The
`.
`ncologIS‘c
`Use of Prednisone With Abiraterone Acetate in Metastatic
`
`
`
`Castration~Resistant Prostate Cancer
`
`Raaneo J. Aucuusf‘ MARGARET K.Yu,b SUZANNE Nouvanf SUNEEL D. MUNDtEc’d
`aDepartment of Internal Medicine, University of Michigan Medical Schooi, Ann Arbor, Michigan, USA; bJanssen Research & Development,
`Los Angeles, California, USA; cJanssen Scientific Affairs LLC, Johnson 31 Johnson, Horsham, Pennsylvania, USA; d{Jr‘epar‘trnentof
`Biochemistry, Rush University Medicai Center, Chicago, Illinois, USA
`Disclosures ofpotential conflicts of interest may be found at the end of this article.
`
`Key Words. Adrenal cortex hormones -
`Prostatic neoplasms
`
`tZ—{a-Pyridyll-S,16-androstaciien-Sfi-acetate - Steroid 17o-hydroxylase ~ Prednisone -
`
`ABSTRACT
`
`
`
`i
`E
`I
`
`a prodrug of the CYPl7A1 inhibitor
`Abiraterone acetate,
`abiraterone that biocks androgen biosynthesés, és approved for
`treatment of patients with metastatic castration~tesistant
`prostate cancer (mCRPC) in combination with prednisone or
`prednisolone 5 mg twice dailyThis review evaluates the basis for
`the effects of prednisone on mineratocorticoidwrelated adverse
`events that artse because of CYP17A1 inhibition with abtrater—
`
`one. Coadministration with the recommended dose of gluco-
`corticoid compensates for abiraterone-induced reductions in
`serumcortisoi 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
`
`on iongitudinal studies in autoimmune and inflammatory
`diseases and cancer. én general, glucocorticoid—related adverse
`events, including bone loss, immunosuppression, hyperglyce-
`mia, mood and cognitive alterations, and myopathy, appear
`dose retated and tend to occur at doses and/or treatment
`durations greater than the low dose of gfucocorticoéd approved
`in combination with abiraterone acetate for the treatment of
`
`mCRPC. Although glucocorticoids are often used to manage
`tumor~re|ated symptoms or to prevent treatment-related
`toxicity, available evidence suggests that prednisone and
`dexamethasone might atso offer modesttherapeutic benefitin
`mCRPC. Given recent improvements in survival achieved for
`mCRPC with novel agents in combination with prednésone,
`the risks of these recommended glucocorticoid closes must
`be balanced with the benefits shown for these regimens.
`
`The Oncologist 2014;19:1231m1240
`
`
`
`tNTRODUCTiON
`
`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 adrenai 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—Iyase (cytochrome
`P450c17 [CYP17A1]) [3]. Abiraterone acetate in combination
`with prednisone or prednisolone at a low dose of 5 mg twice
`
`daiiv has been shown to improve survival of mCRPC patients
`previously treated with docetaxel and those who had not
`received prior chemotherapy [4, 53. The administration of
`abiraterone acetate with glucocorticoids is necessary to
`manage adverse events related to mineralocorticoid excess,
`such as hypokaiemia, hypertension, and fluid retention, which
`can occur as a reSuEt of CYP17A1 inhibétion {6%}. This review
`evaiuates the basis for the remedial effects of low-dose
`
`prednisone to prevent mineralocorticoid excess-related
`
`Correspondence: Richard J. Auchus, MD, Ph.D., University of Michigan, Department of tnternal Medicine,- Division of Metaboiism,
`Endocrinology, and Diabetes. 5560 M588 ll, Ann Arbor, Michigan 481096678, USATelephone: 734-615-9497; E-Mail: rauchus@med.umich.
`edu Received April 24, 2014; accepted for publication September 23, 2014,- first published online in The Oncologist Express on October 31,
`2014. ©A|phaMed Press 1083—7159/2014/S20.00/0 http://dx.doi.orgfio.1634/theoncologist.2{3t4—0167
`
`The Oncologist 2014;19:1231w1240 www.TheOncologist.corn
`
`©AtphaiVled Press 2014
`
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`

`

`1232
`
`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, an d metastatic
`castrateresistont prostate concerfor clinicai trials, reviews, and
`case reports pubiished in Engiish without filtering for dates.
`Information selected for this article was obtained from pre-
`clinicai 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 co—
`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 giucocorticoid
`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 inciuded [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 0N SYNTHESIS OF ADRENAL
`STEROIDS BEYOND ANDROGENS
`
`Abiraterone is a potent, selective, and irreversible inhibitor of
`CYP17A1, a microsomal enzyme with 17a-hydroxylase and
`Cum-iyase 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
`CYPl7A1 activities, cortisol biosynthesis requires onlythe 17a-
`hydroxylase activity of CYP17A1. The efficacy of abiraterone
`in blocking androgen biosynthesis is shown by substantial
`reductions in serum androgen ievels (Fig. 2} E8, 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 ieads 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, hypokaiemia, 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 ng/dL (138—635 nmol/L]
`and midnight serum cortisol <5 ,ug/dL (<138 nmol/L). in
`studies of mCRPC patients, abiraterone reduced serum
`cortisol to near the lower iirnit of the normal range {8] and
`increased ACTH from a median of 17 pg/mL (range: <9w50
`pg/mtlto 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.4ii5, 15,16]. Foliowingthis principle,the potent
`glucocorticoid dexamethasone normalizes the abiraterone-
`induced rise in ACTH (Fig. 5) {13]. Prednisolone or its
`precursor prednisone is approximateiy four times more
`potent as a giucocorticoid 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 giucocorticoid replace-
`ment(Fig. 4) {16]. At this dose, the mineralocorticoid activity of
`prednisolone is minimai [3.9].
`Glucocorticoid replacement therapy, as defined in this
`paper, has been shown to effectively reduce the incidence of
`mineralocorticoid-reiated adverse events in patients with
`mCRi’C treated with abiraterone acetate (discussed below)
`[4, 5]. Similarly, subjects with congenital CYP17A1 deficiency
`produce excessive mineraiocorticoids and develop hypertenw
`sion and hypokalemia [20], which can be mitigated by glu-
`cocorticoid replacement therapy, including low~dose prednisone
`or prednisolone [21]. The use of giucocorticoid replacement
`to correct treatment—related steroid imbaiances is similar to
`
`the use of glucocorticoid replacement therapy for other forms
`ofacute 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
`prednisoione in newly diagnosed patients with metastatic,
`hormone-naive prostate cancer (ClinicalTrials.gov identifier
`NCT01715285). in the phase i and II trials, abiraterone acetate
`was administered without any giucocorticoid, and hyperten-
`sion and hypokalemia were successfuily managed with
`the mineralocorticoid receptor antagonist epierenone at an
`average dose of 50 mg/day, often with addition of dexameth-
`asone 0.5 mg/day on progression [13].
`
`OrTliiologist‘
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 2
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`

`

`1233
`Auchus, Yu, Nguyen at ai.
`
`351,2
`
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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 mineralocorticoid excess [11].
`Abbreviations: DH EAi-Sj, dehydroepiandrosterone {sulfate}; DHT, dihydrotestosterone.
`
`Abiraterone dose {mg}
`
`+ 250
`
`500 +750
`
`+1.000
`
`100
`90
`
`
`
`Baseline
`war—7)
`
`Day 28
`
`9 8
`
`i 7
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`
` 70
`
`
`30
`20
`10
`O
`
`Baseiine
`{day *7)
`
`Day 28
`
`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: DH EA—S, dehydroepiandrosterone sulfate.
`
`PHARMACOLOGIC EFFECTS or Lows—TERM
`GLUCOCDRTICOID THERAPY
`
`It is weli 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 [2346}. Glucocorticoidrrelated 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 proionged
`treatment period or to use of high doses during short-term
`exposure.
`
`Glucocorticoids may induce bone mineral 3055 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 giucocorticoid treatment at 7.5 mg/
`day for longer periods {>6 months) [28}.
`In addition, the
`
`www.TheOncoiogist.com
`
`©AipnaMed Press 2014
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 3
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`

`

`1234
`
`Use of Prednisone With Abiraterone Acetate
`
`10,000
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`
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`
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`
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`
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`
`15,000
`
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`
`(ng/di.) g D
`concentration
`
`250
`
`500
`
`750
`
`1,000 2,000
`
`Dose (mg)
`
`Figure 3. Abiraterone increases steroids with mineralocorticoid activity upstream of CYP17A1. Shown are median serum ievels 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 daily. The right panel shows mean corticosterone levels at day 28 by abiraterone acetate dose [12].
`
`frequency of short‘course oral glucocorticoici bursts has been
`associated with reductions in bone mineral density and ins
`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 yearswith additional
`foliOW—up for a median of 4 years [29, 30].
`For patients who have a set of autosomai recessive diw
`seases known as congenital adrenal hyperplasia (CAH), long-
`term disease management using glucocorticoid therapy often
`negatively affects bone health and quality of life [31]"th most
`common form of CAH is 21~hydroxylase deficiency (210HD),
`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 aidosterone 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 210HD 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 210HD 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 specificaily to a lifetime
`of prolonged exposure to supraphysiologic giucocorticoids
`necessary to control androgen excess. Optimized glucocorti-
`coid 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 eiderly 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 sh0uld
`be done with caution.
`
`Giucocorticoids 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 cumuiative dose for patients with steroid-induced
`hyperglycemia was 26.5 g compared with 11.6 g for those
`without steroiduinduced 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 transpiant 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 giucocorticoid
`maintenance (5%) [35].
`Giucocorticoids exert negative effects on mood and cog-
`nitive function that, again, correlate with the dose and/or
`length of treatment [35]. In a cohort of 27 children (aged 8—15
`years) with severe asthma treated with prednisoione 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 giucocorticoid 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-
`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 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 docetaxei or mitoxantrone, severe
`fatigue was reported in 5% of patients, yet myopathy was not
`reported [40]. Similariy, grade 3 fatigue was reported in 8% of
`men with mCRPC after chemotherapy who received thalido-
`mide plus orai dexamethasone [41]. In the COU-AA—302 trial of
`
`Tiiologist“
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`

`

`Auchus, Yu, Nguyen et al.
`
`300
`
`1235
`
`ACTH median (pg/mt]
`124
`
`120
`
`
`
`Prednisoione(nmol/L)
`
`100
`
`250 -
`
`200 -
`
`
`
`50
`150 -‘
`
`30 L105 "‘" 10
`
`
`8 lw 39w
`Abiraterone + 05 mg
`Single-agent
`Pre-Rxln :26)
`I Hos
`7
`1
`denmethasone (n = 6]
`abiraterone [n = 26)
`
`0
`
`Figure 5. Dexamethasone (0.5 mg/day) suppresses abiraterone—
`mediated increases in adrenocorticotropic hormone (ACTH).
`Abiraterone acetate treatment (n r: 26] was associated with
`a significant increase in median piasma ACTH levels from 17 pg/mi.
`to 124 pg/mi. (660% increase).This rise in ACTH was suppressed to
`below the iower iimit ofsensitivity (10 pg/mL) after administration
`of oral dexamethasone 0.5 mg/day for <14 days. Normal ACTH
`levels in adults (mean : SE): 28.7 i 12 [13, 17].
`Abbreviations: ACTH, adrenocorticotropic hormone; LL05,
`lower iirnit of sensitivity; Rx, treatment.
`
`in vitro,
`for prostate cancer (e.g., prednisone 10 mg/day].
`glucocorticoids stimuiate 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 luM) [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 equivaient to 90 mg/day in
`humans [46].
`The systemic exposure attained with the recommended
`iow~dose glucocorticoids is below the amount shown to inhibit
`immune ceil proiiferation in response to antigens. Pediatric pa-
`tients treated with prednisone (2 mg/kg per day for 5 days,
`or 30.5 rug/kg per day for >6 months) forchronic inflammatory
`disorders, includingjuvenile idiopathic arthritis, systemic iupus
`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 chiidren 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], aithough
`a recent report indicated that prednisone doses 210 mg/day
`were associated with iower antibody responses in patients
`with systemic iupus erythematosus [50].
`
`[Th'éfi'svsteimic .expos'iir'e attained with thiiécom-
`mended g'iow-aosia giucocorticdids is" below the
`amount shown to inhibit immuneceliproliferation in
`.respsnseto antigens-
`
`'
`
`'
`
`The effect of low—dose glucocorticoids on immune re—
`sponses to personalized peptide vaccination was evaluated in
`a study of 11 mCRi’C patients (51]. Most patients, particuiariy
`
`Figure 4. Low-dose prednisolone yields the equivalent of phy-
`siologic cortisol levels. Daily prednisolone (10 mg/dayl with abi-
`raterone acetate (1,000 mg/day) in 15 castration-resistant
`prostate cancer patients led to median prednisolone concen—
`trations of 152 nmoi/L (solid tine). Given an ~4:1 relative potency
`of prednisolone:hydrocortisone, 152 X 4 is equivalent to 608
`nmol/L cortisol, which is within physiologic concentrations [16].
`Dotted line is 10 nmolfL.
`
`chemotherapyanai've mCRPC patients {42], muscie 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—aione arm (data on file, Janssen Research 8: Devel-
`opment, 2012].
`in other disorders, giucocorticoidnlnduced my-
`opathy has been associated primariiy with high-dose steroid
`treatment, a sedentary lifestyle, and the use of fluorinated
`steroids (e.g., triamcinolone, dexarnethasone) rather than non-
`fluorinated steroids (e.g., hydrocortisone, prednisone) [43, 44].
`The giucocorticoid~induced myopathy is fully yet siowly 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, centrai nervous system effects, and myopathym
`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 potentiai adverse
`effects of glucocorticoids in an elderly population of men with
`prostate cancer, the patients‘ comorbiditles, family history,
`and prior giucocorticoid and medication exposure should be
`ta ken into account.
`
`
`EFFECT OF PRsDNISONE on lMMUNE FUNCTioN
`
`Giucocorticoids have been commonly used in cancertreatment,
`although their immunosuppressive properties have aiways
`been of specific concern (23]; nevertheless, the immunosup»
`pressive properties may be seen at doses of glucocorticoids
`above those recommended in approved therapeutic regimens
`
`www.TheOncologist.com
`
`©AlphaMed Press 2014
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 5
`
`

`

`1236
`
`Use of Prednisone With Abiraterone Acetate
`
`COU-AA-BOI
`
`COU-AA-BOZ
`
`
`
`
`
`Adverseevents(56)
`
`
`
`Hypertension
`
`Hypokalemia
`
`Fluid retention]
`edema
`
`Adverseevents
`
`
`
`[96)
`
`Hypertension
`
`Hypokaiemia
`
`Fluid retention]
`edema
`
`I Abiraterone acetate + prednisone
`
`a 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 COlJ-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-ceil
`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, Eow 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 ?RGFILE 0F ABIRATiSRONE ACETATE
`CDADMENISTERED 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 1,083 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 resuits from these studies, abiraterone acetate
`in combination with prednisone was approved for the
`treatment of patients with mCRPC.
`COU-AA—301 and COU-AA—BOZ 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 mineraiocorti-
`coid activity were more common for abiraterone acetate plus
`prednisone than for prednisone alone (Fig. 6) [4, 5], but their
`incidence was largeiy abrogated by low-dose prednisone when
`compared with earlier studies of abiraterone acetate mono—
`therapy [8, 12, 53]. Notably,the majority of mineraiocorticoid“
`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 fiuid
`retention or edema (2.5% vs. 1.0%), was low and manageable
`[15). The incidence of these severe adverse events in CCU—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 of7.4 months (range:
`ill—25.6 months) in CCU—AA—301 [15].
`in COU~AA~302, no
`glucocorticoidwrelated 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 aione for 224 months, with
`cumulative incidence rates of selected adverse events in-
`
`ciuding 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 |ow~dose
`prednisone can be deiivered safely without any consistent
`additional serious adverse effects while adequately managing
`
`031501035?
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 6
`
`

`

`I
`
`Auchus, Yu, Nguyen et al.
`
`1237
`
`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 pred nisolone {European Union sites).
`
`COUAAAHSOZ
`
`cou-AA-sot
`
`Adverse
`event
`
`AA plus
`AA pins
`AA plus
`AA plus
`prednisone Prednisone prednisolone Prednisolone prednisone Prednisone prednisolone Prednisolone
`(:1 = 354)
`(n = 345)
`(n = 188)
`(n = 195}
`(n = 334)
`(n = 159)
`(n = 457)
`{n = 235}
`
`Augrades’nwy . . I.
`ngidretention/I-i11883.3)
`'99i28..7_)_ ._-'=40i21.3)
`-._3_1(15._9)
`eema
`:
`.- . _ .
`Hypotalemia 67118.9) 45(13) . -'..26(_13.8) - 224(123}
`Hypertension
`" 79(223)
`'37i1o.7) 53900.7) --"'3s(18.5)
`Grades 1 and 2, n (96)
`
`.
`
`34(21-4l""148_l32-4l
`"_1_12_i33._$l
`_-_"6_0.i2$-5i
`. _.
`_...
`-"'56(16,8_) 1-15 (9.4)
`' 87119.0)
`.
`_--_21(8.s_i)_
`“40(120) skiing)
`'itsitos)
`11(4.7)
`
`"
`
`._.
`
`Fiélidretention/
`E ema
`Hypokalemia
`Hypertension
`
`114 (32.2)
`57(16.1)
`53 (17.8)
`
`93 (27)
`39(11.3)
`27 (7.8)
`
`39(207)
`22(11.7)
`32 (17)
`
`28(144)
`20 {103)
`29 (14.9)
`
`muses.)
`37(11.1)
`35 (10.8)
`
`34 {21.4)
`14 {8.8)
`13 (3.2)
`
`13380.2)
`71(155)
`42 (9.2)
`
`55 (23.4)
`19 (3.1)
`13 (7.7)
`
`GradeSSand4,n(_%)
`Eluidretention
`-'."'4i1.1)_.
`edema-
`._
`'. “2.1) _
`._: no.7)
`Hypokalemia
`-;t](2.8) _
`'10.i2..9). "-'_'7.i3.7).
`Hypertension
`15:43)
`Abbreviation: AA, abiraterone acetate.
`
`'
`
`"
`
`;
`
`'.'
`:' . '_
`'.
`"
`ism). :_-.T1io.s)_._
`'-
`' 1341.5)
`I' H
`-
`_--.4(2.1)
`713.5)
`
`'.._--.1_0i3)
`
`'.
`..
`
`.;_19i5._7)
`.4i1.2)
`
`-
`
`.
`
`-
`
`.
`0(0)
`..
`_- “0.5)
`-':1io.6)
`
`"
`' 10(22) .-
`
`.
`
`.4.i1.7)
`
`15(35)
`- {5(13)
`
`zine) __
`: -_ oio)
`
`'
`
`.'
`
`mineraiocorticoidrelated adverse events resulting from
`CYP17A1 inhibition by abiraterone.
`
`
`THERAPEUTIC UR ADIUNC'i'lVi'.‘ USE OF GLUCOCOR'l‘ICOIDS
`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]. Giucoe
`corticoids are aiso used in specific situations, such as pain
`palliation and to reduce sweliing from cord compression or
`radiation of brain metastases. Tumor-related cachexla was
`
`in the abiraterone acetate studies. Although
`infrequent
`megestroi acetate is better tolerated than dexamethasone
`£54}, megestrol acetate at high doses acts as a glucocorticoid
`receptor modulator and causes adrenal axis suppr