- © 2002 by American Society of Clinical Oncology
Double-Blind, Randomized Trial Comparing the Efficacy and Tolerability of Fulvestrant Versus Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing on Prior Endocrine Therapy: Results of a North American Trial
- 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
- From the Breast Center at Baylor College of Medicine, Methodist Hospital, US Oncology, and M.D. Anderson Cancer Center, Houston, and Baylor-Sammons Cancer Center, Dallas, TX; Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center, Boston, MA; Lombardi Cancer Center, Washington, DC; Ottawa Regional Cancer Center, Ottawa, Ontario, Canada; Hematology Oncology Association VA Ltd, Richmond, VA; Louisiana State University Health Science Center, Shreveport, LA; and AstraZeneca, Macclesfield, United Kingdom.
- Address reprint requests to C.K. Osborne, MD, Breast Center, Baylor College of Medicine, 1 Baylor Plaza, MS 600, Houston, TX 77030; email: kosborne{at}breastcenter.tmc.edu
Abstract
PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment.
PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability.
RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P = .43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease ≥ 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, −4.00% to 16.41%; P = .26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated.
CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.
THE SELECTIVE estrogen receptor modulator (SERM) tamoxifen (Nolvadex; AstraZeneca, Wilmington, DE) is well established as a highly effective treatment for pre- and postmenopausal patients with either advanced or early breast cancer.1 Tamoxifen has also been shown to be effective in reducing the incidence of breast cancer in patients at risk of developing the disease2 and in women with ductal carcinoma-in-situ.3 Patients who have tumor progression or develop resistance to tamoxifen are often treated with second-line hormonal therapy. The treatment options currently available comprise the third generation of oral, selective nonsteroidal aromatase inhibitors including anastrozole, letrozole, and the steroidal agent exemestane. Fulvestrant (Faslodex; AstraZeneca, Macclesfield, United Kingdom) is a “pure” estrogen antagonist with a novel mode of action, distinct from that of tamoxifen or any other antiestrogen currently available. Fulvestrant, like tamoxifen, binds to estrogen receptors (ERs) competitively. However, in contrast to tamoxifen, fulvestrant’s binding leads to rapid degradation and loss of ER protein.4 Furthermore, fulvestrant antagonizes all of the transactivating functions of the receptor, whereas tamoxifen blocks only one, a feature that contributes to its estrogen agonist activity in some tissues.4 Accordingly, fulvestrant is the first in a new class of antiestrogens—an ER downregulator—and is devoid of agonist activity.5 Fulvestrant has greater potency than tamoxifen at inhibiting the growth of breast tumors and doubles the time to the development of resistance in a xenograft murine model of human breast cancer.6 It also inhibits growth of tamoxifen-resistant tumors in this model.6 In primary breast cancer patients who received a single injection of fulvestrant (at doses of 50, 125, or 250 mg) 14 to 21 days before the initial tumor resection, fulvestrant produced a dose-dependent reduction in both ER and progesterone receptor (PgR) expression.7 In contrast, a separate group of patients in the same study who received tamoxifen 20 mg orally before tumor resection showed an increase in PgR expression, thereby confirming the partial estrogen agonist activity of tamoxifen. A phase II study in postmenopausal women with advanced breast cancer whose disease progresses after tamoxifen therapy given as adjuvant or for advance disease showed that subsequent treatment with fulvestrant was associated with durable responses.8-10
This study provides the first opportunity to compare the relative efficacy of ER suppression with the ER downregulator fulvestrant with that of anastrozole, as second-line therapy in patients with potentially hormone-dependent advanced breast cancer.
PATIENTS AND METHODS
Study Design
The study (trial 0021) was a randomized, double-blind, double-dummy, phase III trial conducted in North America. The trial was originally designed to compare two doses of fulvestrant (125 mg and 250 mg per month) as an intramuscular injection with anastrozole as a 1 mg/d oral dose. A nonblinded, open-label trial using the same drug doses and a similar protocol (trial 0020) was conducted concurrently in Europe, South Africa, and Australia (see accompanying article in this issue of the Journal of Clinical Oncology).11
A preliminary data summary and an interim analysis were planned and conducted to determine the clinical activity of fulvestrant 125 mg, which had not been previously tested. Therefore both trials included a preliminary data summary stage after the first 30 subjects in the fulvestrant 125-mg group (combined from both trials) had been treated and followed up for 3 months. This interim assessment showed insufficient evidence of clinical activity for fulvestrant 125 mg with no objective tumor responses at 3 months. The independent data monitoring committee therefore recommended that recruitment to the fulvestrant 125-mg treatment arm be stopped. Patients already recruited into the 125-mg arm in trial 0021 were permitted to remain on fulvestrant 125 mg or withdraw from the trial and be placed on other treatments at the discretion of their clinician. These patients were not monitored further for efficacy. The lack of an objective response in the low-dose fulvestrant arm also suggests that response due to tamoxifen withdrawal in this study must be uncommon. As a consequence of dropping this treatment arm, the protocol for the study was amended to compare fulvestrant 250 mg with anastrozole 1 mg.
An interim analysis was conducted when 170 progressions or deaths had occurred across the remaining arms and time to progression (TTP) was formally analyzed. The rate of objective response (OR; defined as complete response [CR] + partial response [PR] using Union Internationale Contre le Cancer criteria) and adverse event (AE) data were summarized. As a result of the interim analysis, the independent data monitoring committee recommended that the trial should continue.
The primary end point of the comparison between the two drugs was TTP. Secondary end points included OR, duration of response (DOR), time to treatment failure (TTF), time to death (TTD), and tolerability. Other secondary end points were quality of life, symptomatic response, and pharmacokinetics. Other end points included clinical benefit (CR + PR + stable disease [SD] ≥ 24 weeks) and duration of clinical benefit. All data are reported here except pharmacokinetics, which will be reported elsewhere.
Patient Population
All patients were postmenopausal women with locally advanced or metastatic breast cancer whose disease had progressed on adjuvant endocrine therapy with an antiestrogen or whose disease had progressed after first-line endocrine therapy for advanced disease. All women had a life expectancy of longer than 3 months and tumors with evidence of hormone sensitivity (ie, prior sensitivity to hormonal therapy or known ER or PgR positivity).
For inclusion in the trial, patients had to have a World Health Organization performance status of ≤ 2, histologic or cytologic confirmation of breast cancer, objective evidence of recurrence or 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, ≥ 60 years old or aged ≥ 45 years with amenorrhea for > 12 months or follicle-stimulating hormone levels within postmenopausal range, or having undergone a bilateral oophorectomy).
Exclusion criteria included the following: the presence of life-threatening metastatic visceral disease (defined as extensive hepatic involvement) or any degree of brain or leptomeningeal involvement; symptomatic pulmonary lymphangitic spread; prior treatment for breast cancer with fulvestrant or any aromatase inhibitor; more than one prior endocrine medical treatment for advanced breast cancer; extensive radiation therapy or cytotoxic treatment within the past 4 weeks; estrogen replacement therapy within 4 weeks of randomization; treatment with luteinizing hormone–releasing hormone analogs within 3 months before randomization; and any concurrent medical illness or laboratory abnormalities that would compromise safety or prevent interpretation of results.
Subjects taking bisphosphonates for bone disease were permitted to enter the trial, but their bone lesions were not considered to be assessable for response, although they were assessable for progression. Initiation of bisphosphonate treatment during the trial was discouraged but allowed in the absence of objective evidence of progression. If bisphosphonates were commenced, bone lesions were assessed only for progression.
All patients provided written informed consent, and the relevant ethical committees approved the studies.
Trial Treatments
Fulvestrant was supplied in vials as a single-dose, castor oil–based, 5% solution. Each vial contained 250 mg of fulvestrant at a concentration of 50 mg/mL in a volume of 5 mL. The matched placebo was 5 mL of the oily excipient. Fulvestrant 250 mg or matching placebo was administered slowly as a 2.5-mL injection into each buttock. Injections were given once a month, which was defined as every 28 days (± 3 days).
Anastrozole (Arimidex) 1 mg and matching placebo were supplied as round, white, film-coated tablets and administered orally once daily. Medical personnel saw all patients on a monthly basis because all patients required fulvestrant or placebo injections.
Patients continued treatment until objective disease progression or other events required withdrawal; at such time, trial treatment was stopped and standard therapy was initiated at the discretion of the treating physician. Thereafter, patients were followed up until death. Patients who withdrew from trial treatment before progression were followed up until objective disease progression and death.
All patients were seen by a physician to make objective tumor assessments every 3 months until evidence of either objective disease progression or death. Patients with skin and soft tissue lesions were also assessed every month during the first 3 months of treatment.
Statistical Methodology
The trial was designed to detect the superiority of fulvestrant 250 mg in terms of efficacy and tolerability compared with anastrozole 1 mg in postmenopausal women with advanced breast cancer.
The final analysis was scheduled to occur when 340 events (ie, objective disease progression or death) had occurred across the two groups. This provided 90% power to detect a hazard ratio (HR) ≥ 1.43 or ≤ 0.70 for fulvestrant treatment compared with anastrozole treatment, at a significance level of 5%. It was therefore planned to recruit 392 patients (196 in each treatment group) to achieve the required number of events.
The efficacy analyses were performed according to randomized treatment (ie, “intention to treat”) using a nominal significance level of 5%. However, for the TTP and OR analyses, the significance level was adjusted to 4.86% because of the preliminary data summary of OR and the interim analysis of TTP. As a result, the 95% confidence intervals (CIs) were adjusted accordingly to 95.14%. All significance levels are two-sided.
Although not described in the protocol, fulvestrant was retrospectively compared with anastrozole for noninferiority for OR, TTP, and TTF. Because of the interim analysis, a one-sided CI of 97.57% was used for the evaluation of TTP and OR. For the analysis of TTF, a one-sided CI of 97.5% was used. These limits are identical to using the upper limit of the 95.14% two-sided CI from the analysis of TTP, the lower limit of the 95.14% two-sided CI for the difference in response rates for OR, and the upper limit of the 95% two-sided CI for TTF.
For previous United States regulatory submissions of hormonal treatments for advanced breast cancer, the requirements for showing noninferiority for TTP were based on the upper one-sided confidence limit for the TTP HR not being greater than 1.25 (ie, a potential deficiency of > 25% for the experimental treatment had to be ruled out). In the same submissions, the requirement for demonstrating noninferiority in terms of response rate was based on ruling out a deficiency in the difference in response rates of more than 10%. Consequently, these criteria have been used to assess noninferiority of fulvestrant relative to anastrozole in this trial.
TTP.
TTP was defined as the time from randomization until objective disease progression or death from any cause before progression. Subjects who had not progressed at the time of analysis were right-censored using the last assessment date. Treatments were compared using Cox’s proportional hazards regression model (including the covariates age, performance status, measurable compared with nonmeasurable disease, receptor status, previous response to hormone therapy, previous use of cytotoxic chemotherapy, and use of bisphosphonate therapy for bone disease). A global test was performed to determine whether there were significant treatment-by-baseline covariate interactions. The estimate of the treatment effect was expressed as an HR (fulvestrant/anastrozole), together with the corresponding CI and P value. TTP was also summarized using Kaplan-Meier curves for each treatment group, and the median TTP was calculated.
TTF.
TTF was defined as the number of days from randomization until the earliest occurrence of disease progression, death from any cause, or withdrawal from trial treatment for any reason. Patients whose treatment had not failed at the time of analysis were right-censored in the analysis at the time of their last assessment. Any patient who did not receive any trial therapy was assigned an uncensored TTF of zero days. Statistically, TTF was analyzed in the same way as TTP.
OR rate.
Responders were defined as those patients with a CR or PR. To qualify as a responder, the patient had to satisfy the criteria for CR or PR on one visit with no evidence of disease recurrence or death within 4 weeks after assessment. Treatment differences in OR were assessed by comparing the proportion of responders using a logistic regression model (with the same covariates as for TTP). The estimate of the treatment effect is expressed as an odds ratio (fulvestrant/anastrozole), together with the corresponding CI and P value. In addition, an estimate of the difference in response rates (fulvestrant/anastrozole) and corresponding CI was also produced.
DOR.
The DOR was defined for responding patients only as the period of time from randomization to the first observation of disease progression. Patients who died before reaching progression were classified as completing their response at time of death. The DOR was summarized using Kaplan-Meier curves for each treatment group, and the median DOR was also calculated for each group.
No statistical comparison was performed for DOR in only those patients responding to treatment, because this is not a randomized comparison. Rather, all patients were included in a statistical analysis of DOR, defined for responders as the time from onset of response to disease progression and for nonresponders as zero. These data were also summarized using Kaplan-Meier curves.
Clinical benefit.
Clinical benefit was defined as the sum of CR + PR + SD ≥ 24 weeks. Although a formal analysis of clinical benefit was not protocoled, treatment differences in the rate of clinical benefit were retrospectively assessed in the same way as that of OR rate. The duration of clinical benefit was presented as for DOR.
TTD.
As specified in the protocol, TTD (overall survival) will be analyzed when more than 50% of the patients have died. At the time of this data analysis, only 34.5% of patients had died; therefore, no formal statistical analyses were conducted.
Tolerability
Any detrimental change in a patient’s condition subsequent to them entering the trial and during the follow-up period after the final treatment (8 weeks after last injection or 30 days after the last tablet, whichever was the greater), which was not unequivocally due to progression of disease, was considered to be an AE. No formal statistical analyses were performed on the safety data from this individual trial. However, a planned statistical analysis of predefined AEs was performed on the combined data from this trial and the multinational trial; this will be reported elsewhere. The most common AEs (occurring at an incidence of ≥ 10%) and most common drug-related AEs are reported here by treatment received.
Quality of Life
Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy (FACT)–Breast questionnaire, which is composed of the FACT-General QOL tool for cancer patients plus the breast cancer subscale. This questionnaire has been extensively validated in respect to psychometric properties and sensitivity to clinical changes12,13 and is in use in a number of large breast cancer treatment trials in the United States and Europe.
The analysis was undertaken on data collected up to the date of 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 generalized linear mixed model (ie, a random coefficients model) with the same covariates as for TTP. A graph of the mean TOI (± standard deviation) over time was also produced.
RESULTS
Patients
A total of 400 patients randomized to either fulvestrant 250 mg (n = 206) or to anastrozole (n = 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. 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 and PgR status (Table 1).
Table 1. Demographic and Pretreatment Characteristics
Efficacy
TTP.
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 = .43). The HR (0.92) indicates that the risk of progression (over a given period of time) for patients randomized to fulvestrant was 8% lower than it was for patients randomized to anastrozole. The 95.14% CI indicates that the risk of progression for patients randomized to fulvestrant 250 mg could be between 26% lower and 14% higher than it is for patients randomized to anastrozole. These data demonstrate noninferiority of fulvestrant relative to anastrozole. Median TTP was 5.4 months for fulvestrant and 3.4 months for anastrozole (Fig 1).
Fig 1. Kaplan-Meier estimates for time to progression.
TTF.
The majority of treatment failures were due to objective disease progression (94%), and accordingly, the Kaplan-Meier curves for TTP and TTF are very similar. For fulvestrant, there were 164 treatment failures (79.6%) because of disease progression; for anastrozole, there were 163 (84.0%). Other reasons for treatment failures included AEs, protocol noncompliance, and withdrawal of informed consent. TTF was similar for the two groups, with there being no significant difference between them (HR, 0.96; 95% CI, 0.77 to 1.19; P = .69) (Fig 2). The data also satisfy the criteria for noninferiority. Median TTF was 4.6 months for fulvestrant (n = 206) and 3.3 months for anastrozole (n = 194).
Fig 2. Kaplan-Meier estimates for time to treatment failure.
OR rate and clinical benefit.
Fulvestrant resulted in an OR in 36 patients (17.5%), while anastrozole produced an OR in 34 patients (17.5%) (Table 2). There was no statistically significant difference in OR between fulvestrant and anastrozole (difference in response rates, 0.17%; 95.14% CI, −6.31% to 9.30%). The lower CI shows noninferiority of fulvestrant relative to anastrozole. The odds ratio for achieving an OR in the fulvestrant group versus the anastrozole group was 1.01 (95.14% CI, 0.59 to 1.73; P = .96).
Table 2. Best Objective Responses for Fulvestrant 250 mg IM or Anastrozole 1 mg Orally od
Clinical benefit rates of 42.2% and 36.1% were observed for fulvestrant and anastrozole, respectively (Table 2), with the analysis showing no statistically significant difference (difference in clinical benefit rates, 5.83%; 95% CI, −4.42% to 9.36%; P = .26).
Extended follow-up was performed in order to obtain more complete information for DOR (median follow-up, 21.3 months). The median DOR, as measured from randomization to progression, in those patients who responded to treatment was 19.0 months for fulvestrant (n = 36) and 10.8 months for anastrozole (n = 34). The Kaplan-Meier curves for the DOR are shown in Fig 3. In addition, DOR using all patients—where DOR was defined as from the onset of response to disease progression for responders and zero for nonresponders—was significantly greater for fulvestrant compared with anastrozole (ratio of average response durations, 1.35; 95% CI, 1.10 to 1.67; P < .01). The Kaplan-Meier curves for DOR in all patients are shown in Fig 4. The median duration of clinical benefit was 12.9 months for fulvestrant (n = 87) and 10.9 months for anastrozole (n = 70) (Fig 5).
Fig 3. Kaplan-Meier estimates for duration of response.
Fig 4. Kaplan-Meier estimates for duration of response (all patients).
Fig 5. Kaplan-Meier estimates for duration of clinical benefit (DOCB).
TTD.
At the time of this data analysis, a similar number of deaths had occurred in each treatment group (fulvestrant, n = 73 [35.4%]; anastrozole, n = 65 [33.5%]). However, as specified in the protocol, TTD (overall survival) will be analyzed when more than 50% of the patients have died. Consequently, no formal statistical analyses have been conducted on these data. In line with the study protocol, TTD analyses will be presented in a future publication.
Tolerability
Both fulvestrant and anastrozole were well tolerated, with only five fulvestrant patients (2.5%) and five anastrozole patients (2.6%) withdrawing because of AEs. The profile of AEs (thought to be drug-related or not) was similar for the two drugs, and patients in both treatment groups reported a wide range of AEs. The most frequently reported AEs, graded according to Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) classification, are shown in Table 3 and included asthenia, nausea, pain, headache, vasodilatation, pharyngitis, dyspnea, back pain, bone pain, and vomiting. The incidence and severity (most were mild) of events were generally similar between treatment groups. The 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 thromboembolic 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 groups, respectively.
Table 3. Most Common Adverse Effects Occurring in ≥ 10% of Patients
Table 4. Drug-Related Adverse Events Occurring in ≥ 3% of Patients in Either Group (excluding injection site reactions)
Injection site effects.
Both patient groups received in total 6,908 monthly injections: 3,752 injections in the fulvestrant group and 3,156 placebo injections in the anastrozole group. Fifty-five patients (27.0%) receiving fulvestrant and 45 patients (23.3%) receiving anastrozole (plus placebo injection) reported injection site reactions. Overall, 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 an injection site event. Most of these events were characterized as injection site pain, reaction, and/or inflammation. None of these events was serious, and only one patient complained of severe injection site pain and requested to be withdrawn from fulvestrant treatment (the investigator did not consider the event to be drug related). Two anastrozole-treated patients given placebo injections were also withdrawn because of AEs related to their injections.
QOL
A graph of the mean TOI (± standard deviation) over time is shown in Fig 6. The analysis of QOL data up to the date of progression showed that QOL was maintained over time and that the two treatments were not statistically significantly different.
Fig 6. Quality of life: observed mean (± standard deviation) treatment outcome index over time.
DISCUSSION
This North American, randomized, double-blind, double-dummy, phase III study in postmenopausal women with advanced breast cancer was designed to compare the efficacy and tolerability of fulvestrant with that of the well-established third-generation aromatase inhibitor anastrozole. Although the results did not show superiority of fulvestrant over anastrozole, the primary analysis of TTP showed fulvestrant to be at least as effective as anastrozole. The CIs observed for TTP, TTF, and OR for the two hormone agents allow us to rule out inferiority of fulvestrant to anastrozole. Furthermore, DOR using all patients was significantly greater in the fulvestrant group than in the anastrozole group. The clinically durable response observed with fulvestrant is in accordance with preclinical observations in tumor models, where fulvestrant was shown to double the DOR compared with tamoxifen or withdrawal of estrogen,6 as well as with phase II clinical data,10 where long responses were observed in tamoxifen-resistant, advanced breast cancer patients. Furthermore, in the clinical benefit group, where patient numbers were higher, the duration of clinical benefit also favored fulvestrant. With respect to other end points of the study, fulvestrant showed a numerical improvement in TTP (median, 5.4 months) and TTF (median, 4.6 months) compared with anastrozole (median, 3.4 and 3.3 months, respectively), although the analyses of TTP and TTF showed no statistically significant differences. OR was identical in the fulvestrant and anastrozole groups (17.5%). A greater number of patients in the fulvestrant group achieved long-term SD, giving a slightly higher clinical benefit rate (42.2% for fulvestrant v 36.1% for anastrozole), although the analysis of clinical benefit rate showed no statistically significant difference. Thus, trends for all major end points favored fulvestrant. Reassuringly, the summary data of QOL showed that the use of fulvestrant in this patient population maintained QOL as well as anastrozole did. It is premature to perform survival analyses, which by protocol design require that more than 50% of patients have died. Given the results to date and the multiple additional therapies given after progression in such patients, it seems highly unlikely that patients randomized to fulvestrant would have worse overall survival. The double-dummy design provided the opportunity to determine more thoroughly the toxicity profile of fulvestrant. In this trial, fulvestrant and anastrozole were both very well tolerated, with the AE profile for fulvestrant being similar to that of anastrozole. Similar numbers of AEs were observed in both treatment arms, with the majority being mild. Most importantly, a low percentage of patients in each group withdrew because of AEs (2.5% with fulvestrant v 2.6% with anastrozole). Many of the AEs in both groups could have been related more to the serious underlying and progressive disease or to concomitant therapy (eg, opiates for pain). Statistical analysis of AEs was prospectively protocoled for the combined data from this North American trial 0021 and the multinational trial 0020. These results will be presented separately; therefore, the comparative tolerability of fulvestrant and anastrozole in the present study is not discussed further.
With regard to the route of administration, fulvestrant was well tolerated, with only one patient withdrawing from treatment because of an injection site reaction. The data from the placebo treatment in the anastrozole arm provided confirmation that injection site reactions to fulvestrant are related to the injection itself (or the excipients used to carry fulvestrant) and not to the local effects of fulvestrant itself. injection site reactions were also few in the companion multinational study, in which patients received a larger single 5-mL injection. A potential advantage of the parenteral injection is that compliance, which can be a problem (particularly in elderly patients), can be assured.
This study confirms that an antiestrogen with a dominant estrogen antagonist profile and unique mechanism of action can induce long remissions in tumors with acquired resistance to tamoxifen, a SERM with mixed agonist/antagonist properties. This lack of cross-resistance between tamoxifen and fulvestrant has not been observed clinically with other antiestrogens. Raloxifene was found to be ineffective in metastatic breast cancer patients who were refractory to tamoxifen.14,15 Multiple phase II metastatic breast cancer trials investigating toremifene in tamoxifen-refractory patients also demonstrated cross-resistance to tamoxifen.16,17 Clearly, the fact that fulvestrant 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 progression, in those patients who responded to treatment was greater in trial 0021 compared with trial 0020. However, the DOR using all patients, where DOR was defined as from the onset of response to disease progression for responders and as zero for nonresponders, was significantly greater for fulvestrant compared with anastrozole in both trials. An advantage for fulvestrant compared with estrogen deprivation or tamoxifen treatment was also shown in a preclinical model, leading to the hypothesis that it might take breast cancer cells longer to develop resistance to fulvestrant.6 Although the difference in these clinical trials could be a chance finding, there were some differences in the trials that could contribute to this discrepancy. In trial 0021, all patients were seen monthly by medical personnel to receive injections; therefore, disease symptoms could be followed more closely. In trial 0020, only fulvestrant patients were seen monthly, whereas patients receiving anastrozole were followed up every 3 months, potentially biasing efficacy in favor of anastrozole. More patients in trial 0021 were known to be ER-positive, which could also have influenced benefit from treatments designed to target the receptor. Finally, patients in trial 0021 had greater body weight and had more frequently received prior chemotherapy, although it is not clear how these differences could affect the results.
In conclusion, this study shows that fulvestrant is the first antiestrogen to show clinically relevant activity in tamoxifen-resistant advanced breast cancer, confirming that fulvestrant represents the first of a new class of antiestrogen. Although fulvestrant was not statistically significantly superior to anastrozole, it is the first antiestrogen to be at least as effective as anastrozole in the treatment of patients with advanced breast cancer whose disease has progressed after prior endocrine treatment. Given its efficacy and tolerability profile, fulvestrant will provide a new endocrine treatment option for the management of women with advanced breast cancer resistant to tamoxifen.
APPENDIX
The appendix listing fulvestrant study group investigators is available online at www.jco.org.
The fulvestrant study group was composed of the following investigators:Irving Berkowitz, Christiana Care Health System, Newark, DE; Joel Bernstein, Scripps Memorial Hospitals, Oncology Research Program La Jolla, CA; William Berry, Raleigh Hematology and Oncology Association, Rex Cancer Center, Raleigh, NC; Daniel Budman, North Shore University Hospital–New York University, Manhasset, NY; Peter Byeff, New Britain General Hospital, New Britain, CT; Lawrence Canning, Waco Hematology Oncology, Waco, TX; John Carpenter, Jr, University of Alabama at Birmingham, Birmingham, AL; Ray Lark, Hematology/Oncology Associates, Jackson, MI; Frank Cummings, Roger Williams Hospital, Providence, RI; Alan Grosbach, Schumpert Cancer Treatment Center, Shreveport, LA; Nikolay Dimitrov, Michigan State University Protocol Office, East Lansing, MI; Tracy Dobbs, Baptist Regional Cancer Center, Knoxville, TN; William Edwards, Rockford Clinic, Rockford, IL; Peter Eisenberg, Marin Oncology Associates, Greenbrae, CA; Eduardo Gomez, Miami, FL; M. Francisco Gonzalez, University of South Carolina, Columbia, SC; William Gradishar, Northwestern University Medical School, Chicago, IL; Mark Graham, University of North Carolina at Chapel
APPENDIX (Cont’d)
Hill, Chapel Hill, NC; Generosa Grana, Cooper University Hospital, Camden, NJ; Kenneth M. Lam, Huntington Cancer Center, Pasadena, CA; Jayne Gurtler, Professional Medical Corporation, Metairie, LA; John T Hamm, Alliant Medical Pavilion, Louisville, KY; Karen Hoelzer, Memorial Medical Center Regional Cancer Center, Springfield, IL; James Ingle, Mayo Clinic Cancer Center, Rochester, MN; Vicky Jones, University of California San Diego, La Jolla, CA; Glen Justice, Pacific Coast Hematology/Oncology Medical Group, Fountain Valley, CA; Carl Kardinal, Ochsner Cancer Institute, New Orleans, LA; Richard Kosierowski, North Penn Hospital, Lansdale, PA; Charles Kossman, John R Wilkinson, San Diego, CA; Leslie Laufman, Columbus, OH; Eric P. Lester, Lakeland Memorial Medical Center, St Joseph, MI; Ellis Levine, Roswell Park Cancer Institute, Buffalo, NY; Gershon Locker, The Evanston Hospital, Kellogg Cancer Center, Evanston, IL; Alan Lyss, Missouri Baptist Cancer Center, St Louis, MO; Aroop Mangalik, University of New Mexico, Albuquerque, NM; Michael Meshad, The Cancer Center at Providence Hospital Mobile, AL; Gerald P. Miletello, Hematology-Oncology Clinic, Baton Rouge, LA; Joanne Mortimer, Washington University, St Louis, MO; Hyman Muss, Fletcher Allen Health Care, Burlington, VT; David Myers, Billings Interhospital Oncology, Billings, MT; Dustan C. Osborn, Western Washington Cancer Treatment Center, Olympia, WA; Peter Ravdin, The University of Texas Health Science Center San Antonio, TX; Ravi Patel, Comprehensive Blood & Cancer Center, Bakersfield, CA; Edith Perez, Mayo Clinic Jacksonville, Jacksonville, FL; Peter Pickens, Meadowbrook, PA; G. Dastgir Qureshi, St Lukes Cancer Center, Richmond, VA; Joseph Readling, Lourdes Hospital Regional Cancer Center, Binghamton, NY; Saul E. Rivkin, Swedish Medical Center Tumor Institute, Seattle, WA; Nicholas Robert, Fairfax Prince William Hematology/Oncology Associates, Annandale, VA; Michael Roberts, Hematology/Oncology Associates Ltd., Phoenix, AZ; Rene Rothstein Rubin, Philadelphia, PA; Gregory Sarna, Cedars Sinai Comprehensive Cancer Center, Los Angeles, CA; Lynn Schuchter, University of Pennsylvania Cancer Center, Philadelphia, PA; Jeffery Schneider, Winthrop University Hospital, Mineola, NY; Joel Schwartz, North Shore Cancer Center, Peabody, MA; Harvey Sher, Jacksonville Oncology Group, Jacksonville, FL; Peter Silberstein, North Iowa Mercy Health Center, Mercy Cancer Center, Mason City, IA; Mary Simmonds, Central Pennsylvania & Hematology, Medical Oncology Associates, Lemoyne, PA; Gregory Smith, Southwest Regional Cancer Center, Austin, TX; Jack Sternberg, Clinical Investigation Specialists, Inc, Little Rock, AR; Kala Seetharaman, St Vincent Hospital, Worcester, MA; Stuart Tipping, Marshfield Clinic, Marshfield, WI; Debasish Tripathy, University of California San Francisco Cancer Center, San Francisco, CA; Victor Vogel, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Jane Wolter, Rush-Presbyterian/St Lukes Medical Center, Chicago, IL; Furhan Yunus, Boston Cancer Group, Memphis, TN; Robyn Young, Scott and White Clinic, Temple, TX; Margot Burnell, Atlantic Health Sciences Corporation, Saint John, New Brunswick, Canada; Jose Chang, Lakeridge Health Oshawa, Oshawa, Ontario, Canada; Brian Findlay, Hotel Dieu Hospital Oncology Clinic, St Catharines, Canada; Rashida Haq, St Michaels Hospital, Toronto, Canada; Lawrence Panasci, Jewish General Hospital, Montreal, Canada; Bryn Pressnail, The Royal Victoria Hospital of Barrie, Ontario, Canada; Kathleen Pritchard, Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada; Jean Robert, Hopital du Saint-Sacrement, Quebec, Canada; Malcolm Brigden, Penticton Regional Hospital, Penticton, Canada; Bruce Colwell, II Health Science Centre, Nova Scotia Cancer Center, Halifax, Canada; Shailendra Verma, Ottawa Regional Cancer Centre, Ottawa, Canada; Jonathan Wilson, Humber River Regional Hospital, Weston, Canada; and Shou-Ching Tang, H. Bliss Murphy Cancer Center, St Johns, Canada.
Acknowledgments
Supported by a grant from AstraZeneca Pharmaceuticals, Wilmington, DE.
- Received October 10, 2001.
- Accepted March 22, 2002.
