`
`ELSEVIER
`
`GLUCOCORTICOIDS AND TREATMENT OF PROSTATE
`CANCER: A PRECLINICAL AND CLINICAL REVIEW
`
`MARWAN FAKIH, CANDACE S. JOHNSON, AND DONALD L. TRUMP
`
`G lucocorticoids have been used for a substan(cid:173)
`
`tial period to treat patients with advanced an(cid:173)
`drogen-independent prostate cancer (AIPC). Al(cid:173)
`though known for their anti-inflammatory activity,
`glucocorticoids have antitumor activity in various
`hematologic malignancies. The role of glucocorti(cid:173)
`coids as antineoplastic agents in epithelial tumors
`is less well defined. Their use in these tumors has
`been strictly palliative.
`Glucocorticoids have been widely used in the
`treatment of advanced prostate cancer and have
`served as the "standard" therapy arm in several
`randomized studies. Although multiple studies of
`glucocorticoid use in prostate cancer have been
`conducted, their therapeutic role remains unclear.
`We review the information regarding the mecha(cid:173)
`nisms underlying glucocorticoid antitumor effects
`in prostate cancer and critically review the results
`of clinical trials using these agents.
`
`MECHANISMS OF ACTIVITY
`
`The cytotoxic effect of glucocorticoids in hema(cid:173)
`tologic cells is well defined. 1
`4 Glucocorticoids
`-
`bind to a cytosolic receptor that localizes to the
`nucleus, leading to a variety of transcriptional
`modifications. This ultimately results in upregula(cid:173)
`tion of multiple caspases, leading to apoptotic cell
`death. 5 Glucocorticoids do not induce apoptosis in
`prostate cancer cells, let growth inhibitory effects
`are well documented. '7 We have demonstrated di(cid:173)
`rect antiproliferative effects in the hormone-refrac(cid:173)
`tory human PC-3 and rat Mat-Ly-Lu cell lines as
`
`Supported by grants from the Mary Hillman Jennings Foundation
`and CaPCURE. D. L. Trump and C. S.]ohnson receive research
`fundingfrom Bristol Myers Squibb, Aventis, and D-Novo.
`From the Departments of Medicine, Division of Hemato1ogy(cid:173)
`Onco1ogy and Pharmacology, University of Pittsburgh School of
`Medicine; and University of Pittsburgh Cancer Institute, Pitts(cid:173)
`burgh, Pennsylvania
`Reprint requests: DonaldL. Trump, M.D., Department of Med(cid:173)
`icine, University of Pittsburgh Cancer Institute, Montefiore Uni(cid:173)
`versity Hospital, N 723, 200 Lothrop Street, Pittsburgh, PA
`15213
`Submitted: January 30, 2002, accepted (with revisions): March
`28,2002
`
`measured by cell cycle arrest and modulation of the
`cdk inhibitors, p21 and p27. The mechanisms of
`this growth inhibitory effect are not clear. How(cid:173)
`ever, several mechanisms have been postulated.
`
`SUPPRESSION OF ADRENAL ANDROGEN
`SECRETION
`
`Glucocorticoids may exert an antitumor effect
`on androgen-independent prostate cancer by sup(cid:173)
`pression of adrenal androgens. Low-dose glu(cid:173)
`cocorticoids produce negative feedback on the pi(cid:173)
`tuitary gland, leading to a decrease in both
`testicular and adrenal androgens. 8
`9 Plowman et
`'
`al. 10 reported on 17 orchiectomized patients with
`progressive prostate cancer who were treated with
`hydrocortisone 30 mg/day. A significant decrease
`in testosterone, androstenedione, and dihydroan(cid:173)
`drostenedione (DHEAS) levels was noted with
`therapy. Similarly, Tannock et al. 11 noted a de(cid:173)
`crease
`in
`testosterone, androstenedione, and
`DHEAS levels in association with low-dose pred(cid:173)
`nisone therapy (7.5 to 10 mg daily) in surgically or
`medically castrated patients with advanced pros(cid:173)
`tate cancer. Symptomatic relief was associated with
`a decrease in the adrenal androgen levels. Eight of
`13 patients who had a decrease in DHEAS levels by
`1 µ,mol/L or greater had improvement in pain and
`only 1 of 8 patients with unchanged or increased
`DHEAS levels had symptomatic improvement.
`
`PARACRINE/AUTOCRINE FACTOR
`MODULATION
`
`Glucocorticoids can inhibit prostate cancer cell
`growth by modulating cellular growth factors such
`as lipocortin, tumor growth factor beta-I (TGF/3-
`1), urokinase-type plasminogen activator (uPA),
`and interleukin-6 (IL-6).
`
`LIPOCORTIN
`Glucocorticoids mediate their anti-inflammatory
`effects in part by way of lipocortin, a member of the
`annexin family (calcium and phospholipid-bind(cid:173)
`ing proteins) .12
`13 Lipocortin gene transcription is
`'
`upregulated by glucocorticoids, resulting in in-
`
`© 2002, EISEVIER SCIENCE lNC.
`Ali RIGHTS RESERVED
`
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`creased cellular levels. Lipocortin is subsequently
`secreted from the cells to mediate its anti-inflam(cid:173)
`matory effects at the membrane level by inhibiting
`15 Lipocortin also mediates,
`phospholipase A2. 14
`'
`at least in part, the antiproliferative effects of glu(cid:173)
`cocorticoids. Carollo et al. 6 showed that the inhib(cid:173)
`itory effect of dexamethasone on androgen inde(cid:173)
`pendent PC-3 cells is completely abolished if the
`cells are incubated with sheep antihuman lipocor(cid:173)
`tin antibodies. The mechanism through which li(cid:173)
`pocortin mediates its antiproliferative effect is not
`well defined.
`
`TRANSFORMING GROWTH FACTOR BETA-1
`TGF-/31 is a member of a group of dimeric pep(cid:173)
`tides that modulate multiple cellular functions, in(cid:173)
`cluding extracellular matrix expression, differenti(cid:173)
`ation, and cellular proliferation. 16 TGF-/31 has
`dual inhibitory and stimulatory effects on the
`growth of prostate cancer. Hsing et al. 17 treated
`both tumorigenic (NRP-154) and nontumorigenic
`(NRP-152) rat prostate cell lines with TGF-/31.
`TGF-/31 induced cell death by apoptosis in both
`cell lines. The effects were enhanced by dexameth(cid:173)
`asone and inhibited by insulin growth factor-1.
`Dexamethasone increased TGF-/31 mRNA expres(cid:173)
`sion in androgen-insensitive PA-Ill prostate cancer
`cell lines in association with growth inhibitory ef(cid:173)
`fects.18 Co-treatment of PA-Ill with TGF-/31 anti(cid:173)
`body reversed the dexamethasone antiprolif erative
`effects. This suggests that the inhibitory role of
`dexamethasone may be mediated by TGF-{31. 18
`Barrack19 and Morton and Barrack,20 on the other
`hand, showed that TGF-/31 was implicated in tu(cid:173)
`mor progression. They showed that although
`TGF-/31 had no inhibitory effects on the growth of
`the hormone-independent, rat prostate Mat-Ly-Lu
`cancer cell line, it stimulated motility and fibronec(cid:173)
`tin expression. 20
`
`UROKINASE-TYPE PLASMINOGEN ACTIVATOR
`uPA, a serine protease, is implicated in the pro(cid:173)
`gression of various malignancies, including pros(cid:173)
`tate cancer. Serum uPA levels are higher in patients
`with metastatic prostate cancer than in those with
`localized disease. 21 uP A increases the invasiveness
`and stimulates tumor migration and growth when
`expressed in hormone-responsive human prostate
`LNCaP cell lines.22'23 Furthermore, uPA has direct
`stimulatory effects on osteosarcoma cells and may
`play an important role in the patho~hysiology of
`blastic lesions in prostate cancer. 24- 6 Dexameth(cid:173)
`asone downregulates uPA mRNA and its protein
`expression in both PC-3 and PA-Ill cell lines. 24 By
`downregulating uPA, glucocorticoids may inhibit
`the growth and invasiveness of prostate cancer
`cells.
`
`lNTERLEUKIN-6
`Recently, Nishimura et al. 27 showed that dexa(cid:173)
`methasone had growth inhibitory effects on the
`DU-145 AIPC human cell line. These inhibitory
`effects were associated with a dose-dependent up(cid:173)
`regulation of inhibitor of kappa B (IKBa) a key
`inhibitor of nuclear factor-kappa B (NF-KB). A
`subcellular localization evaluation of DU-145 cells
`pretreated with dexamethasone confirmed the loss
`of NF-KB nuclear localization. NF-KB is an impor(cid:173)
`tant regulator of several cytokines, including IL-
`6.28 lt is believed that loss of nuclear compartmen(cid:173)
`talization of NF-KB leads to inhibition of IL-6
`secretion, thus leading to a favorable growth inhib(cid:173)
`itory effect. Consistent with this hypothesis is the
`inhibition of DU-145 cell growth by IL-6 antibod(cid:173)
`ies, as well as the fourfold decrease in IL-6 levels in
`patients treated with low-dose dexamethasone. 27
`
`SUPPRESSION OF ANDROGEN-DEPENDENT
`TRANSCRIPTION
`
`Androgen and glucocorticoid receptors share a
`significant degree of homology, especially in their
`DNA-binding domain (DBD). Both receptors bind
`through their DBD to a common DNA site termed
`the hormone receptor element. AR, GR, and MR
`(mineralocorticoid receptors) bind to hormone re(cid:173)
`ceptor element as homodimers. Although these re(cid:173)
`ceptors bind to the same DNA site, they result in
`different transcriptional activities. Factors other
`than DBD-hormone receptor element interaction
`determine the specificity of the transcriptional ac(cid:173)
`tivity. Chen et al. 29 has recently demonstrated that
`GR and AR can associate through their DBD to
`form a heterodimer. This heterodimer formation
`results in an inhibitory effect on androgen-specific
`transcription in vitro. This transcriptional inhibi(cid:173)
`tion can lead to inhibition of the necessary down(cid:173)
`stream events for the growth of prostate cancer
`cells. These results should be extrapolated with
`caution, because it has not been shown yet that GR
`and AR form heterodimers in vivo.
`
`GLUCOCORTICOID-DRIVEN CELLULAR
`PROLIFERATION
`
`Although the data discussed above point to an
`inhibitory effect of glucocorticoids on prostate
`cancer cell lines, a stimulatory effect has been also
`documented. Zhao et al. 30 described two cell lines
`(MDA PCa 2a and 2b) derived from bony metasta(cid:173)
`ses of a patient with progressing prostate cancer
`despite hormonal therapy. These cells carry a mu(cid:173)
`tated AR (L701H and T877 A) that has a high affin(cid:173)
`ity to cortisol and cortisone. Both cortisol and cor(cid:173)
`tisone resulted in enhanced cellular prolif era ti on
`and prostate-specific antigen (PSA) secretion in
`these two cell lines.3° Chang et al. 31 studied the
`
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`effects of various endogenous and synthetic glu(cid:173)
`cocorticoids on LNCaP prostate cancer cell line
`(AR T877 A mutant) growth and PSA secretion.
`Both 11-deoxycorticosterone (DOC) and dexa(cid:173)
`methasone stimulated the AR-dependent PSA se(cid:173)
`cretion. Furthermore, DOC was able to stimulate
`cellular growth at physiologically achievable lev(cid:173)
`els, and dexamethasone seemed to have only a
`modest agonistic effect. These effects were medi(cid:173)
`ated through the mutated T877 A AR.
`
`CLINICAL UTILITY OF GLUCOCORTICOIDS
`IN AIPC
`
`Despite the limited preclinical data regarding the
`mechanism of their inhibitory effects on prostate
`cancer cell growth, glucocorticoids are used exten(cid:173)
`siveli in the treatment of AIPC. Miller and Hin(cid:173)
`man 2 were the first to report on the clinical activ(cid:173)
`ity of glucocorticoids in AIPC. Ten patients with
`advanced prostate cancer who had progressed de(cid:173)
`spite prior orchiectomy and estrogen therapy were
`treated with cortisone 50 to 200 mg/day. Subjective
`symptomatic improvements were noted in 8 of IO
`patients.32 Since this initial publication, multiple
`studies have evaluated single-agent glucocorti(cid:173)
`coids in the treatment of AIPC. These studies have
`ranged from retrospective analyses to Phase Ill tri(cid:173)
`als.
`
`RETROSPECTIVE AND PHASE II TRIALS
`Phase II and retrospective studies before 1995
`did not use PSA as a marker of disease activity
`and relied on subjective response criteria
`33 ·34 Tannock et al. 11 evaluated retro(cid:173)
`(Table I). 11
`•
`spectively in 28 patients and prospectively in 3 7
`patients, the palliative effects of daily prednisone
`7.5 to IO mg. All enrolled patients had symptom(cid:173)
`atic bony metastases with evidence of disease pro(cid:173)
`gression despite orchiectomy and/or estrogen ther(cid:173)
`apy. Of 28 patients analyzed retrospectively, 7 had
`improvement in pain and reduced requirements
`for analgesics lasting a median of 5 months. In 3 7
`patients evaluated prospectively, 14 patients
`(38%) had improvements in pain and a leveling or
`a decrease in their analgesic requirements for at
`least I month. The reduction in pain was associ(cid:173)
`ated with improvements in quality of life ( QOL).
`The clinical benefits lasted 3 to 30 months in 7
`patients. Alkaline phosphatase and acid phospha(cid:173)
`tase were evaluated in this study but did not show
`any evidence of correlation with clinical response.
`Patel et al. 34 treated patients with prostate cancer
`and measurable disease that had progressed de(cid:173)
`spite orchiectomy or estrogen therapy with low(cid:173)
`dose dexamethasone. Fifty-eight patients were
`randomized to receive either megestrol acetate or
`dexamethasone 0.75 mg daily. The study had com-
`
`plex response criteria that involved evaluations of
`multiple variables (bone scan, computed tomogra(cid:173)
`phy, chest radiography, pain evaluation, acid phos(cid:173)
`phatase, weight, performance status, alkaline
`phosphatase, and hemoglobin). Two of 29 patients
`on the dexamethasone arm had evidence of disease
`regression each lasting 359 and 512 days. Twenty(cid:173)
`one patients had stable disease at a median of 86
`days. The median survival on the dexamethasone
`arm was 246 days.
`Studies conducted since 1995 used PSA as a
`marker for response (Table I). PSA is not a perfect
`response endpoint, but it is agreed as an indicator
`of biologic activity.35'36 The Prostate-Specific An(cid:173)
`tigen Working Group has developed guidelines for
`using PSA as a measurement of outcome. Only a
`PSA decrease of more than 50% with a sustained
`decrease for 4 weeks is considered a PSA re(cid:173)
`sponse.36 Such a decrease has been associated with
`an extension in overall survival in several stud(cid:173)
`ies.37,38
`Storlie et al. 39 retrospectively evaluated 38 pa(cid:173)
`tients who had progressive disease despite orchiec(cid:173)
`tomy and were treated with 0.75 mg dexametha(cid:173)
`sone two or three times a day. They reported a 63%
`subjective symptomatic improvement and a 79%
`PSA decrease of more than 50%. The median time
`to biochemical progression in responders (PSA in(cid:173)
`creases of greater than 50%) was 245 days (range
`99 to 660). Thirty-five percent of PSA responders
`had some evidence of bony disease regression and
`none of the nonresponders did. The study included
`only patients who had adequate follow-up. Thus,
`the study has potentially excluded nonresponders
`with early dropout because of disease progres(cid:173)
`sion.39
`Kelly et al. 40 conducted a Phase II trial in which
`30 patients with AIPC were treated with hydrocor(cid:173)
`tisone 40 mg/day. Suramin was added to the treat(cid:173)
`ment regimen at the time of PSA progression. All
`patients must have had evidence of disease pro(cid:173)
`gression and documented castrate testosterone lev(cid:173)
`els before entry on study. Patients who were taking
`flutamide had to have the drug discontinued; they
`were entered on trial only if they showed disease
`progression after flutamide withdrawal. Six pa(cid:173)
`tients (20%) had a decrease in PSA of more than
`50% and the median duration of the decline was 16
`weeks. One patient had a PSA decline of 99% last(cid:173)
`ing more than 52 weeks and I patient had PSA and
`bone scan stabilization lasting more than 44 weeks.
`Sartor37 retrospectively reviewed the results of
`29 consecutive patients with AIPC treated with
`prednisone IO mg twice daily. All patients had to
`have a rising PSA despite adequate androgen abla(cid:173)
`tion to be entered in the trial. Flutamide with(cid:173)
`drawal was ruled out as a possible confounding
`variable in all assessable patients. Ten (34%) of 29
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`TABLE I. Phase II and retrospective studies evaluating glucocorticoids in the treatment of progressive hormone-resistant prostate cancer
`Patients (n) and
`Quality of Life and
`Objective Responses and
`MST and TIP
`(mo)
`Treatment
`Post-Therapy PSA Decline
`Subjective Responses
`37; prednisone 7.5-10
`NA
`38% had improvement
`mg
`in pain score at 1 mo;
`19% had sustained
`improvement in pain
`for 3-30 mo
`
`Entry Criteria
`Failed orchiectomy and/or
`estrogen therapy
`
`Study
`Tannock et al., 11
`1989, prospective
`study
`
`Patel et a/., 34 1990,
`prospective study
`
`29; dexamethasone
`0.75 mg BID
`
`Nishiyama,41 1998,
`prospective study
`
`7; low-dose
`dexamethasone 1 .5-
`0.5 mg/day
`
`Sartor, 37 1998,
`retrospective study
`Storlie et a/., 39 1995,
`retrospective study
`
`Kelly et a/., 40 1995,
`prospective study
`
`Weitzman et a/.,42
`2000, prospective
`study
`Nishimura et a/.,43
`2000, prospective
`study
`
`29; prednisone 10 mg
`BID
`38; low-dose
`dexamethasone 0.75
`BID/TID
`30; hydrocortisone 25
`mg 0AM and 1 5 mg
`0PM
`12; dexamethasone 20
`mg PO 06 x 3 03
`wk
`37; dexamethasone
`0.5-2 mg OD
`
`Failed orchiectomy or
`diethyl-stilbestrol
`therapy
`Patients with orchiectomy
`or LHRH therapy with
`progression after
`secondary hormonal
`therapy withdrawal
`Failed orchiectomy or
`LHRH agonist
`Failed orchiectomy;
`progressive disease
`
`Progressive AIPC
`
`Progressive AIPC
`
`Progressive AIPC
`
`2/29 objective responses
`(decrease in measurable
`disease)
`417 (PSA decrease of >90%)
`after 3 mo of therapy
`
`MST 6.7
`
`TIP 3-11
`
`MST 12.8; median
`TIP 2
`
`63% had symptomatic
`improvement
`
`34% (PSA decrease of
`>50%)
`PSA response: 79% had a
`PSA decrease >50% (not
`confirmed at 4 wk)
`20% (PSA decrease of
`>50%); 1 Pt had >99%
`PSA decrease
`0% PSA response
`
`62% PSA response (>50%
`decrease confirmed in 4
`wk)
`
`MTP 9
`
`11 /18 had improvement
`in pain
`
`KEY: PSA = prostate-specific antigen; MST = mean survival time; TTP = time to progression; NA = not available; BID = twice daily; LHRH = luteinizing hormone-releasing hormone; TID = three times daily; Q = every; Pt = patient; PO = orally;
`AIPC = androgen-independent prostate cancer; QD = every day; MTP = median time to progression.
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`patients achieved a PSA decline of more than 50%.
`Patients who had more than a 50% decline in their
`PSA level had a median survival time (MST) of 17. 4
`months compared with 12.8 months in the overall
`patient population. The median progression-free
`survival was 2 months; however, 14% had a pro(cid:173)
`gression-free survival of more than 6 months. Al(cid:173)
`though the PSA response rate of 34% was higher
`than what has been reported with a daily 10-mg
`prednisone regimen, the retrospective nature of
`the study and the small number of patients limited
`result interpretation. The results of the study, how(cid:173)
`ever, suggest an association between a decline of
`more than 50% in PSA and prolonged survival.
`Nishiyama41 evaluated in a small prospective
`study 16 patients with bony metastases in whom
`hormonal therapy had failed. All patients had been
`treated with orchiectomy or a luteinizing hor(cid:173)
`mone-releasing hormone analogue in combination
`with chlormadinone acetate, estramustine, or flut(cid:173)
`amide. Patients underwent hormonal withdrawal
`before study entry. Seven patients progressed de(cid:173)
`spite hormonal withdrawal and were treated with
`dexamethasone 1.5 mg daily. Three of these pa(cid:173)
`tients had a PSA response of more than 50%, and
`all responses lasted more than 6 months.
`Weitzman et al. 42 evaluated a high-dose inter(cid:173)
`mittent schedule of dexamethasone in patients
`with progressive prostate cancer despite androgen
`ablation. Twelve patients were treated with 20 mg
`dexamethasone every 6 hours for three doses re(cid:173)
`peated every 3 weeks. None of the patients had a
`decrease in PSA of more than 50%. Although the
`number of patients was small, these data suggest a
`lack of efficacy of an intermittent schedule using
`glucocorticoids.
`Most recently, Nishimura et al. 43 evaluated, in a
`prospective trial, the use of low-dose dexametha(cid:173)
`sone in AIPC. Thirty-seven patients with a rising
`PSA and castrate testosterone levels were treated
`with daily dexamethasone 0.5 to 2 mg. Forty-nine
`of these patients had symptomatic metastases on
`entry. The median pretreatment PSA was 38 ng/mL
`(range 2.4 to 3570). Antiandrogens were discon(cid:173)
`tinued at least 4 weeks before initiation of dexa(cid:173)
`methasone. Twenty-three patients (62%) had a
`PSA decline of more than 50% that was sustained
`for more than 4 weeks. Four of the responders had
`decreasing PSA after antiandrogen withdrawal and
`before the start of dexamethasone. The median
`time to PSA progression in the responders was 9
`months. The MST in the PSA responders was 22
`months versus 8 months in the nonresponders.
`The favorable results seen in this trial were, at least
`partially, influenced by the responses to antiandro(cid:173)
`gen withdrawal and perhaps the relatively low vol(cid:173)
`ume of systemic disease.
`
`PHASE III TRIALS
`Glucocorticoids have served as the control arm
`in several Phase Ill trials of cytotoxic or hormonal
`therapies (Table II). Tannock et al. 44 randomized
`161 symptomatic patients with AIPC to mitox(cid:173)
`antrone plus prednisone or prednisone alone at 10
`mg/day and evaluated QOL as an endpoint. They
`described a 12% palliative response in patients re(cid:173)
`ceiving single-agent prednisone. The PSA level de(cid:173)
`creased by more than 50% in 22% of patients, but
`these responses were not reconfirmed in 4 weeks.
`Osoba et al. 45 analyzed this same patient popula(cid:173)
`tion for health-related QOL. 45 Patients receiving
`prednisone had a significant improvement in
`health-related QOL scores at 6 weeks. This statis(cid:173)
`tical significance was lost at 12 weeks of therapy.
`Kantoff et al. 38 randomized 242 patients with
`AIPC to mitoxantrone plus hydrocortisone or hy(cid:173)
`drocortisone 45 mg daily and evaluated the sur(cid:173)
`vival and response rates as endpoints. The MST in
`the hydrocortisone arm was 12.6 months, and the
`median time
`to progression (MTP) was 2.3
`months. Twenty-two percent of patients had a
`maximal PSA decrease of more than 50%. Patients
`who had a maximal decrease in PSA responses of
`more than 50% had a significantly higher MST
`(20.5 versus 10.3 months). This study did not
`show a statistically significant difference between
`the two arms in survival or quality-of-life (QOL)
`measures.
`Gregurich46 randomized 120 asymptomatic pa(cid:173)
`tients with progressive hormone-resistant prostate
`cancer to mitoxantrone plus prednisone or pred(cid:173)
`nisone 5 mg twice daily. A PSA decrease of more
`than 50% occurred in 24% of patients on the pred(cid:173)
`nisone arm. The MTP in the prednisone arm was
`3.8 months, significantly lower than in the combi(cid:173)
`nation arm. The overall survival was equivalent in
`both arms.
`Small et al. 47 randomized 460 patients with
`symptomatic, metastatic AIPC
`to
`low-dose
`suramin plus hydrocortisone or hydrocortisone 40
`mg daily. The primary endpoint of the trial was the
`evaluation of pain and analgesic use as primary
`indicators of response. Twenty-eight percent of pa(cid:173)
`tients receiving single-agent hydrocortisone had a
`pain response and 8% had both a pain response and
`a decrease in opioid analgesic use. The PSA level
`decreased by more than 50% in 16% of patients
`receiving single-a}ent prednisone, and the MST
`was 9.2 months. 4
`Fossa et al. 48 randomized 201 patients with
`symptomatic AIPC to receive prednisone 5 mg four
`times a day or flutamide 250 mg 3 times a day. The
`subjective response was assessed on the basis of the
`performance status, reduction in analgesic use, and
`reduction of the pain score (World Health Organi(cid:173)
`zation criteria). At 6 weeks of therapy, the subjec-
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`Phase Ill Trials
`Tannock et a/., 44 1996
`Osobay et a/., 45
`1999
`
`Patients in GC arm
`(n) and Treatment
`
`81; prednisone 5 mg
`BID
`
`TABLE II. Phase Ill trials with glucocorticoids as control arm
`Objective Responses
`and Post-Therapy
`PSA Decline
`22% (PSA decrease of
`>50%)-not
`reconfirmed in 4 wk
`
`Entry Criteria
`Symptomatic, metastatic
`disease, progressing
`despite standard
`hormonal therapy
`
`MST and Median
`TIP (mo)
`
`MST 11
`
`Kantoff et a/., 38 1999
`(hydrocortisone and
`mitoxantrone +
`hydrocortisone)
`
`123; hydrocortisone
`30 mg 0AM, 1 5 mg
`0PM
`
`Progressive, metastatic
`disease despite
`orchiectomy or LHRH
`analogue therapy
`
`Gregurich, 46 2000
`(prednisone and
`mitoxantrone +
`prednisone)
`
`Small et a/., 47 2000
`(hydrocortisone and
`suramin +
`hydrocortisone)
`Fossa et a/., 48 2001
`(prednisone and
`flutamide)
`
`60; prednisone 5 mg
`BID
`
`231; hydrocortisone
`40 mg daily
`
`101; prednisone 5
`mg QID
`
`Asymptomatic
`metastatic HRPC with
`progressive disease
`despite standard
`hormonal therapy
`Symptomatic, metastatic
`disease, progressing
`despite standard
`hormonal therapy
`Symptomatic metastatic
`disease with
`progression despite
`orchiectomy or LHRH
`analogues
`
`21.5% (PSA decrease
`of >50%); PR 4%
`(PR based on PSA
`necessitates a
`decrease in PSA of
`>80% lasting 6 wk
`24% (PSA decrease
`>50%)
`
`MST 12.6; median TIP
`2.3
`
`Median TIP 3.8
`
`16% (PSA decrease
`>50% lasting 4 wk)
`
`MST 9.2
`
`21 % PSA decrease
`>50%
`
`Median TIP 3.4; OS 10.6
`
`KEY: GC ~ glucocorticosteroids; HQL ~ health-related quality of life; PR ~ partial response; HRPC ~ hormone-refractory prostate cancer; OS ~ overall survival; QOL ~ quality of life; other abbreviations as in Table I.
`
`Quality of Life and
`Subjective Responses
`12.3% had a palliative
`response; HQL improved
`at 6 wk of therapy
`compared with initial time
`of recruitment; statistical
`significance lost at 12 wk
`
`28% pain response based on
`decrease in pain level or
`analgesic use
`
`56% had a subjective
`response (physician
`assessed: decrease in pain
`and improved general
`condition); QOL scores
`favored prednisone arm
`
`DEF-ABIRA-0000080
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1079, p. 6 of 9
`
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`
`rive response rate was 49% in the prednisone
`group. Subjective responses lasted for a median of
`4.8 months. Twenty-one percent of patients in the
`prednisone arm had a decrease in PSA of more than
`50%. In 9% of patients receiving prednisone, a PSA
`decline of more than 50% lasted more than 4
`weeks. A PSA decline was associated with a subjec(cid:173)
`tive response. A PSA decline of more than 50% was
`associated with a favorable survival outcome. The
`MTP and MST for the prednisone arm was 3.4 and
`10.6 months, respectively.
`
`COMMENT
`
`We conclude that glucocorticoids have an inhib(cid:173)
`itory effect on AIPC in vitro and in vivo. Cell
`growth inhibition is linked to several potential
`mechanisms: downregulation of adrenal andro(cid:173)
`gens, modulation of cellular growth factors, and
`downregulation of AR-dependent transcription.
`Other, nongenomic pathways of glucocorticoids
`have recently been described, especially in the ner(cid:173)
`vous system. The role of such pathways in prostate
`cancer antitumor activity has not yet been delin(cid:173)
`eated. Thus, a full understanding of the mecha(cid:173)
`nism of activity or resistance to glucocorticoids is
`far from complete.
`In total, the laboratory data show a heteroge(cid:173)
`neous effect of glucocorticoids on prostate cancer.
`This heterogeneous effect reflects the interplay of
`two main variables: glucocorticoids and tumor bi(cid:173)
`ology. Glucocorticoid activity varies depending on
`the chemical agent used, as well as on its dosage.
`The stimulatory effects of DOC compared with the
`neutral effect of dexamethasone on LNCaP exem(cid:173)
`plify class-dependent activity. 31 A dose-dependent
`response is manifested in the inhibitory effects of
`dexamethasone on the DU 145 cell line in which
`increasing activity is seen at concentrations be(cid:173)
`tween I0-9M and I0- 7M. 27 Glucocorticoid activ(cid:173)
`ity is also dependent on tumor biology such as GR
`expression or the presence of AR mutations. Dexa(cid:173)
`methasone inhibitory activity is lacking in GR-neg(cid:173)
`ative LNCaP cells, but it is clearly present in GR(cid:173)
`expressing cells such as PC-3 and DU-145. 27 AR
`mutations such as the combined mutation L70IH/
`T877 A or T877 A have been associated with a par(cid:173)
`adoxical stimulatory response to glucocorticoids,
`and the wild-type AR has not been shown to pro(cid:173)
`duce such effects. Limited data are available on GR
`expression in human prostate cancer tissue. One
`study of 20 patients with localized prostate adeno(cid:173)
`carcinoma reported minimal GR staining in neo(cid:173)
`plastic epithelial cells. 49 More recently, Nishimura
`et al. 27 reported intense nuclear GR staining in 8 of
`16 patients with localized prostate cancer. To our
`knowledge, GR expression in AIPC samples has
`not been evaluated.
`
`The clinical data clearly indicate that glucocorti(cid:173)
`coids have an overall palliative effect in the treat(cid:173)
`ment of hormone-refractory prostate cancer when
`used on a daily basis. On the basis of data collected
`in Phase Ill trials, a PSA decrease of more than 50%
`in 16% to 20% of patients, a MTP of 2.3 to 3.4
`months, and a MST ranging between 9.2 and 12.6
`months are to be expected. The reported greater
`than 50% decrease in most of the studies listed
`does not constitute a partial response by the Pros(cid:173)
`tate-Specific Antigen Working Group criteria be(cid:173)
`cause of the lack of a 4-week confirmation of re(cid:173)
`sponse. However, patients with a PSA decrease of
`greater than 50% had a longer lasting palliative
`effect and survival advantage than did non-PSA re(cid:173)
`sponders. The QOL is improved, but the improve(cid:173)
`ment is often limited to the first 6 weeks of therapy.
`Phase II and retrospective studies using low-dose
`dexamethasone have reported higher response
`rates.
`None of the randomized studies so far has shown
`a survival advantage of any combination therapy
`over glucocorticoids; however, the combination of
`mitoxantrone and prednisone or hydrocortisone
`seems to provide better palliation and an improved
`MTP and QOL. When randomized against the an(cid:173)
`tiandrogen flutamide, prednisone resulted in a
`similar median survival but was associated with
`improved subjective responses and QOL. This fur(cid:173)
`ther supports the use of glucocorticoids in the pal(cid:173)
`liative setting or on failure of primary chemother(cid:173)
`apy in AIPC.
`Although the clinical activity of glucocorticoids
`has been consistently reproduced, the benefits
`have been usually limited to a small subgroup of
`the target patient population. Careful study to de(cid:173)
`termine the factors associated with clinical benefit
`in AIPC should be done. Do these responders have
`specific patterns of adrenal androgen production?
`Do specific AR mutations correlate with a pro(cid:173)
`longed response to glucocorticoids? ls the re(cid:173)
`sponse dependent on GR expression or overex(cid:173)
`pression? Such efforts should identify the most
`active class and dose to be used, and most impor(cid:173)
`tantly, in which patients. Until then, the optimal
`dose and schedule of glucocorticoids in AIPC will
`remain a subject of debate. Future progress in the
`use of glucocorticoids in AIPC can only happen by
`achieving a better understanding of the molecular
`pathology of this disease.
`
`REFERENCES
`1. Riccardi C, Zollo 0, Nocentini G, et al: Glucocorticoid
`hormones in the regulation of cell death. Therapie 55: 165-
`169, 2000.
`2. Smets LA, Salomons G, and van den Berg]: Glucocor(cid:173)
`ticoid induced apoptosis in leukemia. Adv Exp Med Biol 457:
`607-614, 1999.
`
`UROLOGY 60 (4), 2002
`
`559
`
`DEF-ABIRA-0000081
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`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1079, p. 7 of 9
`
`
`
`3. Miyoshi H, Ohki M, Nakagawa T, et al: Glucocorticoids
`induce apoptosis in acute myeloid leukemia cell lines with a
`t(8;21) chromosome translocation. Leuk Res 21: 45-50, 1997.
`4. Arai Y, Nakamura Y, Inoue F, et al: Glucocorticoid(cid:173)
`induced apoptotic pathways in eosinophils: comparison with
`glucocorticoid-se