Clinical report 843
`
`Effect of combination therapy with aminoglutethimide and
`hydrocortisone on prostate-specific antigen response in
`metastatic prostate cancer refractory to standard endocrine
`therapy
`W. H. J. Kruita, G. Stotera and J. G. M. Klijna
`
`A prospective study was performed to investigate the
`combination of the aromatase inhibitor aminoglutethimide
`and hydrocortisone in androgen-independent prostate
`cancer with changes in prostate-specific antigen (PSA)
`level as main determinant for response. Thirty-five patients
`were treated with aminoglutethimide 1000 mg daily and
`hydrocortisone acetate 40 mg daily. PSA measurements
`were performed every month. If evaluable lesions were
`present, objective tumor assessment was done by
`computed tomography scan and X-ray investigations. In 12
`patients (37%) the PSA value showed a confirmed
`response with a decline in serum level of at least 50%.
`Median time to progression in responding and all patients
`was 10.5 and 4.5 months, respectively. Median duration of
`response in responding patients was 9 months. Median
`survival for these two groups was 23 and 14.5 months,
`respectively. Of seven patients with measurable disease,
`two showed a partial response and five a stable disease.
`Improvement in general condition, pain and feeling of
`
`well-being was noted in two-thirds of patients. Therapy was
`well tolerated with mainly grade I and II adverse events
`in 20% of patients. We conclude that aminoglutethimide
`is a valuable second-line therapy for patients with
`androgen-independent prostate cancer. Anti-Cancer Drugs
`15:843–847 c 2004 Lippincott Williams & Wilkins.
`
`Anti-Cancer Drugs 2004, 15:843–847
`
`Keywords: aminoglutethimide, androgen independent, prostate cancer,
`prostate-specific antigen
`
`aDepartment of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus
`Medical Center, Rotterdam, The Netherlands.
`
`Correspondence to W. H. J. Kruit, Department of Medical Oncology, Daniel den
`Hoed Cancer Center, Erasmus Medical Center, PO Box 5201, 3008 AE
`Rotterdam, The Netherlands.
`Tel: + 3110 439 17 54; fax: + 3110 439 10 03;
`e-mail: w.kruit@erasmusmc.nl
`
`Received 17 February 2004 Revised form accepted 7 July 2004
`
`Introduction
`Standard first-line therapy of proven efficacy for meta-
`static prostate carcinoma consists of hormonal manipula-
`tion by androgen ablation, achieved either by surgical
`castration or by the use of a luteinizing hormone-releasing
`hormone agonist (LHRH) in combination with antian-
`drogen therapy [1]. However, all patients will eventually
`relapse and once the disease becomes progressive after
`complete androgen blockade, further therapeutic options
`are limited [2]. As second-line therapy, various modalities
`have been explored such as other hormonal manipula-
`tions, cytotoxic chemotherapy and also the naphthylurea
`derivative suramin, but none of these treatments has
`demonstrated substantial efficacy, while they are accom-
`panied by sometimes significant side-effects [2]. Only
`recently, a new class of cytostatics, the taxanes, has shown
`notable antitumor activity in hormone-refractory prostate
`carcinoma. However, the final significance of taxanes has
`to be demonstrated in phase III trials [3].
`
`A major problem in determining the exact antitumor
`activity of agents in metastatic prostate cancer is the
`objectivity of response assessment. In most patients
`disease is restricted to bone localizations which are
`0959-4973 c 2004 Lippincott Williams & Wilkins
`
`notoriously difficult to evaluate. Prostate-specific antigen
`(PSA) is a glycoprotein almost exclusively present in
`normal and malignant prostate cells. Approximately 10
`years ago a correlation was demonstrated between
`changes in PSA levels and tumor response [4]. Since
`then, PSA measurements have become an early indicator
`of progression and response [5–8]. After a consensus
`conference held in the USA, PSA had been accepted as a
`surrogate parameter for response evaluation in prostate
`cancer [9–11]. Standards were defined and guidelines
`were formulated.
`
`first-line
`In patients with progressive disease after
`endocrine therapy, a small proportion can respond to a
`secondary hormonal manipulation, suggesting that the
`prostate cancer cells have retained a certain degree of
`hormone sensitivity. After surgical or medical castration
`the adrenal gland is the main extratesticular source of
`androgens and can produce sufficient testosterone to
`maintain a continued stimulation of tumor cells. Initially,
`adrenal ablation was achieved by major surgical proce-
`dures
`such as adrenalectomy and hypophysectomy,
`which yielded some antitumor activity [12–15]. Later
`on, surgical adrenalectomy was replaced by medical
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`DEF-ABIRA-0000188
`
`MYLAN PHARMS. INC. EXHIBIT 1110 PAGE 1
`
`

`

`844 Anti-Cancer Drugs 2004, Vol 15 No 9
`
`adrenalectomy with adrenal-suppressive agents. Amino-
`glutethimide is a potent inhibitor of adrenal steroid
`biosynthesis by blocking the enzyme aromatase. The
`effectivity of aminoglutethimide as second-line therapy
`in patients with metastatic prostate carcinoma was
`suggested in a number of studies [16–27]. However,
`most of these reports were published in the 1980s. At
`that time, PSA determinations were not yet available and
`response evaluation was mainly done by difficult to
`interpret X-rays and bone scintigraphy. We have carried
`out a prospective phase II study with aminoglutethimide
`and hydrocortisone in patients with prostate cancer
`refractory to standard hormone therapy with the pre-
`dominant use of PSA measurements
`to determine
`antitumor activity.
`
`Patients and methods
`Patients with biopsy-proven stage D2 prostate carcinoma
`and disease progression following orchidectomy or
`refractory to standard endocrine therapy with LHRH
`agonists with or without the concomitant use of an
`antiandrogen were prospectively included in the study.
`Prior treatment with chemotherapy was allowed. A rising
`PSA level and/or radiological investigations demonstrated
`progressive disease. Prior to start of treatment an initial
`evaluation was carried out including medical history,
`physical examination, hematology, serum biochemistry
`with PSA measurement, urinalysis, bone scintigraphy,
`skeletal X-rays and, if indicated, computed tomography
`(CT) or magnetic resonance imaging. All patients gave
`their informed consent.
`
`Aminoglutethimide 250 mg 2 times a day was given orally
`for the first 2 weeks. All patients received hydrocortisone
`acetate 40 mg daily (20 mg in the morning, 10 mg in the
`afternoon, 10 mg in the evening) as glucocorticoid
`replacement. If no side-effects such as skin rash, lethargy,
`nausea and dizziness occurred, aminoglutethimide ad-
`ministration was further escalated to 500 mg 2 times a
`day. In case of grade 2 toxicity the hydrocortisone dose
`was increased to 80 mg/day until the adverse event
`subsided. In patients who developed grade 3 other than
`skin toxicity, aminoglutethimide was discontinued per-
`manently. Toxicity was determined according to NCI-
`CTC criteria. In patients under therapy with a LHRH
`agonist this medication was continued. Other antitumor
`medication was not allowed.
`
`Repeat clinical evaluation and measurement of hemato-
`logy and biochemical indices including PSA were carried
`out monthly for the first 3 months and at 2-monthly
`intervals thereafter. At each visit patients were routinely
`asked to indicate whether there was any improvement in
`pain or other symptoms during treatment with study
`medication.
`
`PSA response criteria were those proposed by the
`National Prostate Cancer Project Group for phase II
`trials in hormone refractory prostate cancer [9]. A PSA
`response was defined as a decline in PSA value by at least
`50%, which had to be confirmed by a second PSA
`measurement four or more weeks later. Moreover, no
`increase in the size of pre-existing metastases, no
`appearance of new lesions and no clinical signs of tumor
`progression were allowed. The term ‘complete PSA
`response’ was not used. In patients whose PSA had not
`decreased, progressive disease was a 25% increase over
`the baseline level and confirmed by a second value. In
`patients whose PSA had decreased but had not reached
`response criteria, progressive disease was considered to
`have occurred when PSA had increased 25% over the
`nadir and was confirmed by a second measurement. Time
`to PSA progression was defined from the first treatment
`day until the date PSA values had increased by 50% from
`the nadir levels for responders or by 25% for patients not
`reaching a 50% decline in PSA levels. Duration of PSA
`response was measured from time at which PSA had
`declined to 50% or less to the time when PSA had risen
`by 50% above nadir. If clinical progression occurred before
`PSA progression, the date of clinical progression was
`used.
`
`In patients with measurable soft tissue lesions response
`evaluation by PSA measurements was complemented by
`repeated radiological examinations. A complete response
`was defined as the disappearance of any pre-treatment
`tumor lesions for a duration of at least 4 weeks. Partial
`response was a 50% or greater reduction in the sum of the
`products of the largest perpendicular diameters of all
`measurable lesions for at least 4 weeks. Other criteria for
`progressive disease were an increase of more than 25% of
`any of the measurable lesions and/or the appearance of a
`new lesion, decline in performance status (WHO) or the
`need for radiation therapy.
`
`The survival and progression-free survival durations were
`calculated from the on-study date until date of progres-
`sion, death or last follow-up as appropriate.
`
`Results
`Patient characteristics
`Thirty-five patients were included in the study. An
`overview of the demographics is given in Table 1. The
`median age was 67 years (range 39–92). The median
`WHO performance status was 1 (range 0–2). Thirty-three
`patients (94%) had bone, six (17%) lymph node and one
`(3%) lung metastases. Metastatic disease was confined to
`one, two or three organ sites in 26 (74%), eight (23%) and
`one patients (3%), respectively. Fifteen patients (43%)
`had undergone an orchidectomy with or without the
`concomitant use of an antiandrogen, and 20 (57%) had
`received prior treatment with the combination of a
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`DEF-ABIRA-0000189
`
`MYLAN PHARMS. INC. EXHIBIT 1110 PAGE 2
`
`

`

`Table 1 Patient characteristics
`
`No. patients
`Age (median, range)
`Performance status (WHO)
`Initial PSA level (ng/ml) (median, range)
`Localization of metastases
`bone
`lymph node
`lung
`liver
`miscellaneous
`No. metastatic sites
`1
`2
`3
`Prior therapies
`orchidectomy
`orchidectomy + antiandrogen
`LHRH agonist + antiandrogen
`chemotherapy (including estramustine)
`estrogens
`radiotherapy (for metastasis)
`No. prior therapies
`1
`2
`3
`
`35
`67 (39–92)
`1 (0–2)
`216 (15–6719)
`
`33
`6
`1
`0
`3
`
`26
`8
`1
`
`9
`6
`20
`12
`1
`15
`
`12
`15
`8
`
`LHRH agonist and an antiandrogen. Twelve patients
`(37%) were progressive after chemotherapy including
`estramustine. The patient group was heavily pre-treated
`with 23 patients (66%), who had received at least two
`prior treatment regimes.
`
`Treatment results
`All 35 patients were evaluable for response. An overview
`of the treatment results is given in Table 2. According to
`the defined criteria for PSA response, 13 patients (37%)
`developed a confirmed response [95% confidence interval
`(CI) 22–53%]. Furthermore, minor reductions in PSA
`levels (37, 38, 40 and 43%) were seen in another four
`patients. Only five patients (14%) demonstrated a
`straightforward progressive increase in PSA levels within
`8 weeks after treatment start. For the total patient cohort
`the median PSA value fell from 216 ng/ml at baseline to
`43 ng/ml, a decrease of at least 80%.
`
`The median time to progression for responding patients
`was 10.5 months (range 3.5–23.5). The median response
`duration was 9 months (range 3–21.5). Median survival for
`responding patients was 23 months (range 7–38). For all
`patients median time to progressive disease as measured
`by PSA levels was 4.5 months (range 0.5–23.5). The
`median survival was 14.5 months (range 0.5–38). The
`progression-free survival after 1 year with aminoglutethi-
`mide based on PSA determinations was 14%.
`
`In seven patients, measurable soft tissue metastases were
`present at the start of therapy with aminoglutethimide.
`One patient developed a complete response of retro-
`peritoneal lymph node metastases with a concomitant
`decline in PSA level of more than 50%. A second patient
`with lymph node metastases showed a partial response of
`
`Aminoglutethimide in metastatic prostate cancer Kruit et al. 845
`
`Table 2 Treatment results
`
`PSA response
`Time to progressionFresponders (median)
`Response duration (median)
`Time to progressionFall patients (median)
`Survival (median)
`SurvivalFresponders (median)
`SurvivalFnon-responders (median)
`Progression-free survival at 1 year
`
`12 (37%)
`10.5 months (3.5–23.5)
`9 months (3–21.5)
`4.5 months (0.5–23.5)
`14.5 months (0.5–38)
`23 months (7–38)
`13 months (0.5–32)
`14%
`
`a PSA
`accompanied by
`localizations
`these tumor
`response. In the other five patients, tumor evaluation
`by CT revealed stable disease. In three of them, PSA
`levels remained unchanged, and in two, PSA increased
`progressively. All other patients had non-evaluable or non-
`measurable lesions, mostly bone.
`
`Although no validated quality of life questionnaire or
`standardized symptom improvement scoring system was
`used in this study, therapy with aminoglutethimide
`showed subjective benefits as improvement of perfor-
`mance status,
`increase in appetite, weight gain and
`decrease of pain complains in a considerable number of
`patients. All responding patients except one showed a
`clear improvement in their sense of well-being. These
`positive effects of
`treatment were not
`limited to
`responding patients only, because overall 24 patients
`(69%) indicated an improved general condition and
`quality of life while on therapy with aminoglutethimide.
`In addition, 22 patients (62%) indicated a significant
`decrease in pain complaints.
`
`Toxicity
`The median treatment duration was 4.5 months. In all
`patients
`the dose of
`aminoglutethimide could be
`escalated to 1000 mg/day. The frequency of adverse
`events induced by aminoglutethimide in this patient
`group was low. Only eight episodes of toxicity, mostly
`grade I and II, were observed in seven patients. Fever
`(grade II) occurred in two patients. One patient
`developed grade I anorexia. Increase in liver transaminase
`levels was observed twice (one grade I, one grade II).
`There were three episodes of skin toxicity consisting of
`an erythematous itching skin rash, one grade I and two
`grade III. In both patients with grade III skin toxicity
`treatment with aminoglutethimide was interrupted and
`the hydrocortisone dose doubled. In one patient amino-
`glutethimide could be resumed without reappearance of
`any adverse event, in the other patient treatment had to
`be discontinued permanently. No dose modifications of
`aminoglutethimide in the other patients turned out to be
`necessary.
`
`Discussion
`In this study of the combination of aminoglutethimide
`and hydrocortisone in patients with androgen-indepen-
`dent prostate cancer a PSA response rate of 37% was
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`DEF-ABIRA-0000190
`
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`

`846 Anti-Cancer Drugs 2004, Vol 15 No 9
`
`achieved with a median response duration of 9 months.
`Overall for the whole group the median survival was 14.5
`months and for the responders 23 months. The response
`analysis was based on PSA measurements, which have
`been shown to accurately reflect the treatment benefit
`for the patients, both in terms of palliation and survival
`[8–10]. In previously published trials using aminoglu-
`tethimide, response percentages of 0–50% have been
`reported (Table 3) [16–28]. However, all these studies
`were performed more than a decade ago with response
`evaluation based on non-reproducible imaging with X-rays
`and bone scans. Of note, in most of these trials patients
`with clinically stable disease have been considered as
`responding patients and were included in the response
`percentage. The observed median survival of more than
`14 months is noteworthy in comparison with survival data
`reported in androgen-independent prostate cancer pati-
`ents, varying between 6 and 12 months [18,21,23–26].
`It is clear that the treatment results of the study
`presented here, based on the course of PSA values, are
`at least comparable with those observed in other trials.
`Additionally, the improvement in subjective feelings of
`well-being and symptom control in two-thirds of patients
`is striking.
`
`The assumption that PSA changes could be of value in
`predicting the outcome of therapy in patients with
`androgen-independent prostate cancer was first intro-
`duced by Ferro et al. [4]. Since then several investigators
`have reported a correlation between a decrease in PSA
`levels and clinical benefit and survival [5–8]. A decline of
`at least 50% in PSA during therapy was associated with
`improved survival. Meanwhile an increasing number of
`
`phase II trials has incorporated PSA as a marker. In 1999
`the Prostate-Specific Antigen Working Group formulated
`eligibility criteria and response guidelines for the use of
`PSA as a parameter for treatment outcome [9]. It was
`concluded that PSA determinations could be used as an
`accurate method to evaluate new agents for the treat-
`ment of metastatic prostate cancer. The experience in
`the here presented study is in agreement with this
`observation. To our knowledge, one other study has
`been published demonstrating a therapeutic effect of
`aminoglutethimide on PSA in hormone-refractory pros-
`tate cancer [27]. A PSA decrease of at least 80% was
`observed in 48% of patients with a concomitant
`improvement in soft tissue lesions, bone scans, anemia
`and thrombocytopenia if present. The authors reported a
`median decrease in PSA levels of 73%,
`remarkably
`comparable with the nadir of 80% of the baseline value
`found in our study. In another study the combination of
`aminoglutethimide and suramin was investigated in
`patients with androgen-independent prostate cancer.
`The response rate (greater than 50% decline in PSA)
`was 23.5%, time to progression 4.4 months and survival
`time 15.3 months [28].
`
`Treatment with aminoglutethimide resulted in a sig-
`nificant improvement of general condition in more than
`two-thirds of our patients. This was not only the case in
`patients with a clear PSA response, but also patients
`without a decrease in PSA level of 50% or more fared
`significantly better with regard to subjective parameters
`such as
`feeling of well-being, pain, appetite and
`performance status. Other investigators have also docu-
`mented these positive effects of aminoglutethimide on
`
`Table 3 Summary of prior performed trials with aminoglutethimide
`
`Author/year/reference
`
`Patient no.
`
`Response objective
`
`Response
`subjective
`
`Response marker
`
`TTP
`
`Survival
`
`(A) Monotherapy aminoglutethimide
`Robinson 1974 [16]
`Rostom 1982 [18]
`Ponder 1984 [19]
`
`Drago 1984 [20]
`
`Murray 1985 [21]
`
`Harnett 1987 [22]
`
`Elomaa 1988 [23]
`
`Samojlik 1988 [24]
`
`Labrie 1989 [25]
`
`Chang 1989 [26]
`
`Sartor 1994 [27]
`
`26
`15
`40
`
`43
`
`58
`
`34
`
`20
`
`50
`
`119
`
`28
`
`29
`
`0
`0
`15%
`1 PR, 5 SD
`40%
`1 CR, 6 PR, 10 SD
`33%
`1 CR, 10 PR, 8 SD
`21%
`1 PR, 6 SD
`22%
`4 PR
`50%
`8 PR, 17 SD
`
`14%
`1 CR, 2 PR, 14 SD
`32%
`9 SD
`21%
`6 PR
`
`(B) Combination therapy/aminoglutethimide and suramin
`Dawson 1998 [28]
`81
`
`20%
`
`70%
`75%
`48%
`
`NE
`
`29%
`
`21%
`
`75%
`
`NE
`
`NE
`
`32%
`
`56%
`
`NE
`
`31%
`NE
`20%
`2 CR, 6 PR
`NE
`
`NE
`
`NE
`
`40%
`8 PR
`NE
`
`NE
`
`11%
`1 CR, 2 PR
`48%
`7 CR, 7 PR
`
`24%
`19 PR
`
`NE
`NE
`resp: 8 months
`non-resp: NE
`34 weeks
`
`10 months
`
`4–18 months
`
`NE
`6.5 months
`NE
`
`NE
`
`resp: 12 months
`non-resp: 5 months
`NE
`
`4 months (subjective)
`
`8 months
`
`NE
`
`NE
`
`NE
`
`resp: 88 weeks
`stable: 38 weeks
`non-resp: 18 weeks
`resp: 21 months
`non-resp: 9 months
`6 months
`
`16 weeks
`
`NE
`
`4.5 months
`
`15 months
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`DEF-ABIRA-0000191
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`MYLAN PHARMS. INC. EXHIBIT 1110 PAGE 4
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`

`

`subjective indicators of therapeutic efficacy [16,18,19,
`21–23,26,27]. The precise mechanism of action of
`aminoglutethimide is unknown.
`It
`is unlikely that
`suppression of estrogen production by aromatase inhibi-
`tion is responsible for the observed tumor regression or
`clinical improvement. In several small studies the new
`selective aromatase inhibitors such as 4-hydroxyandroste-
`nedione and anastrozole have been investigated in
`androgen-independent prostate carcinoma [29,30]. No
`objective antitumor activity or PSA response was observed.
`
`In conclusion, combination therapy with aminoglutethi-
`mide and hydrocortisone is an effective treatment
`modality for androgen-independent prostate cancer.
`
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