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`Cancer Investigation, 16(6), 385—390 (1998)
`
`NEW DRUG
`
`Anastrozole (Arimidex®), a New
`Aromatase Inhibitor for Advanced
`
`Breast Cancer: Mechanism of Action
`
`and Role in Management
`
`Gabriel N. Hortobagyi, M.D., and Aman U. Buzdar, M.D.,
`F.A.C.P.
`
`Department of Breast Medical Oncology
`The University of Texas M. D. Anderson Cancer Center
`Houston, Texas
`
`INTRODUCTION
`
`Breast cancer is the most common cancer in American
`
`women, and is estimated to be the cause of 46,000 deaths
`per year (1—3). The incidence of breast cancer increases
`with age, with breast cancer more common in
`menopausal and postmenopausal women than in younger
`women (4). Approximately one-third of all breast cancers
`are hormone dependent; because estrogen is the primary
`steroidal mitogen, hormonal manipulation has proven to
`be a successful modality in these cases (3,5,6). Tumors
`likely to respond to endocrine therapy can be identified
`through the presence of estrogen and progesterone recep-
`tors, with positive response rates as high as 60% in
`patients with estrogen receptor (ER)-positive tumors and
`75% in cases in which both estrogen and progesterone
`receptors have been detected (6,7). Postmenopausal
`women are more likely than younger women to have
`breast tumors positive for both estrogen and progesterone
`receptors; in addition, the absolute concentration of these
`receptors may also be higher in tumors in post—
`menopausal women (8). A relatively new strategy for the
`blockade of estrogen synthesis in the management of
`
`advanced breast cancer in postmenopausal women is aro—
`matase inhibition with the selective, nonsteroidal
`inhibitor anastrozole (Arimidex®) (9—15). Aromatase
`inhibition presents a number of advantages over other
`endocrine therapies, including a well-defined mechanism
`of action, specific inhibition of estrogen synthesis, a lack
`of estrogenic effects, and lack of cross-resistance with
`antiestrogens (5). When compared with other aromatase
`inhibitors (e.g., aminoglutethimide, formestane, fadro-
`zole), anastrozole has a number of advantages, including
`high potency, high specificity for the aromatase enzyme,
`a favorable safety profile, a convenient mode of admin-
`istration, and no requirement for corticosteroid replace-
`ment therapy (9—12,15,16).
`
`ESTROGEN SYNTHESIS AND
`AROMATASE INHIBITION
`
`Steroid hormones (aldosterone, cortisol, androgens, and
`estrogens) are synthesized via a well-defined series of
`complex reactions involving cytochrome P450 hydrolases,
`lyases, and/or aromatase, with cholesterol as a precursor
`
`385
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`Copyright © 1998 by Marcel Dekker, Inc.
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`www.dekker.com
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`fit it a H ‘I' n L.
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`AstraZeneca Exhibit 2012 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
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`386
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`Cholesterol
`
`[(cyt r450 20,12 lyase)
`l
`Pug-lanolin:e
`l
`Progeslins
`
`l
`l (cylP450 HIS/18hydroxylase)
`ldcytP45021 hydroxylase)
`.
`,
`.
`_
`Glucocortlcoids
`MJneralomrtiemds
`
`“I
`‘L(Cyt P450 17a hydroxylasc/
`17 201),“)
`Andmgens
`F“)
`
`Testosterone
`
`Androstened'lole
`
`Anastmmle —)
`
`Jr
`Elf“)!!!
`
`(cyt p450 aromatase)
`(——)
`
`i
`Estradinl
`
`Figure 1. Estrogen synthesis (16).
`
`(16,17) (Fig. 1). The aromatase enzyme acts at the last
`step in the estrogen—synthesis pathway, catalyzing the con-
`version of androgens to estrogens (16,17). Thus, inhibition
`of the aromatase reaction does not impair the synthesis
`of progestins, glucocorticoids, mineralcorticoids, or andro—
`
`Hortobagyi and Buzdar
`
`gens (3,16,17).
`Aromatization of adrenal androgen precursors in
`peripheral tissues is the primary source of estrogen in
`postmenopausal women (5,16,17). Approximately 50—100
`ug of estrone can be produced daily by the extraglandu-
`lar conversion of androstenedione, and some of this
`
`estrone is converted to produce 10—20 pg/mL of circulat-
`ing estradiol (5). In addition to its presence in adipose,
`muscle, ovarian, brain, and liver tissue, aromatase activ-
`
`ity (5—100 pg/g tissue/hr) has also been detected in breast
`tumors (5,16,18,19). Although this tumor aromatase activ—
`ity would appear to be too low to account for a significant
`amount of estradiol, biochemical measurements might
`underestimate local levels, since aromatase may be local-
`ized in specific tumor-cell types (e.g., stromal or fat cells)
`(5,16,20).
`Aromatase inhibitors can be classified as either mech—
`
`anism—based (“suicida ”) or competitive inhibitors (3,16).
`Mechanism-based aromatase inhibitors (e.g., formes—
`tane) are enzyme-specific, steroidal compounds that act
`as substrate analogues, covalently binding to the active
`site of the aromatase enzyme complex and irreversibly
`inactivating it (3,5,16,17). Competitive aromatase
`inhibitors bind reversibly to the aromatase enzyme com-
`
`Results of Preclinical Studies Evaluating the Selectivity ofAnastrozole“
`
`Table 1
`
`
`
` P-450 enzyme Species Results
`
`
`
`Rat
`20,22-Desmolase
`(cholesterol side-chain Monkey
`cleavage)
`11—Hydroxylase
`(glucocorticoid
`production)
`
`Monkey
`Dog
`
`18-Hydroxylase
`(aldosterone synthesis)
`
`Rat
`
`17—Hydroxylase/
`1 7 ,20—Desmolase
`(androgen production)
`
`Rat
`Monkey
`Dog
`
`No adrenal hypertrophy or histological changes at 100
`times the MED.b
`
`Margin of selectivity was 30—fold in monkeys, IOU-fold in
`dogs. No increase in circulating concentrations of 11-
`deoxycorticosterone, no hypokalemia, no adrenal
`hypertrophy after 6—10 mg/kg doses.
`2 ZOO-fold margin of selectivity. No effect on plasma
`aldosterone concentration, no effect on sodium or
`potassium excretion in saline-loaded animals given 10—20
`mg/kg doses.
`No effect on prostate-gland weight or plasma
`concentrations of testosterone or luteinizing hormone in
`rats given 1—10 mg/kg/day for 7—21 days. Increased plasma
`testosterone concentrations in monkeys (52x) and dogs
`(9x); no inhibition of androgen production of 10—100
`times the MED.
`
`Lanosterol— 14-
`
`Rat
`
`2 30-fold margin of selectivity. No reduction in plasma
`cholesterol following administration of 25 mg/kg in
`Dog
`demethylase
`rats or 3 mg/kg in dogs.
`(cholesterol synthesis)
`aFrom reference 15.
`bMED, maximum effective dose for aromatase inhibition.
`
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`Anastrozole: Role in Advanced Breast Cancer
`
`387
`
`plex and inhibit aromatization only for as long as they
`occupy the active site (3,5). Steroidal competitive aro—
`matase inhibitors (e. g., 60t—bromo-androstenedione) are
`inherently specific but are associated with agonist and
`antagonist effects on estrogen, glucocorticoid, andro—
`gen, and progesterone receptors (5,16). Compared with
`steroidal inhibitors, nonsteroidal competitive inhibitors
`(e.g., aminoglutethimide) have a greater potential for
`blockade of several cytochrome P450—mediated steroidal
`hydroxylations, but tend not to exhibit steroidal agonist
`or antagonist activity (5,16).
`The prototype aromatase inhibitor, aminoglutethimide,
`was initially developed as an anticonvulsant. This nons—
`teroidal competitive aromatase inhibitor provides
`95%—98% inhibition of aromatase; however, aminog—
`lutethimide also inhibits cholesterol side—chain cleavage,
`producing a “medical adrenalectomy” that necessitates
`corticosteroid replacement therapy (3,5,16). In addition,
`aminoglutethimide has low potency and is associated with
`a high incidence of side effects (35%) and discontinuation
`of therapy (5%) (5,16).
`In recent years, the development strategy for aromatase
`inhibitors in the management of advanced breast cancer
`has been to synthesize agents with increased potency and
`selectivity, as well as an improved toxicity profile com—
`pared with aminoglutethimide. The third-generation,
`nonsteroidal, competitive aromatase inhibitor anastrozole
`was recently approved by the U.S. Food and Drug
`Administration (FDA) for the treatment of advanced
`breast cancer in postmenopausal women following failure
`with tamoxifen therapy.
`
`ANASTROZOLE
`
`Potency and Specificity
`
`Anastrozole {2,2’-[5—(1H—1,2,4-triazol—1—ylmethyl)-
`1,3—phenylene] bis (2—methyl-propionitrile)} has a high
`intrinsic potency and is able to inhibit human placental
`aromatase activity in vitro by 50% at a concentration
`of 0.043 ug/mL (15 nM) (9,11,15). In vivo studies of
`aromatase activity in rats have shown that an oral 0.1
`mg/kg dose of anastrozole inhibits ovulation when
`administered to mature females on day 2 or 3 of the
`estrous cycle, and inhibits androstenedione-induCed
`uterine hypertrophy when administered to prepubertal
`animals for 3 days (9,11,15). Daily oral anastrozole
`doses 2 0.1 mg/kg have been shown to inhibit periph-
`eral aromatase activity in male pig-tailed monkeys,
`resulting in 50%—60% reductions in circulating estradiol
`levels (9,15).
`
`The high selectivity of anastrozole for aromatase has
`been demonstrated in a series of studies evaluating its effect
`on other cytochrome P450 enzymes involved in steroido-
`genesis in rat, dog, and monkey models (Table 1) (9,1 1,15).
`At concentrations up to 2200 times that of its maximally
`effective aromatase-inhibitory dose, anastrozole did not pro-
`duce pathological changes in the adrenal gland nor affect
`aldosterone concentrations, sodium or potassium excretion,
`or testosterone synthesis (9,11,15). In comparison, fadro—
`zole (another aromatase inhibitor) has been shown to
`increase 1 1—deoxycorticosterone concentrations in monkeys,
`and to reduce aldosterone concentrations, as well as alter
`
`Table 2
`
`Estrogen Suppression by Anastrozole”
`
`
` Population Dose regimen Results
`
`
`
`29 Male volunteers
`(6-7/dose)
`
`0—60 mg,
`single dose escalation
`
`Doses 2 7.5 mg produced at least an 80% suppression of estradiol.
`
`14 Healthy
`postmenopausal
`female volunteers
`
`8 Healthy
`postmenopausal
`female volunteers
`
`7 days; placebo
`
`0.5 or 1 mg daily
`for 14 days
`
`Estradiol lowered to limits of detection of assay by 3—4 days of treatment in
`2/6 patients in 0.5 mg group and 7/7 patients in 1 mg group. Suppression
`maintained for at least 6 days after study drug discontinued.
`
`3—mg single dose, Estradiol levels lowered 70% (first dose) to 80% (subsequent dosing)
`followed 3 days later
`compared with placebo. Suppression maintained for 4 days after last dose.
`by 3 mg daily for
`Circulating levels of estrone minimally suppressed by first dose,
`7 days; placebo
`significantly decreased with subsequent dosing.
`crossover
`
`l9 Postmenopausal
`5 mg/day for first Estradiol concentration suppressed 80% from baseline to limits of detection of
`women with advanced 14 days, followed by
`assay. Estrone lowered 69%—86%; estrone sulfate lowered 83%—92%.
`breast cancer
`10 mg/day for an
`
`additional 14 days
`
`aFrom references 9712, 15.
`
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`Hortobagyi and Buzdar
`
`Table 3
`
`Tumor Response in Two Phase III Clinical Trials Involving 263 Patients Given Arimidex®
`(1 mg daily) and 253 Patients Given Megestrol Acetate (40 mg q. id. )‘1
`
`Number Responseb Stable Diseasec
`
`Progression
`
`Prog Timed
`
`Trial #1
`
`Arimidex®
`Megestrol acetate
`Trial #2
`
`Arimidex®
`Megestrol acetate
`3From references 12—14.
`
`128
`128
`
`135
`125
`
`10.2%
`5.5%
`
`10.4%
`10.4%
`
`26.6%
`29.7%
`
`23.7%
`22.4%
`
`48.4%
`51.6%
`
`58.5%
`56.0%
`
`170 days
`151 days
`
`132 days
`120 days
`
`bEither a complete or partial objective tumor response.
`CStable for 2 6 months.
`
`dMedian time to progression; conservative estimate based on strict UICC criteria.
`
`sodium and potassium excretion in rats at doses only 5 times
`its aromatase-inhibitory dose (9,11).
`Anastrozole was not associated with direct progesto—
`genic, estrogenic, or androgenic activity in rats, even at up
`to 10 times its maximally effective aromatase-inhibitory
`dose (11,12). In addition, in rats, mice, dogs, and cats,
`anastrozole did not show any significant pharmacological
`activity other
`than aromatase inhibition (11,15).
`Anastrozole did not affect autonomic, neuromuscular, or
`
`respiratory function at an intravenous dose of 1 mg/kg.
`At an oral dose of 10 mg/kg, anastrozole did not affect the
`central nervous system (CNS), cardiovascular function
`(other than causing a small reduction in blood pressure
`and shortening of the electrocardiographic Q—T interval in
`dogs), renal function, gastrointestinal motility, gastric acid
`secretion, pain perception, inflammatory response, clotting
`ability, or local anesthetic activity.
`Anastrozole's high selectivity and lack of adverse effect
`on steroidogenesis were also demonstrated in clinical
`pharmacology studies (9—12,15).
`In healthy post-
`menopausal volunteers and patients with advanced breast
`cancer, anastrozole did not affect cortisol or aldosterone
`secretion, response to adrenocorticotrophic hormone
`(ACTH), or thyroid-stimulating hormone (TSH) concen—
`trations when administered at up to 10 mg daily (i.e., up
`to 10 times the recommended daily dose).
`
`Estrogen Suppression
`
`Clinically significant suppression of serum estradiol
`(by 80% of its pretreatment baseline value) following
`0.5—10 mg daily oral doses of anastrozole was demon-
`strated in four clinical pharmacological studies using a
`highly sensitive, validated radioimmunoassay method with
`a 3.7 pmol/L detection limit (Table 2) (9—12,15). In these
`
`studies, only about one third of postmenopausal volun-
`teers and patients who were given 0.5 mg anastrozole
`achieved estrogen suppression close to the assay limit of
`detection, whereas 100% of those given 1 mg, 75% of
`those given 3 mg, 95% of those given 5 mg, and 100% of
`those given 10 mg achieved estrogen suppression to the
`lower limit of the assay (9,11,15). Therefore, a 1 mg daily
`dose of anastrozole is considered to be the minimal dose
`
`that provides maximal estrogen suppression (Table 2).
`In a recent pharmacological study involving post—
`menopausal women with breast cancer who were given 1
`mg anastrozole daily for 28 days, whole-body aromatase
`activity was reduced by 96% (21). Plasma concentrations
`of estradiol and estrone were reduced by approximately
`85%, from 19.3 pmol/L at pretreatment to 3.0 pmol/L, and
`from 72.0 pmol/L to 11.1 pmol/L, respectively. In addition,
`plasma concentrations of estrone sulfate were reduced from
`426.2 pmol/L to 32.5 pmol/L (92% reduction).
`
`Clinical Trials
`
`In two phase III, multicenter, randomized, parallel-group
`trials, postmenopausal women with advanced breast cancer
`whose disease had progressed following antiestrogen
`(tamoxifen) therapy were given either anastrozole (1
`mg/day) or the progestin megestrol acetate (40 mg q.i.d.),
`and were evaluated with respect to objective response and
`time to disease progression (Table 3), as well as duration of
`response,
`survival,
`and quality of
`life
`(12—14).
`Approximately one-third of the patients given either anas-
`trozole or megestrol acetate derived clinical benefit from
`this therapy (i.e., a positive objective tumor response or sta-
`bilization of disease for at least 6 months) (Table 3). There
`were no statistically significant differences between the treat-
`ment groups with respect to tumor response or time to pro-
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`Anastrozole: Role in Advanced Breast Cancer
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`Table 4
`
`Role in Clinical Practice
`
`Comparison of the Incidence of Potentially Drug-Related“
`Adverse Events in Two Phase III Clinical Trials Involving 262
`Patients Given Arimidex® (1 mg daily) and 253 Patients
`Given Megestrol Acetate (40 mg q. id. )b
`Arimidex® Megestrol acetate
`
`Withdrawn due to AE
`Gastrointestinal disturbance
`Hot flushes
`Edema
`Thromboembolic disease
`
`2.7%
`29.4%
`12.6%
`7.3%
`3.4%
`
`4.0%
`21.3%
`13.8%
`13.8%
`4.7%
`
`0.8%
`1.9%
`Vaginal dryness
`11.9%c
`1.5%
`Weight gain
`34.4%C
`12.6%
`25% weight gain
`
`210% weight gain 10.7%C 2.3%
`
`
`“Anticipated to be potentially causally related to one or both therapies
`based on drug pharmacology.
`bFrom references 12—14.
`CSignificantly different from Arimidex treatment group at p S 0.01.
`
`gression, indicating that anastrozole (1 mg once daily) was
`as effective as the standard regimen of megestrol acetate
`(40 mg q.i.d.) in these patients.
`Objective tumor response, based on conservative inter—
`pretation of the stringent Union Internationale Contre 1e
`Cancer (UICC) criteria, was observed in approximately 10%
`of patients given anastrozole and 8% of those given mege-
`strol acetate. Although these rates appear low, they are con—
`sistent with those reported in other studies of second-line
`hormonal treatment using UICC criteria in patients in whom
`tamoxifen therapy failed (22—26). In addition, the observed
`response rates were not unexpected, since 36% of the
`patients in these two phase III studies had had previous cyto-
`toxic therapy, 46% had visceral lesions, 43% relapsed while
`receiving adjuvant tamoxifen, 62% had bone metastases,
`and 28% had nonmeasurable disease and therefore could
`
`not attain a partial-response (PR) classification.
`Anastrozole was well-tolerated in both clinical trials,
`with the incidence of withdrawal because of adverse
`
`events and the type, severity, and incidence of individual
`adverse events generally comparable with the results
`found with megestrol acetate. In contrast, the number of
`patients gaining weight, as well as the amount of weight
`gained, was significantly greater with megestrol acetate
`than with anastrozole (p S 0.01); also, more patients
`receiving megestrol acetate continued to gain weight over
`time (Table 4). Although some benefit may be realized in
`patients with cachexia, persistent, continuing weight gain
`is undesirable, psychologically distressing, and may be
`problematic for patients undergoing chronic treatment of
`breast cancer.
`
`Postmenopausal women with estrogen receptor-positive,
`metastatic breast cancer and who do not have rapidly pro-
`gressing visceral disease or tumor-related lung or liver dys-
`function are suitable candidates for endocrine therapy. The
`nonsteroidal antiestrogen tamoxifen is currently the most
`widely used first-line hormonal agent in patients with
`metastatic breast cancer (6,27). However, up to 53% of
`patients who initially respond to tamoxifen eventually
`exhibit tamoxifen-resistant disease and require treatment
`with an alternative endocrine agent (27). For these patients,
`the third—generation aromatase inhibitor anastrozole offers a
`new option for second-line hormonal therapy.
`Cross-resistance from tamoxifen, to anastrozole has
`not been observed, and clinical experience supports the
`safety and efficacy of anastrozole in the management of
`advanced breast cancer in postmenopausal women with
`disease progression following treatment with tamoxifen
`(12—14). Aromatase-inhibitory doses of anastrozole do
`not affect the cytochrome P450 hydroxylase or lyase
`enzymes involved in steroidogenesis, and corticosteroid
`replacement therapy is therefore unnecessary in patients
`treated with anastrozole (12). In addition, alterations in
`TSH concentrations have not been observed with anas—
`
`trozole (12). Anastrozole can be given orally in a conve—
`nient, once-daily dosing regimen; is well-tolerated; and
`is not associated with weight gain (12—14). A potential
`
`Postmenopausal patients with
`
`primary disease
`
`Postmenopausal patients with
`
`advanced or recurrent disease
`
`Adjuvant tamoxifen therapy
`
`Adjuvant tamoxifen therapy
`
`Relapse during
`
`Treatment 2-5 years
`
`Relapse
`
`therapy
`
`Anastrozole
`
`Relapse 6-12 months
`
`Aliastrmle
`
`afier discontinuing
`tamoxifen
`
`l
`
`Tamoxifen rechallenge
`
`l
`
`Relapse
`
`l
`Anastroznle
`
`Figure 2. Potential algorithm for hormonal
`metastatic breast cancer.
`
`treatment of
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`algorithm for hormonal treatment of metastatic breast can—
`cer in postmenopausal women is shown in Figure 2.
`
`CONCLUSIONS
`
`Anastrozole provides a new therapeutic option for post-
`menopausal patients with advanced breast cancer whose dis-
`ease has progressed after tamoxifen therapy. Anastrozole
`offers greater selectivity and potency, improved tolerability,
`and a more convenient method of administration than do
`
`other endocrine agents. Because of its similar eflicacy, once-
`daily dosing regimen, and lack of associated weight gain,
`anastrozole would be preferred to progestins such as mege—
`strol acetate for second-line therapy in the management of
`advanced breast cancer in postmenopausal women.
`
`Address correspondence and reprint requests to: Gabriel N. Hortobagyi,
`M.D., MD. Anderson Cancer Center, 1515 Holcombe Blvd, Box 56,
`Houston, TX 77030.
`
`REFERENCES
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`Walton PL, Yates RA, Dukes M: Arimidex: an overview of a new
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