, the immunosup-
`pressive properties may be seen at doses of glucocorticoids
`above those recommended in approved therapeutic regimens
`
`Figure 5. Dexamethasone (0.5 mg/day) suppresses abiraterone-
`mediated increases in adrenocorticotropic hormone (ACTH).
`Abiraterone acetate treatment (n 2* 26) was associated with
`a significant increase in median plasma ACTH levels from 17 pg/mL
`to 124 pg/mL (66096 increase).This rise in ACTH was suppressed to
`below the lower iimit ofsensitivity (10 pg/mL) afteradministration
`of oral dexamethasone 0.5 mgfday for <14 days. Normal ACTH
`levels in adults (mean : SE): 28.7 1 12 {13, 17].
`Abbreviations: ACTH, adrenocorticotropic hormone; LLOS,
`lower limit of sensitivity; Rx, treatment.
`
`in vitro,
`for prostate cancer (e.g., prednisone 10 mg/day).
`giucocorticoids stimulate macrophage function at low con—
`centrations (e.g., 0.1 niVl), 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 pm {45]. In an animal model, prednisone
`did not affect the oxidative burst mediated by complement
`receptors during neutrophii 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
`iow~dose glucocorticoids is beiow 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 50.5 mg/kg perday for >6 months) forchronic inflammatory
`disorders, including juvenile idiopathic arthritis, systemic iupus
`erythematosus, or asthma, showed an appropriate immune
`response when immunized with influenza vaccine, successfuliy
`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]. Simiiarly, prednisone treat-
`ment did not influence the immunogenicity of an infiueriza
`vaccine in adults with rheumatoid arthritis [49], aithough
`a recent report indicated that prednisone doses 210 mg/day
`were associated with iower antibody responses in patients
`with systemic iupus erythematosus £50].
`
`"
`
`fiheilisvfifisniis étfileefie attained. with the (racem-
`'n1_e'ndei~.i_"'iciw'gdose'_'igtu_i:oé'rs_'r'ti_coiti_s'_fis b_e__2'.i9_\'c'v '-the"
`arnount shown to __inhib_it_ir_nr_nu_ne cell _p_r_o_|if_e_ration in —
`.respeF*5‘i._t9 T=."TfiEen_5.-
`. .: -. ..
`
`'_
`
`The effect of iow—dose glucocorticoids on immune re-
`sponses to personaiized peptide vaccination was evaluated in
`a study of 11 mCRPC patients [51]. Most patients, particularly
`
`www.TheOncologist.com
`
`©AlphaMed Press 2014
`
`

`

`1236
`
`Lise of Preclnisone With Abiraterone Acetate
`
`40
`
`40
`
`COU-AA-301
`
`COU-AA-302
`
`
`
`
`
`Adverseevents(96)
`
`30
`
`20
`
`10
`
`
`
`Adverseevents
`
`30
`
`20
`
`($6) 10
`
`Hypertension
`
`Hypokalemia
`
`Fluid retention]
`edema
`
`Hypertension
`
`Hypokalemia
`
`Fluid retention]
`edema
`
`N Abiraterone acetate + prednisone
`
`E Placebo + prednisone
`
`Incidence of mineralocorticoid-related adverse events in metastatic castration-resistant prostate cancer patients treated with
`Figure 6.
`abiraterone acetate plus prednisone compared with placebo pius prednisone in the COU-AA-301 and CCU-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—Twere successfully produced
`in men with mCRPC when administered concurrently with
`or priorto 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 ?ROFiLE OF AB1nAT£RONE ACETATE
`CDADMINISTERED WITH ?REDNIsoNF.
`
`Abiraterone acetate (1,000 mg) coadministerecl with pred-
`nisone (5 mg twice daily) was compared with placebo plus
`prednisone in patients with mCRPC in two phase Ill, multi-
`national, double-blind, randomized, p|acebo—controEleci tri-
`als. Study COU—AA-301 comprised 1,195 patients with mCRPC
`who had progressed after docetaxel treatment [4], and study
`COU-AA-302 invoived 1,088 patients with mCRPC who had
`not received chemotherapy and who did not have clinically
`significant cancer—re!ated symptoms (i.e., asymptomatic or
`minimally symptomatic patients) (51. 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
`
`©Alpha Med Press 2014
`
`comparable to that observed in earlier clinical studies [6, 8]. In
`both studies, adverse events associated with mineraiocorti-
`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, S3]. Notably, the majority of minera|ocorticoid~
`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
`[15I.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:
`0.2-25.5 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
`pius prednisone or prednisone atone for 224 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
`
`Ogiiologist”
`
`

`

`Auchus, Yu, Nguyen et al.
`
`1237
`
`Tabie 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
`
`Adverse
`event
`
`AA plus
`AA plus
`AA plus
`AA plus
`prednisone Prednisone prednisoione Prednisolone prednisone Prednisone prednisolone Prednisolone
`(:1 = 354)
`in = 345)
`(n ¢ 188)
`(n =“—' 195)
`in e 334)
`(n == 159)
`(n = 457)
`(n * 235)
`
`'.
`.
`'99.(2a.7)
`;
`
`':4o(21.3)_
`
`7
`..
`
`-;3_1(1_5._9)
`
`j112(33.s)
`
`34.lt1.4)
`
`.14si32.4)
`
`-_ Z
`_"-60125.5)
`'
`
`'
`
`Al|g_rades,n_(%)_._-"..._I-:___.:',-.-'
`Fiuidretentionl __ 11333.3)
`edema I
`H_ypoka_Ie_rr_ii_a
`.
`Hypertension
`Grades 1 and 2, n (96)
`
`.67{1s.9} --45:13}
`---79(22.3} ='37(1o.7)
`
`'_26l,'13.8)
`39(2o.7}
`
`._-'24(12.3}
`'36(18.5)
`
`'-
`
`':"_-56(_16.8_) '.__'1s_(9.4)
`'4o(12.o)
`14(3.s)
`
`"
`
`__ .-";s7(1_9.o)
`' "4s(1o.5)
`
`'-._21(3.'s)
`"11(4.7)
`
`_
`
`'__'
`
`Fluid retention]
`edema
`
`114 (32.2)
`
`93 £27)
`
`39 (20.7)
`
`28 (14.4)
`
`102 (30.5)
`
`34 (21.4)
`
`138 (30.2)
`
`55 (23.4)
`
`Hypokalernia
`
`57(1s.1)
`
`39:11.3)
`
`22:11.7)
`
`2oi1o.3)
`
`37(11.1)
`
`1443.3)
`
`71(1s.s)
`
`19 (3.1)
`
`27 (7.3)
`5_3(17.s}
`Hypertension
`'3' -
`._
`Grad_es3a_nd4,n_(%)
`Fluid retention[_ 3._ 4(1.1)
`s(1.7)
`
`_
`32:17)
`- _-
`'..'_'_1l0.._s)
`
`2s(14.9_)
`W
`-3(1.5)
`
`3_s{_1o.s)_ 13(8.2)
`- _-
`.'-10(3)
`
`.'.:oio)_
`
`-_
`
`_ 13:7,?)
`4_2(9.2)
`.
`I_
`_. _
`_':
`.1o_(2.2)_._-'.
`.-.4(1,7)
`--
`
`_.'=s(1._7_)
`Hypokaiemia _._'_3'_ioi_2.si
`-21012.9) _
`Hypertension
`- 15:45)
`Abbreviation: AA, abiraterone acetate.
`
`'l_i_i2.1')__
`'_ii3._7';
`
`'-4(2.1)
`. 7(3.5)
`
`_
`
`_-
`
`:;9{s.7)__ -_1_io.e)
`__-5-_ .;4i1.2) _-
`'.1(o._6} .
`
`'
`
`-1_s(3.s)__ (0.9)
`‘a__i1.3) .
`_ocoi_
`
`mineralocorticoid~related adverse events resulting from
`CYP17A1 inhibition by abiraterone.
`
`THERAPEUTIC on AD]U'NC”t"lVE Use or GLti(20C()R'l‘lL'0IDS
`IN MCRPC
`
`Glucocorticoids are often given to cancer patients to manage
`tumor-related symptoms, such as bone pain or weight ioss,
`and to alleviate toxic effects associated with specific cancer
`treatments, such as nausea, vomiting, edema, and hyper-
`sensitivity reactions related to chemotherapy I23]. Giuco~
`corticoids are aiso used in specific situations, such as pain
`palliation and to reduce swelling from cord compression or
`radiation of brain metastases. Tumor-related cachexia was
`
`in the abiraterone acetate studies. Although
`infrequent
`megestrol acetate is better tolerated than dexamethasone
`{S4}, megestrol acetate at high doses acts as a gluc