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D o u b l e - B l i n d , R a n d o m i z e d T r i a l C o m p a r i n g t h e E f fi c a c y
a n d T o l e r a b i l i t y o f F u l v e s t r a n t V e r s u s A n a s t r o z o l e i n
P o s t m e n o p a u s a l W o m e n W i t h A d v a n c e d B r e a s t C a n c e r
P r o g r e s s i n g o n P r i o r E n d o c r i n e T h e r a p y : R e s u l t s o f a
N o r t h A m e r i c a n T r i a l
By C.K. Osborne, J. Pippen, S.E. Jones, L.M. Parker, M. Ellis, S. Come, S.Z. Gertler, J.T. May, G. Burton, I. Dimery, A. Webster, C. Morris, R. Elledge, and A. Buzdar Purpose: To compare the efficacy and tolerability of
sponse ؉ partial response ؉ stable disease > 24 weeks)
fulvestrant (formerly ICI 182,780) with anastrozole in the
were 42.2% for fulvestrant and 36.1% for anastrozole
treatment of advanced breast cancer in patients whose
(95% CI, ؊4.00% to 16.41%; P ؍ .26). In responding
disease progresses on prior endocrine treatment.
patients, median DOR (from randomization to progres-
Patients and Methods: In this double-blind, double-
sion) was 19.0 months for fulvestrant and 10.8 months
dummy, parallel-group study, postmenopausal pa-
for anastrozole. Using all patients, DOR was signifi-
tients were randomized to receive either an intramus-
cantly greater for fulvestrant compared with anastro-
cular injection of fulvestrant 250 mg once monthly or a
zole; the ratio of average response durations was 1.35
daily oral dose of anastrozole 1 mg. The primary end
(95% CI, 1.10 to 1.67; P < 0.01). Both treatments were
point was time to progression (TTP). Secondary end
well tolerated.
points included objective response (OR) rate, duration
Conclusion: Fulvestrant was at least as effective as
of response (DOR), and tolerability.
anastrozole, with efficacy end points slightly favoring
Results: Patients (n ؍ 400) were followed for a me-
fulvestrant. Fulvestrant represents an additional treat-
dian period of 16.8 months. Fulvestrant was as effec-
ment option for postmenopausal women with ad-
tive as anastrozole in terms of TTP (hazard ratio, 0.92;
vanced breast cancer whose disease progresses on
95.14% confidence interval [CI], 0.74 to 1.14; P ؍ .43);
tamoxifen therapy.
median TTP was 5.4 months with fulvestrant and 3.4
J Clin Oncol 20:3386-3395. 2002 by American
months with anastrozole. OR rates were 17.5% with
Society of Clinical Oncology.
both treatments. Clinical benefit rates (complete re-
THE SELECTIVE estrogen receptor modulator (SERM) with ductal carcinoma-in-situ.3 Patients who have tumor tamoxifen (Nolvadex; AstraZeneca, Wilmington, DE) progression or develop resistance to tamoxifen are often is well established as a highly effective treatment for pre- treated with second-line hormonal therapy. The treatment and postmenopausal patients with either advanced or early options currently available comprise the third generation of breast cancer.1 Tamoxifen has also been shown to be oral, selective nonsteroidal aromatase inhibitors including effective in reducing the incidence of breast cancer in anastrozole, letrozole, and the steroidal agent exemestane.
patients at risk of developing the disease2 and in women Fulvestrant (Faslodex; AstraZeneca, Macclesfield, UnitedKingdom) is a “pure” estrogen antagonist with a novelmode of action, distinct from that of tamoxifen or any otherantiestrogen currently available. Fulvestrant, like tamox- From the Breast Center at Baylor College of Medicine, Methodist Hospital, US Oncology, and M.D. Anderson Cancer Center, Houston, and ifen, binds to estrogen receptors (ERs) competitively. How- Baylor-Sammons Cancer Center, Dallas, TX; Dana-Farber Cancer Insti- ever, in contrast to tamoxifen, fulvestrant’s binding leads to tute and Beth Israel Deaconess Medical Center, Boston, MA; Lombardi rapid degradation and loss of ER protein.4 Furthermore, Cancer Center, Washington, DC; Ottawa Regional Cancer Center, Ot- fulvestrant antagonizes all of the transactivating functions tawa, Ontario, Canada; Hematology Oncology Association VA Ltd,Richmond, VA; Louisiana State University Health Science Center, Shreve- of the receptor, whereas tamoxifen blocks only one, a port, LA; and AstraZeneca, Macclesfield, United Kingdom. feature that contributes to its estrogen agonist activity in Submitted October 10, 2001; accepted March 22, 2002. some tissues.4 Accordingly, fulvestrant is the first in a new Supported by a grant from AstraZeneca Pharmaceuticals, Wilming- class of antiestrogens—an ER downregulator—and is de- This article was published ahead of print at www.jco.org. void of agonist activity.5 Fulvestrant has greater potency Address reprint requests to C.K. Osborne, MD, Breast Center, than tamoxifen at inhibiting the growth of breast tumors and Baylor College of Medicine, 1 Baylor Plaza, MS 600, Houston, TX doubles the time to the development of resistance in a 77030; email: [email protected]. xenograft murine model of human breast cancer.6 It also 2002 by American Society of Clinical Oncology.
0732-183X/02/2016-3386/$20.00 inhibits growth of tamoxifen-resistant tumors in this mod- Journal of Clinical Oncology, Vol 20, No 16 (August 15), 2002: pp 3386-3395 FULVESTRANT v ANASTROZOLE IN ADVANCED BREAST CANCER el.6 In primary breast cancer patients who received a single The primary end point of the comparison between the two drugs was injection of fulvestrant (at doses of 50, 125, or 250 mg) TTP. Secondary end points included OR, duration of response (DOR),time to treatment failure (TTF), time to death (TTD), and tolerability.
14 to 21 days before the initial tumor resection, fulves- Other secondary end points were quality of life, symptomatic response, trant produced a dose-dependent reduction in both ER and pharmacokinetics. Other end points included clinical benefit (CR ϩ and progesterone receptor (PgR) expression.7 In contrast, PR ϩ stable disease [SD] Ն 24 weeks) and duration of clinical benefit.
a separate group of patients in the same study who All data are reported here except pharmacokinetics, which will be received tamoxifen 20 mg orally before tumor resection showed an increase in PgR expression, thereby confirm- ing the partial estrogen agonist activity of tamoxifen. Aphase II study in postmenopausal women with advanced All patients were postmenopausal women with locally advanced or metastatic breast cancer whose disease had progressed on adjuvant breast cancer whose disease progresses after tamoxifen endocrine therapy with an antiestrogen or whose disease had pro- therapy given as adjuvant or for advance disease showed gressed after first-line endocrine therapy for advanced disease. All that subsequent treatment with fulvestrant was associated women had a life expectancy of longer than 3 months and tumors with evidence of hormone sensitivity (ie, prior sensitivity to hormonal This study provides the first opportunity to compare the therapy or known ER or PgR positivity).
For inclusion in the trial, patients had to have a World Health relative efficacy of ER suppression with the ER downregu- Organization performance status of Յ 2, histologic or cytologic lator fulvestrant with that of anastrozole, as second-line confirmation of breast cancer, objective evidence of recurrence or therapy in patients with potentially hormone-dependent progression of disease that was not amenable to curative treatment, and the presence of at least one measurable or assessable (nonmeasurable)lesion. All patients had to be postmenopausal (ie, Ն 60 years old or aged Ն 45 years with amenorrhea for Ͼ 12 months or follicle-stimulating hormone levels within postmenopausal range, or havingundergone a bilateral oophorectomy).
Exclusion criteria included the following: the presence of life- threatening metastatic visceral disease (defined as extensive hepatic The study (trial 0021) was a randomized, double-blind, double- involvement) or any degree of brain or leptomeningeal involvement; dummy, phase III trial conducted in North America. The trial was symptomatic pulmonary lymphangitic spread; prior treatment for breast originally designed to compare two doses of fulvestrant (125 mg and cancer with fulvestrant or any aromatase inhibitor; more than one prior 250 mg per month) as an intramuscular injection with anastrozole as a endocrine medical treatment for advanced breast cancer; extensive 1 mg/d oral dose. A nonblinded, open-label trial using the same drug radiation therapy or cytotoxic treatment within the past 4 weeks; doses and a similar protocol (trial 0020) was conducted concurrently in estrogen replacement therapy within 4 weeks of randomization; treat- Europe, South Africa, and Australia (see accompanying article in this ment with luteinizing hormone–releasing hormone analogs within 3 issue of the Journal of Clinical Oncology).11 months before randomization; and any concurrent medical illness or A preliminary data summary and an interim analysis were planned laboratory abnormalities that would compromise safety or prevent and conducted to determine the clinical activity of fulvestrant 125 mg, which had not been previously tested. Therefore both trials included a Subjects taking bisphosphonates for bone disease were permitted preliminary data summary stage after the first 30 subjects in the to enter the trial, but their bone lesions were not considered to be fulvestrant 125-mg group (combined from both trials) had been treated assessable for response, although they were assessable for progres- and followed up for 3 months. This interim assessment showed sion. Initiation of bisphosphonate treatment during the trial was insufficient evidence of clinical activity for fulvestrant 125 mg with no discouraged but allowed in the absence of objective evidence of objective tumor responses at 3 months. The independent data monitor- progression. If bisphosphonates were commenced, bone lesions ing committee therefore recommended that recruitment to the fulves- trant 125-mg treatment arm be stopped. Patients already recruited into All patients provided written informed consent, and the relevant the 125-mg arm in trial 0021 were permitted to remain on fulvestrant ethical committees approved the studies.
125 mg or withdraw from the trial and be placed on other treatments atthe discretion of their clinician. These patients were not monitored further for efficacy. The lack of an objective response in the low-dosefulvestrant arm also suggests that response due to tamoxifen with- Fulvestrant was supplied in vials as a single-dose, castor oil– based, drawal in this study must be uncommon. As a consequence of dropping 5% solution. Each vial contained 250 mg of fulvestrant at a concen- this treatment arm, the protocol for the study was amended to compare tration of 50 mg/mL in a volume of 5 mL. The matched placebo was fulvestrant 250 mg with anastrozole 1 mg.
5 mL of the oily excipient. Fulvestrant 250 mg or matching placebo An interim analysis was conducted when 170 progressions or deaths was administered slowly as a 2.5-mL injection into each buttock.
had occurred across the remaining arms and time to progression (TTP) Injections were given once a month, which was defined as every 28 was formally analyzed. The rate of objective response (OR; defined as complete response [CR] ϩ partial response [PR] using Union Interna- Anastrozole (Arimidex) 1 mg and matching placebo were supplied tionale Contre le Cancer criteria) and adverse event (AE) data were as round, white, film-coated tablets and administered orally once daily.
summarized. As a result of the interim analysis, the independent data Medical personnel saw all patients on a monthly basis because all monitoring committee recommended that the trial should continue.
patients required fulvestrant or placebo injections.
Patients continued treatment until objective disease progression or TTF was defined as the number of days from randomization other events required withdrawal; at such time, trial treatment was until the earliest occurrence of disease progression, death from any stopped and standard therapy was initiated at the discretion of the cause, or withdrawal from trial treatment for any reason. Patients treating physician. Thereafter, patients were followed up until death.
whose treatment had not failed at the time of analysis were right- Patients who withdrew from trial treatment before progression were censored in the analysis at the time of their last assessment. Any patient followed up until objective disease progression and death.
who did not receive any trial therapy was assigned an uncensored TTF All patients were seen by a physician to make objective tumor of zero days. Statistically, TTF was analyzed in the same way as TTP.
assessments every 3 months until evidence of either objective disease Responders were defined as those patients with a CR or progression or death. Patients with skin and soft tissue lesions were also PR. To qualify as a responder, the patient had to satisfy the criteria for assessed every month during the first 3 months of treatment.
CR or PR on one visit with no evidence of disease recurrence or deathwithin 4 weeks after assessment. Treatment differences in OR were assessed by comparing the proportion of responders using a logistic The trial was designed to detect the superiority of fulvestrant 250 mg regression model (with the same covariates as for TTP). The estimate in terms of efficacy and tolerability compared with anastrozole 1 mg in of the treatment effect is expressed as an odds ratio (fulvestrant/ postmenopausal women with advanced breast cancer.
anastrozole), together with the corresponding CI and P value. In The final analysis was scheduled to occur when 340 events (ie, addition, an estimate of the difference in response rates (fulvestrant/ objective disease progression or death) had occurred across the two anastrozole) and corresponding CI was also produced.
groups. This provided 90% power to detect a hazard ratio (HR) Ն 1.43 The DOR was defined for responding patients only as the or Յ 0.70 for fulvestrant treatment compared with anastrozole treat- period of time from randomization to the first observation of disease ment, at a significance level of 5%. It was therefore planned to recruit progression. Patients who died before reaching progression were 392 patients (196 in each treatment group) to achieve the required classified as completing their response at time of death. The DOR was summarized using Kaplan-Meier curves for each treatment group, and The efficacy analyses were performed according to randomized the median DOR was also calculated for each group.
treatment (ie, “intention to treat”) using a nominal significance level of No statistical comparison was performed for DOR in only those 5%. However, for the TTP and OR analyses, the significance level was patients responding to treatment, because this is not a randomized adjusted to 4.86% because of the preliminary data summary of OR and comparison. Rather, all patients were included in a statistical analysis the interim analysis of TTP. As a result, the 95% confidence intervals of DOR, defined for responders as the time from onset of response to (CIs) were adjusted accordingly to 95.14%. All significance levels are disease progression and for nonresponders as zero. These data were also summarized using Kaplan-Meier curves.
Although not described in the protocol, fulvestrant was retrospec- Clinical benefit was defined as the sum of CR ϩ tively compared with anastrozole for noninferiority for OR, TTP, and PR ϩ SD Ն 24 weeks. Although a formal analysis of clinical benefit TTF. Because of the interim analysis, a one-sided CI of 97.57% was was not protocoled, treatment differences in the rate of clinical benefit used for the evaluation of TTP and OR. For the analysis of TTF, a were retrospectively assessed in the same way as that of OR rate. The one-sided CI of 97.5% was used. These limits are identical to using the duration of clinical benefit was presented as for DOR.
upper limit of the 95.14% two-sided CI from the analysis of TTP, the As specified in the protocol, TTD (overall survival) will be lower limit of the 95.14% two-sided CI for the difference in response analyzed when more than 50% of the patients have died. At the time of rates for OR, and the upper limit of the 95% two-sided CI for TTF.
this data analysis, only 34.5% of patients had died; therefore, no formal For previous United States regulatory submissions of hormonal statistical analyses were conducted.
treatments for advanced breast cancer, the requirements for showingnoninferiority for TTP were based on the upper one-sided confidence limit for the TTP HR not being greater than 1.25 (ie, a potential Any detrimental change in a patient’s condition subsequent to them deficiency of Ͼ 25% for the experimental treatment had to be ruled entering the trial and during the follow-up period after the final out). In the same submissions, the requirement for demonstrating treatment (8 weeks after last injection or 30 days after the last tablet, noninferiority in terms of response rate was based on ruling out a whichever was the greater), which was not unequivocally due to deficiency in the difference in response rates of more than 10%.
progression of disease, was considered to be an AE. No formal Consequently, these criteria have been used to assess noninferiority of statistical analyses were performed on the safety data from this fulvestrant relative to anastrozole in this trial.
individual trial. However, a planned statistical analysis of predefined TTP was defined as the time from randomization until AEs was performed on the combined data from this trial and the objective disease progression or death from any cause before progres- multinational trial; this will be reported elsewhere. The most common sion. Subjects who had not progressed at the time of analysis were AEs (occurring at an incidence of Ն 10%) and most common right-censored using the last assessment date. Treatments were com- drug-related AEs are reported here by treatment received.
pared using Cox’s proportional hazards regression model (including thecovariates age, performance status, measurable compared with non- measurable disease, receptor status, previous response to hormonetherapy, previous use of cytotoxic chemotherapy, and use of bisphos- Quality of life (QOL) was assessed using the Functional Assessment phonate therapy for bone disease). A global test was performed to of Cancer Therapy (FACT)–Breast questionnaire, which is composed determine whether there were significant treatment-by-baseline covari- of the FACT-General QOL tool for cancer patients plus the breast ate interactions. The estimate of the treatment effect was expressed as cancer subscale. This questionnaire has been extensively validated in an HR (fulvestrant/anastrozole), together with the corresponding CI respect to psychometric properties and sensitivity to clinical chang- and P value. TTP was also summarized using Kaplan-Meier curves for es12,13 and is in use in a number of large breast cancer treatment trials each treatment group, and the median TTP was calculated.
FULVESTRANT v ANASTROZOLE IN ADVANCED BREAST CANCER The analysis was undertaken on data collected up to the date of Table 1. Demographic and Pretreatment Characteristics
progression using the trial outcome index (TOI) within the FACT- Breast. This measure is the sum of the functional well-being, physical well-being and breast cancer subscale dimensions of the questionnaire.
The difference in TOI over time between the fulvestrant 250-mg group and the anastrozole 1-mg group was compared using a general- ized linear mixed model (ie, a random coefficients model) with the same covariates as for TTP. A graph of the mean TOI (Ϯ standard deviation) over time was also produced.
A total of 400 patients randomized to either fulvestrant 250 mg (n ϭ 206) or to anastrozole (n ϭ 194) were followed for a median period of 16.8 months. The majority (95% of the fulvestrant group and 96% of the anastrozole group) had been treated previously with tamoxifen either as adjuvant therapy or as initial therapy for advanced disease.
Metastatic or recurrent disease at baseline Ninety-four patients in each group had received endocrine therapy as adjuvant treatment. Of these, 67 patients in the fulvestrant group and 75 patients in the anastrozole group stopped treatment less than 365 days before randomization.
The characteristics of the patients are presented in Table 1. Patients in the fulvestrant and the anastrozole groups were similar for age, weight, breast cancer history, and ER Extent of metastatic or recurrent disease at At the time of analysis, 83.5% of the fulvestrant group and 86.1% of the anastrozole group had experienced disease progression. There was no significant difference for TTP between the two treatment groups (HR, 0.92; 95.14% CI, 0.74 to 1.14; P ϭ .43). The HR (0.92) indicates that the NOTE. Patients may be in more than one category.
risk of progression (over a given period of time) for patients Abbreviations: ER, estrogen receptor; PgR, progesterone receptor.
randomized to fulvestrant was 8% lower than it was for *Mixed is defined as breast and/or a combination of skin, bone, liver, lung, patients randomized to anastrozole. The 95.14% CI indi- cates that the risk of progression for patients randomized to †Measurable lesions were lesions that were clinically measurable in two perpendicular axes with at least one dimension being Ն 2.5 cm or measurable fulvestrant 250 mg could be between 26% lower and 14% using imaging in two perpendicular axes with at least one dimension being Ն higher than it is for patients randomized to anastrozole.
These data demonstrate noninferiority of fulvestrant relativeto anastrozole. Median TTP was 5.4 months for fulvestrantand 3.4 months for anastrozole (Fig 1).
(HR, 0.96; 95% CI, 0.77 to 1.19; P ϭ .69) (Fig 2). The The majority of treatment failures were due to data also satisfy the criteria for noninferiority. Median objective disease progression (94%), and accordingly, the TTF was 4.6 months for fulvestrant (n ϭ 206) and 3.3 Kaplan-Meier curves for TTP and TTF are very similar. For fulvestrant, there were 164 treatment failures (79.6%) be- cause of disease progression; for anastrozole, there were OR in 36 patients (17.5%), while anastrozole produced an 163 (84.0%). Other reasons for treatment failures in- OR in 34 patients (17.5%) (Table 2). There was no cluded AEs, protocol noncompliance, and withdrawal of statistically significant difference in OR between fulvestrant informed consent. TTF was similar for the two groups, and anastrozole (difference in response rates, 0.17%; with there being no significant difference between them 95.14% CI, Ϫ6.31% to 9.30%). The lower CI shows Fig 1. Kaplan-Meier estimates
for time to progression.
noninferiority of fulvestrant relative to anastrozole. The patients—where DOR was defined as from the onset of odds ratio for achieving an OR in the fulvestrant group response to disease progression for responders and zero for versus the anastrozole group was 1.01 (95.14% CI, 0.59 to nonresponders—was significantly greater for fulvestrant compared with anastrozole (ratio of average response dura- Clinical benefit rates of 42.2% and 36.1% were observed tions, 1.35; 95% CI, 1.10 to 1.67; P Ͻ .01). The Kaplan- for fulvestrant and anastrozole, respectively (Table 2), with Meier curves for DOR in all patients are shown in Fig 4.
the analysis showing no statistically significant difference The median duration of clinical benefit was 12.9 months for (difference in clinical benefit rates, 5.83%; 95% CI, fulvestrant (n ϭ 87) and 10.9 months for anastrozole (n ϭ Extended follow-up was performed in order to obtain At the time of this data analysis, a similar more complete information for DOR (median follow-up, number of deaths had occurred in each treatment group 21.3 months). The median DOR, as measured from random- (fulvestrant, n ϭ 73 [35.4%]; anastrozole, n ϭ 65 ization to progression, in those patients who responded to [33.5%]). However, as specified in the protocol, TTD treatment was 19.0 months for fulvestrant (n ϭ 36) and 10.8 (overall survival) will be analyzed when more than 50% months for anastrozole (n ϭ 34). The Kaplan-Meier curves of the patients have died. Consequently, no formal for the DOR are shown in Fig 3. In addition, DOR using all statistical analyses have been conducted on these data. In Fig 2. Kaplan-Meier estimates
for time to treatment failure.
FULVESTRANT v ANASTROZOLE IN ADVANCED BREAST CANCER Table 2. Best Objective Responses for Fulvestrant 250 mg IM or
were generally similar between treatment groups. The Anastrozole 1 mg Orally od
most common drug-related AEs are shown in Table 4.
The incidence of hot flashes was similar for both drugs (23.5% for fulvestrant and 24.9% for anastrozole).
The incidence of weight gain (fulvestrant v anastrozole: 1.5% v 1.6%), vaginitis (3.4% v2.6%), and thromboem- bolic disease (3.4% v 6.7%) was low for both fulvestrant and anastrozole. Joint disorders (including arthritis, arthralgia, and arthrosis) were reported by 9.3% and 13.5% of patients in the fulvestrant and anastrozole total 6,908 monthly injections: 3,752 injections in the fulvestrant group and 3,156 placebo injections in the anas- Abbreviations: CR, complete response; PR, partial response; SD, stable trozole group. Fifty-five patients (27.0%) receiving fulves- trant and 45 patients (23.3%) receiving anastrozole (plusplacebo injection) reported injection site reactions. Overall, line with the study protocol, TTD analyses will be 86 fulvestrant courses (4.6%) of the total of 1,879 and 71 placebo courses (4.4%) of the total of 1,624 resulted in aninjection site event. Most of these events were charac- terized as injection site pain, reaction, and/or inflamma- Both fulvestrant and anastrozole were well tolerated, tion. None of these events was serious, and only one with only five fulvestrant patients (2.5%) and five anas- patient complained of severe injection site pain and trozole patients (2.6%) withdrawing because of AEs. The requested to be withdrawn from fulvestrant treatment (the profile of AEs (thought to be drug-related or not) was investigator did not consider the event to be drug similar for the two drugs, and patients in both treatment related). Two anastrozole-treated patients given placebo groups reported a wide range of AEs. The most fre- injections were also withdrawn because of AEs related to quently reported AEs, graded according to Coding Sym- (COSTART) classification, are shown in Table 3 andincluded asthenia, nausea, pain, headache, vasodilatation, A graph of the mean TOI (Ϯ standard deviation) over pharyngitis, dyspnea, back pain, bone pain, and vomiting.
time is shown in Fig 6. The analysis of QOL data up to the The incidence and severity (most were mild) of events date of progression showed that QOL was maintained over 3. Kaplan-Meier
mates for duration of response.
4. Kaplan-Meier
mates for duration of response
(all patients).
time and that the two treatments were not statistically significantly greater in the fulvestrant group than in the anastrozole group. The clinically durable response observedwith fulvestrant is in accordance with preclinical observa- tions in tumor models, where fulvestrant was shown to This North American, randomized, double-blind, double- double the DOR compared with tamoxifen or withdrawal of dummy, phase III study in postmenopausal women with estrogen,6 as well as with phase II clinical data,10 where advanced breast cancer was designed to compare the effi- long responses were observed in tamoxifen-resistant, ad- cacy and tolerability of fulvestrant with that of the well- vanced breast cancer patients. Furthermore, in the clinical established third-generation aromatase inhibitor anastro- benefit group, where patient numbers were higher, the zole. Although the results did not show superiority of duration of clinical benefit also favored fulvestrant. With fulvestrant over anastrozole, the primary analysis of TTP respect to other end points of the study, fulvestrant showed showed fulvestrant to be at least as effective as anastrozole.
a numerical improvement in TTP (median, 5.4 months) and The CIs observed for TTP, TTF, and OR for the two TTF (median, 4.6 months) compared with anastrozole hormone agents allow us to rule out inferiority of fulvestrant (median, 3.4 and 3.3 months, respectively), although the to anastrozole. Furthermore, DOR using all patients was analyses of TTP and TTF showed no statistically significant 5. Kaplan-Meier
mates for duration of clinical
benefit (DOCB).
FULVESTRANT v ANASTROZOLE IN ADVANCED BREAST CANCER differences. OR was identical in the fulvestrant and anastrozole tively protocoled for the combined data from this North groups (17.5%). A greater number of patients in the fulvestrant American trial 0021 and the multinational trial 0020.
group achieved long-term SD, giving a slightly higher clinical These results will be presented separately; therefore, the benefit rate (42.2% for fulvestrant v 36.1% for anastrozole), comparative tolerability of fulvestrant and anastrozole in although the analysis of clinical benefit rate showed no the present study is not discussed further.
statistically significant difference. Thus, trends for all major With regard to the route of administration, fulvestrant end points favored fulvestrant. Reassuringly, the summary data was well tolerated, with only one patient withdrawing from of QOL showed that the use of fulvestrant in this patient treatment because of an injection site reaction. The data population maintained QOL as well as anastrozole did. It is from the placebo treatment in the anastrozole arm provided premature to perform survival analyses, which by protocol confirmation that injection site reactions to fulvestrant are design require that more than 50% of patients have died. Given related to the injection itself (or the excipients used to carry the results to date and the multiple additional therapies given fulvestrant) and not to the local effects of fulvestrant itself.
after progression in such patients, it seems highly unlikely that Injection site reactions were also few in the companion patients randomized to fulvestrant would have worse overall multinational study, in which patients received a larger survival. The double-dummy design provided the opportunity single 5-mL injection. A potential advantage of the paren- to determine more thoroughly the toxicity profile of fulves- teral injection is that compliance, which can be a problem trant. In this trial, fulvestrant and anastrozole were both very (particularly in elderly patients), can be assured.
well tolerated, with the AE profile for fulvestrant being similar This study confirms that an antiestrogen with a dominant to that of anastrozole. Similar numbers of AEs were observed estrogen antagonist profile and unique mechanism of action in both treatment arms, with the majority being mild. Most can induce long remissions in tumors with acquired resistance importantly, a low percentage of patients in each group to tamoxifen, a SERM with mixed agonist/antagonist proper- withdrew because of AEs (2.5% with fulvestrant v 2.6% ties. This lack of cross-resistance between tamoxifen and with anastrozole). Many of the AEs in both groups could fulvestrant has not been observed clinically with other anties- have been related more to the serious underlying and trogens. Raloxifene was found to be ineffective in metastatic progressive disease or to concomitant therapy (eg, opi- breast cancer patients who were refractory to tamoxifen.14,15 ates for pain). Statistical analysis of AEs was prospec- Multiple phase II metastatic breast cancer trials investigatingtoremifene in tamoxifen-refractory patients also demonstratedcross-resistance to tamoxifen.16,17 Clearly, the fact that fulves- Table 3. Most Common Adverse Effects Occurring in > 10% of Patients
trant is effective in women progressing after prior tamoxifen therapy emphasizes that it has a mode of action distinct from that of tamoxifen and the other SERMs.
The results of trial 0021 are similar to those found in the another multinational trial (0020), also published in this of the Journal.11 The difference in DOR between fulvestrant and anastrozole, as measured from randomization to pro- gression, in those patients who responded to treatment was greater in trial 0021 compared with trial 0020. However, the Table 4. Drug-Related Adverse Events Occurring in > 3% of Patients in
Either Group (excluding injection site reactions)
Fig 6. Quality of life: observed
mean (؎ standard deviation)
treatment outcome index over
time.
DOR using all patients, where DOR was defined as from the ER-positive, which could also have influenced benefit onset of response to disease progression for responders and as from treatments designed to target the receptor. Finally, zero for nonresponders, was significantly greater for fulves- patients in trial 0021 had greater body weight and had trant compared with anastrozole in both trials. An advantage more frequently received prior chemotherapy, although it for fulvestrant compared with estrogen deprivation or tamox- is not clear how these differences could affect the results.
ifen treatment was also shown in a preclinical model, leading In conclusion, this study shows that fulvestrant is the first to the hypothesis that it might take breast cancer cells longer to antiestrogen to show clinically relevant activity in tamox- develop resistance to fulvestrant.6 Although the difference in ifen-resistant advanced breast cancer, confirming that ful- these clinical trials could be a chance finding, there were some vestrant represents the first of a new class of antiestrogen.
differences in the trials that could contribute to this discrep- Although fulvestrant was not statistically significantly su- ancy. In trial 0021, all patients were seen monthly by perior to anastrozole, it is the first antiestrogen to be at least medical personnel to receive injections; therefore, dis- as effective as anastrozole in the treatment of patients with ease symptoms could be followed more closely. In trial advanced breast cancer whose disease has progressed after 0020, only fulvestrant patients were seen monthly, prior endocrine treatment. Given its efficacy and tolerability whereas patients receiving anastrozole were followed up profile, fulvestrant will provide a new endocrine treatment every 3 months, potentially biasing efficacy in favor of option for the management of women with advanced breast anastrozole. More patients in trial 0021 were known to be The appendix listing fulvestrant study group investigators is available online at www.jco.org.
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