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Exemestane Is Superior to Megestrol Acetate After Tamoxifen Failure in Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Randomized Double-Blind Trial

From the Universitätsklinik, Frankfurt, Germany; Istituto Nazionale Tumori, Milan, Italy; Sint-Augustinus Ziekenhuis, Antwerpen, Belgium; Centro Oncologico de Rosario, Santa Fe, Argentina; Physicians Reliance Network Research, Baylor-Sammons Cancer Center, Dallas, Texas; Institute of Oncology, Ljubljana, Slovenia; and Pharmacia & Upjohn, Italy and United States.

Address reprint requests to Manfred Kaufmann, MD, Department of Gynecology and Oncology, Johann Wolfgang Goeth-Universität Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated.

RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P = .039), as were the median duration of overall success (OR or stable disease 24 weeks; 60.1 v 49.1 weeks; P = .025), time to tumor progression (20.3 v 16.6 weeks; P = .037), and time to treatment failure (16.3 v 15.7 weeks; P = .042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P = .001).

CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
TREATMENT OPTIONS for second-line hormonal therapy in postmenopausal women who experience failure of tamoxifen (TAM) include progestins, such as megestrol acetate (MA) or medroxyprogesterone acetate, and aromatase inhibitors. The conversion of circulating androstenedione to estrone by the aromatase enzyme is the primary source of estrogen in postmenopausal women,¹ which makes this enzyme an attractive target for hormonal therapy of breast cancer. Moreover, compared with the progestins, the aromatase inhibitors have an improved safety profile^2-4 and similar or improved activity.^5-8

Aromatase inhibitors can be divided into two classes. Type II aromatase inhibitors, such as aminoglutethimide, anastrozole, letrozole, and vorozole, act by reversibly binding to the aromatase enzyme. Reversible inhibitors, which have nonsteroidal structures, interfere with the iron atom of the porphyrin of the cytochrome P-450 moiety of the enzyme. Because blockade is reversible, ongoing estrogen deprivation requires the continued presence of the drug.^2,3,9

Type I, or irreversible inhibitors (also known as suicide inactivators), interact with the substrate-binding site on the peptidic moiety. They have an androstenedione-like (ie, steroidal) structure and are highly specific. Because the inhibition is irreversible, renewed estrogen production requires synthesis of new aromatase molecules.⁹ Therefore, type I aromatase inhibitors are more appropriately called aromatase inactivators. Exemestane (EXE) is an example of an aromatase inactivator.^10,11 Development of irreversible inactivators is of particular interest because evidence suggests a lack of cross-resistance between them and type II inhibitors.^12,13

The novel aromatase inactivator EXE has been evaluated extensively in phase I and II studies at dosages of up to 600 mg/d. It is well tolerated, and as a consequence, a maximum-tolerated dose has not been identified.^14-24 Oral EXE 10 to 25 mg/d suppresses plasma estrogens as much as 6% to 15% of pretreatment levels.¹⁴ In two phase II uncontrolled studies, objective response (OR) rates with EXE as second-line therapy in postmenopausal women with advanced breast cancer were 22% and 28% and overall success rates (defined as the proportion of patients with OR or stable disease for 24 weeks; sometimes described by other authors as "clinical benefit"^6,7) were 47% and 48%.^15,16 When EXE was used as third-line hormonal therapy in postmenopausal women with advanced breast cancer who experienced failure of TAM, progestins, and/or nonsteroidal aromatase inhibitors, the OR rate ranged from 7% to 26% and the overall success rate from 25% to 39%.^17-20

We describe the results of a randomized, controlled, multicenter study designed to determine the antitumor activity and tolerability of EXE as second-line therapy in postmenopausal women with progressive advanced breast cancer after therapy with TAM. At the time this trial was initiated, MA was a standard second-line treatment for advanced breast cancer, with good tolerability and wide acceptance by the international medical community.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
Study Design
This phase III, randomized, double-blind, parallel-group study was conducted at 144 centers in 19 countries. Patients were randomized to receive either EXE (Aromasin, Pharmacia & Upjohn, Milan, Italy) 25 mg/d or MA (Megace, Bristol-Myers Squibb, Princeton, NJ) 40 mg four times daily using a double-dummy technique and matching placebo tablets. Patients with ORs or stable disease continued treatment until progressive disease (PD) or unacceptable toxicity occurred. Randomization was performed within each country for logistical reasons and was based on a minimization procedure to balance the treatment groups according to the following major stratification factors: previous response to TAM (ie, failure of TAM for advanced disease, PD on TAM after initial response, PD on adjuvant TAM after 12 months for unknown estrogen receptor [ER] and/or progesterone receptor [PgR] status or after 24 weeks for positive ER and/or PgR, or PD within 12 months of discontinuation of TAM), previous chemotherapy (none, neoadjuvant or adjuvant only, or one regimen for advanced metastatic disease ± neoadjuvant or adjuvant therapy), and site(s) of metastases (visceral ± others, bone only, soft tissue only, or bone + soft tissue). Treatment compliance was monitored by tablet count at each patient visit.

The relevant local ethical boards reviewed and approved the study protocol, including consent procedures. All patients gave written informed consent before study enrollment. The study was conducted in accordance with the ethical principles that originated in the Declaration of Helsinki.

Inclusion Criteria
Postmenopausal women with advanced histologically or cytologically confirmed breast cancer that progressed or relapsed during treatment with TAM were eligible. At least one bidimensionally measurable or one evaluable bony lesion that was shown on radiography or computed tomography (CT) scan as lytic and that was surrounded by calcified bone was required. Patients were required to have positive ER and/or PgR status. Patients with unknown receptor status who previously demonstrated a clear success (OR or disease stabilization of 24 weeks) with TAM therapy for advanced disease were also eligible. No more than one regimen of prior single-agent or combination chemotherapy for advanced metastatic disease was allowed. Prior neoadjuvant and/or adjuvant chemotherapy was allowed. Chemotherapy was allowed as the last therapy if the patient had experienced PD before study entry; however, patients must have discontinued chemotherapy at least 4 weeks before study entry and recovered from all acute toxicities (except alopecia). Other inclusion criteria included the following: an Eastern Cooperative Oncology Group performance status (PS) of 0, 1, or 2; adequate hematologic function (defined as neutrophil count 1.5 x 10⁹ cells/L and platelet count 75 x 10⁹ platelets/L); adequate renal function (defined as serum creatinine level 1.5 times the upper limit of normal); adequate liver function (defined as total serum bilirubin level 1.5 times the upper limit of normal and alanine and aspartate aminotransferase levels 2.5 times the upper limit of normal for patients without liver metastases or five times the upper limit of normal for patients with liver metastases); and alkaline phosphatase level less than or equal to 2.5 times the upper limit of normal for patients without bone or liver metastases.

Exclusion Criteria
Exclusion criteria included the following: prior treatment with hormonal agents other than TAM, high-dose chemotherapy that required stem-cell rescue, or strontium 89; conditions for which hormonal therapy is not indicated (eg, presence of inflammatory breast carcinoma, history or presence of rapid PD, massive visceral disease, brain metastases, or leptomeningeal disease); history of thromboembolic disease; presence of uncontrolled cardiac disease; presence of uncontrolled diabetes mellitus; or mental incapacitation. Patients with concomitant malignancies other than adequately treated carcinoma-in-situ of the uterine cervix or basal or squamous cell carcinoma of the skin were also excluded. Patients with a medical history of cancer other than breast carcinoma were eligible provided that the cancer had been surgically resected and was noninvasive and that the disease-free interval was at least 10 years.

Treatment with other anticancer therapies was not allowed during the study. Corticosteroids were allowed if the tumor had progressed on previous long-term corticosteroid therapy, if they were given for 10 days or less for a concomitant condition, or if they were given topically for an obstructive airway disease or a nonmalignant skin lesion. Palliative surgery or irradiation of the only evaluable lesion before the first assessment of tumor response rendered the patient nonevaluable for efficacy; patients in whom these procedures were performed after week 8 were considered to have PD unless otherwise indicated by the study director. Adequate analgesic treatment was allowed, but local analgesic procedures rendered patients nonevaluable for pain. Patients could receive long-term bisphosphonate treatment if they had bidimensionally measurable lesions outside the bone that could be evaluated for response (bone lesions were considered nonevaluable), and they could receive short-term bisphosphonate treatment for hypercalcemia. Patients could not receive other investigational drugs.

Clinical and Radiologic Assessments
A complete medical history and ECG were obtained at baseline. Physical examination, analysis of hematology and blood chemistry, and urinalysis were performed at baseline, repeated every 8 weeks for 24 weeks, every 12 weeks from weeks 25 to 108, every 24 weeks after week 108, and at the time of treatment discontinuation. Chest radiography, bone radiography or CT scan (the latter only in the case of an abnormal bone scan), liver ultrasound, and liver CT scan or magnetic resonance imaging were performed at baseline and, if abnormal, repeated as described above. Bone scintigraphy was performed at baseline and every 24 weeks. After disease progression, patients were monitored for survival at 6-month intervals.

Primary Efficacy Assessments
The primary efficacy end point was OR rate. Tumor response was measured every 8 weeks until week 24, then every 12 weeks until week 108, then every 24 weeks until treatment discontinuation, and at the time of medication discontinuation. Evaluation of complete response (CR), partial response (PR), stable disease (ie, no change; SD), or PD was based on modified World Health Organization criteria, which consider all tumor sites collectively rather than individually. The OR rate was defined as the proportion of patients who achieved CRs or PRs. ORs were confirmed by blinded external peer review and are presented as a consensus of the reviewers.

Secondary Efficacy Assessments
Secondary end points included overall success rate, overall success duration, time to OR, duration of OR, duration of SD greater than or equal to 24 weeks, time to tumor progression (TTP), time to treatment failure (TTF), survival time, subjective response, and effects on circulating estrogen levels. Overall success rate was defined as the proportion of patients who achieved CRs, PRs, or SDs for at least 24 weeks. Secondary end points were measured at baseline and at weeks 8, 16 (except serum estrogen level), and 24, every 24 weeks thereafter until discontinuation of study medication, and at medication discontinuation.

Subjective response was evaluated using several different methods: an overall pain score that included pain severity, PS, and analgesic consumption; tumor-related signs and symptoms (TRSS); and quality of life (QOL). TRSS included pain and other signs and symptoms considered by the investigator to be tumor-related. Pain severity was graded from 0 (none) to 5 (intolerable),²⁵ and the average severity grade for each week was recorded. Changes from baseline in TRSS other than pain were graded according to the National Cancer Institute common toxicity criteria (version 1.0) at each visit. QOL was assessed by means of the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire.²⁶

Serum estradiol, estrone, and estrone sulfate levels were measured in a subset of patients from selected centers. Blood samples were drawn just before the morning dose of study medication. Serum samples were stored at -20°C until they were assayed under blind conditions at a central laboratory. Estrogen levels were measured using solid-phase extraction and high-performance liquid chromatography purification followed by radioimmunoassay, according to a previously described procedure.¹⁴ The detection limits of the procedure were 0.7, 1.8, and 6 pg/mL for estradiol, estrone, and estrone sulfate, respectively. Hormone levels that fell below the limits of detection of the assay were recorded as the value of the detection limit.

Safety Assessments
Safety was assessed through physical examination (which included assessment of blood pressure, pulse, and body weight) and ECG and from hematology, blood chemistry, and urinalysis laboratory test results. All adverse events were recorded using a checklist and open questionnaire, and their severity was graded according to National Cancer Institute common toxicity criteria (version 1.0).

Statistical Methods
A sample size of 750 patients was determined to be adequate to demonstrate equivalence in the OR rate with a power of 80%. Because the trial was designed to show equivalence, the type I error was set at 0.1. This calculation assumed an OR rate of 8% to 16% for the MA arm. The upper limit of the 90% confidence interval (CI) of the difference between the tumor OR rate in the two treatment groups was calculated and the equivalence accepted if it did not exceed 25% of the MA response rate. A sample size of 750 patients also allowed testing of the hypothesis of equivalent TTP using a hazards ratio of less than or equal to 1.25. The assumptions on which this calculation was based were a median TTP of 5 months for the MA arm, an exponentially distributed survival function, a power of 80%, and = 0.10 (one-sided).

The efficacy analysis was conducted using an intent-to-treat approach; that is, patients were evaluated according to the randomization assignment even if they never received study medication or were inadvertently given the wrong study medication. Minimum follow-up was 16 weeks. The supportive analyses performed by applying the logistic regression model to OR and overall success rate included prestratification factors (ie, previous response to TAM, previous chemotherapy, and site of metastasis). Duration of overall success, TTP, TTF, and survival times were compared between groups by nonparametric methods for survival analysis (log-rank test and Kaplan-Meier curves) and Cox modeling. The 95% CI of the observed relative risk was calculated. Patients who withdrew from the study without PD and patients still on treatment at the time of analysis and with no evidence of PD were censored from the analysis of duration of response and TTP. Deaths that resulted from tumor or unknown cause were considered PD. TTF was censored for patients who remained on trial at the time of analysis and who had no evidence of PD.

TRSS were analyzed over time (worsening, improving, no change) in the whole patient population and by objective tumor response status. The overall pain score, calculated by adding the physician’s pain score, analgesic consumption score, and PS, was standardized over the maximum score possible. Patients with a reduction from baseline in overall pain score greater than 20% on at least two consecutive assessments were classified as subjective responders.

QOL data were summarized using descriptive statistics at each assessment point. Patients were included if they completed at least one questionnaire item. All patients who completed the QOL questionnaire at baseline and at least once during the treatment (assessments after disease progression were excluded) were included in the following analyses. A between-treatment comparison of changes in QLQ-C30 scores observed at the last assessment available versus baseline was performed by Student’s t test.²⁷ In addition, the general linear model approach was used to account for responses to the QLQ-C30 questionnaire over time by applying a repeated-measures analysis of variance²⁸ to the changes in QOL assessment at each time point. The treatment x time interaction term was used to test for statistically significant differences between the two treatment groups over time. Serum estrogen levels were summarized by descriptive statistics.

Randomized patients who never received the study drug were excluded from the safety analysis, as were patients without safety assessments. Only treatment-emergent adverse events were considered in the analyses. For any adverse event term, a patient was counted once, even if the event occurred multiple times in that patient. In the analyses by patient for body system totals, each patient was counted once, even if that patient had several different events in that body system. Odds ratios and their 95% CIs were used to compare the incidence of a selected type of adverse event between the two treatment groups. The analysis of adverse events according to both patient and visit considered severity and the most likely cause. Laboratory examination results were presented by descriptive analysis. Odds ratios and their 95% CIs were provided for the comparison of treatment-emergent laboratory abnormalities.

No statistical comparisons of baseline characteristics between treatment groups were performed, because treatments were randomly allocated. Patient heterogeneity between treatment groups was accounted for by adjusting for relevant baseline characteristics and/or prognostic factors in the analysis of study end points.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
A total of 769 postmenopausal women with progressive advanced breast cancer after therapy with TAM were randomized to treatment with EXE (n = 366) or MA (n = 403) between October 1995 and May 1998 and were included in the intent-to-treat analysis. By chance, a slight imbalance occurred in the randomization of patients to each arm. The 2.4% imbalance (with respect to the anticipated randomization of 50% per group) can be explained by the fact that there were 36 different combinations of levels for the stratification factors and by the decision to randomize patients by country (most of the countries accrued fewer than 30 patients).

Patient characteristics in the two treatment arms were comparable (Table 1). The majority of patients were known to have had symptoms related to their cancer as evidenced by a median baseline Eastern Cooperative Oncology Group PS of 1. A requirement for analgesics was present in more than 40% of patients in each group. The predominant site of disease was visceral for more than one half of the patients and often occurred with liver and lung involvement. Largely because 17% to 18% of patients had only bone involvement, 20% of patients in each group actually had lesions that were not bidimensionally measurable for response evaluation. All patients had received prior TAM therapy. Approximately 27% to 28% of patients had undergone prior chemotherapy as adjuvant treatment, and approximately 16% had received prior chemotherapy for advanced disease.

Efficacy
Although a higher OR rate was observed in patients treated with EXE than in those treated with MA, the difference was not statistically significant (15.0% v 12.4%; difference, -2.6%; 95% two-side CI for difference, -7.5% to +2.3%). Therefore, the protocol objective of demonstrating equivalence between the two treatments was fulfilled. There was no statistically significant between-group difference in overall success rate (EXE = 37.4%; MA = 34.6%). Table 2 summarizes response and overall success rates based on an independent peer review consensus.

View larger version (19K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves for (A) duration of overall success, (B) time to tumor progression, (C) time to treatment failure, and (D) survival, in postmenopausal women with progressive advanced breast cancer after therapy with TAM and subsequently treated with EXE or MA.

All three stratification variables were significant predictors of overall treatment success by logistic regression analysis (previous response to TAM, P = .02; prior chemotherapy, P = .02; and site of metastasis, P < .01). The odds of overall treatment success were higher in patients who received TAM for advanced disease than in patients who received adjuvant TAM (odds ratio, 1.81; 95% CI, 0.87 to 3.79). Patients previously treated with chemotherapy for advanced disease had a significantly lower probability of success compared with patients never treated with chemotherapy (odds ratio, 0.57; 95% CI, 0.35 to 0.8). The probability of overall treatment success in patients with only soft tissue metastasis was two times the probability of overall treatment success in patients with visceral disease (odds ratio, 2.0; 95% CI, 1.29 to 3.11).

Consistent with the findings for overall success, application of the Cox model shows that significant predictors of TTP included response to TAM (P = .005), prior chemotherapy (P = .004), and site of metastasis (P < .001). All three stratification variables were also significant predictors of time to treatment failure (P .003 for response to TAM and prior chemotherapy and P < .0001 for site of metastasis). TAM for advanced disease versus adjuvant TAM, no prior chemotherapy versus chemotherapy for advanced disease, and soft tissue site of metastasis versus visceral disease were positive predictors of TTP and time to treatment failure. Only prior chemotherapy and site of metastasis were significant predictors of survival (P = .037 and P < .0001, respectively). When treatment effect was adjusted by the stratification variables, EXE-treated patients had an approximately 20% lower risk of PD (odds ratio, 0.82; 95% CI, 0.70 to 0.97; P = .023), treatment failure (odds ratio, 0.84; 95% CI, 0.72 to 0.99; P = .035), and death (odds ratio, 0.77; 95% CI, 0.59 to 0.99; P = .046) than did MA-treated patients. ER or PgR status, age, PS, type of lesion, number of sites, prior systemic therapies, and time to menopause were not observed to predict tumor response.

Estrogen Levels
Serum samples were evaluable for estrogens in 61 EXE-treated women and 65 MA-treated women. The mean baseline levels of estradiol (10.3 and 9.5 pg/mL), estrone (40.8 and 35.6 pg/mL), and estrone sulfate (349.8 and 315.7 pg/mL) were comparable in groups treated with EXE and MA, respectively. At study weeks 8, 24, and 48, EXE caused a marked reduction (% of baseline) in the geometric means of estradiol (range, 7.9% to 11.7%), estrone (range, 11.1% to 19.9%), and estrone sulfate (range, 8.1% to 9.2%) levels (Fig 2). In 37%, 44%, and 50% of patients, estradiol levels fell to below the limit of detection at 8, 24, and 48 weeks, respectively. The suppressive effect of EXE was maintained over time.

View larger version (24K): [in this window] [in a new window]   Fig 2. Inhibitory effect of EXE (25 mg/d) or MA (160 mg/d) on serum estrogen levels.

Subjective Response and QOL
In the pain score evaluation, 24.7% and 24.2% of EXE- and MA-treated women, respectively, were classified as subjective responders. A somewhat greater percentage of EXE-treated patients with ORs had improved overall pain scores compared with MA-treated patients with ORs (EXE = 51.4% [95% CI, 34.0% to 68.6%]; MA = 46.2% [95% CI, 30.1% to 62.8%]).

A greater percentage of patients treated with EXE showed an improvement in TRSS compared with MA-treated patients (12.1% v 7.5%; ² [1 df] = 2.98; P = .084). Patients with objective tumor responses showed the greatest improvement.

In the QOL assessment, patients treated with EXE showed a statistically significant improvement (interaction, P < .01) in physical functioning, role functioning, global health, fatigue, dyspnea, and constipation compared with patients who received MA, who remained substantially unchanged or worsened. Patients treated with MA displayed a significant improvement in emotional function, appetite loss, and pain compared with EXE-treated patients; however, both treatments led to an improvement. MA therapy was associated with less insomnia than was EXE. No significant between-group differences were noted for cognitive function, social function, nausea and vomiting, diarrhea, or financial difficulties.

Safety
Seven hundred fifty-eight patients were evaluable for safety. Two hundred eighty-four (79.3%) of 358 EXE-treated patients and 320 (80.0%) of 400 MA-treated patients experienced one or more treatment-emergent adverse events. More MA-treated patients (n = 183 [45.8%]) reported adverse events that were considered drug-related or of indeterminate cause than did EXE-treated patients (n = 140 [39.1%]). The most frequently reported adverse events in EXE-treated women were low-grade hot flashes, nausea, and fatigue. Greater weight gain (especially in patients overweight at study entry) was observed in MA-treated patients. A weight gain greater than or equal to 10% was noted in 4% of overweight patients treated with EXE and in 21.3% of overweight patients treated with MA. In the overall population, grade 3 or 4 weight changes were observed in 17.1% of MA-treated patients and in 7.6% of EXE-treated patients (² [1 df] = 13.5; P = .001) (Fig 3). Significantly more women treated with EXE experienced hot flashes (12.6% v 5.0%), nausea (9.2% v 5.0%), and vomiting (2.8% v 0.8%) than did women treated with MA, respectively. Significantly more MA-treated women experienced dyspnea (3.0% v 0.3%) than did EXE-treated women, respectively (Table 4).

View larger version (12K): [in this window] [in a new window]   Fig 3. Mean body weight over time in women treated with EXE (25 mg/d) or MA (160 mg/d).

Laboratory abnormalities (mostly grade 1 or 2) occurred more frequently in EXE-treated patients and included decreases in WBC count or lymphocyte count and increases in alanine aminotransferase or alkaline phosphatase levels. Grade 3 or 4 increases in liver enzymes (mostly gamma-glutamyltransferase) were occasionally observed, but these patients typically had liver metastases or other hepatic disease. No correlation between treatment-emergent laboratory abnormalities and clinical events was observed. No clear, clinically significant changes in blood pressure, pulse, ECG, or urinalysis results were identified.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
Once breast cancer has recurred or metastasized, it is incurable. Because most available therapies have not been shown to alter survival, the primary goal of hormonal, cytotoxic, and radiation therapies has largely been the palliation of tumor-related symptoms. Hormonal therapy is associated with less morbidity and, therefore, is preferred to cytotoxic treatment, if clinically appropriate. TAM is the hormonal agent of choice for first-line therapy of metastatic disease. After progression of disease on TAM, second-line hormonal therapy traditionally includes progestins, usually MA. In recent randomized trials that used formal response criteria and independent review, response rates to second-line MA treatment were 8% to 16%.^5-8 However, MA is associated with bothersome side effects; particularly troubling to women has been the potential for substantial unwanted weight gain.⁴

This phase III, randomized, double-blind study was designed to evaluate the efficacy, safety, and pharmacodynamic properties of the new oral aromatase inactivator EXE compared with second-line MA in postmenopausal women with progressive advanced breast cancer after therapy with TAM. Use as second-line hormonal therapy was selected as the focus of this trial because of the continuing need to identify well-tolerated methods for controlling this life-threatening illness after failure of established first-line treatment.

The results demonstrate that EXE can induce an OR rate of 15%, which is comparable to the 12.4% OR rate induced by MA. OR rates with EXE were similar whether patients previously responded to TAM or received chemotherapy. OR rates were higher in patients with disease limited to soft tissue and lower in patients with disease limited to bone. These differences in OR rate by site may represent, in part, an enhanced ability to evaluate OR in soft tissue disease and a relative inability to observe tumor shrinkage at sites of bone involvement. Importantly, OR rates were observed in women with visceral disease (EXE = 13.5%; MA = 10.5%). Overall success (OR or SD lasting at least 24 weeks or approximately 6 months) rates in women with visceral disease were 36.3% with EXE and 30.0% with MA (data not shown). In a separate retrospective analysis of these data among women with measurable disease, treatment with EXE led to higher OR rates in both lung and liver sites than did treatment with MA. The OR rate in 76 women with measurable lung metastases treated with EXE was 25% (95% CI, 15.8 to 36.3) versus 17% (95% CI, 11.0 to 29.4) in 95 women treated with MA. The OR rate in 79 women with measurable liver metastases treated with EXE was 19% (95% CI, 11.0 to 29.4) versus 11% (95% CI, 5.4 to 18.3) in 105 women treated with MA.²⁹

Bone disease is common in women with metastatic breast cancer, but assessment of response in bone often can be difficult. For example, in this trial, only 20% of patients in each arm had disease that was evaluable. To address this limitation, disease stabilization for 24 weeks or more has been introduced as another measure of antitumor efficacy.³⁰ Overall success was observed in 37.4% of patients treated with EXE, a rate that is similar to those observed in phase III studies that compare the reversible aromatase inhibitors letrozole and anastrozole with MA.^6,7 EXE, however, was associated with a significant increase in the median duration of overall success (medians were 60.1 weeks for EXE and 49.1 weeks for MA; P = .025).

In addition to the expected prognostic effect of the site of metastasis, we found that no previous chemotherapy and previous treatment with TAM for advanced disease rather than as adjuvant treatment were significant predictors of a positive outcome. The poorer outcome for patients treated only with adjuvant TAM is surprising. A possible explanation for this finding is that patients enrolled onto our study and stratified to the adjuvant TAM group had either progressed while on TAM as adjuvant therapy or had progression of their disease within a short time after discontinuing adjuvant TAM and, thus, likely had more aggressive disease. This is supported by the observation that the frequency of OR and overall success in patients who were treated with EXE and had either progressed on TAM or had received TAM as adjuvant therapy were similar (11.9% and 31.7% v 13.1% and 31.2%, respectively; data not shown). The observation that ER or PgR status did not predict for tumor response is less surprising, given that patients with unknown receptor status were eligible only if they had previously responded to hormones (TAM) and were, therefore, most likely receptor-positive.

Unlike the results reported with reversible aromatase inhibitors (Table 5),^6-8 our phase III study showed a statistically significant prolongation in TTP and TTF with EXE. With a median duration of follow-up of nearly 1 year, EXE also demonstrated significantly improved survival times. Because the median survival for EXE had not been reached and the upper limits of the 95% CIs for both treatments were inestimable, 75% survival (25^th percentile) was estimated. The 75% survival was 74.6 weeks for EXE (95% CI, 59.1 to 91.0) and 55.0 weeks for MA (95% CI, 46.1 to 70.3), yielding a 19.6-week (approximately 4.5-month) or 36% survival advantage in favor of EXE. The survival advantage was apparent soon after the initiation of EXE, as demonstrated by early separation of the survival curve (Fig 1D), and was significant at first analysis. EXE-treated patients had a 23% lower risk of death compared with MA-treated patients when treatment effect was adjusted by the stratification variables using Cox model analysis. A review of poststudy treatments does not suggest that these therapies could account for the observed survival advantage.

EXE caused a profound suppression ( 90%) of estradiol, estrone, and estrone sulfate serum levels. Suppression was maintained over time, which confirmed the data previously reported.^14,17 The exact mechanism of the antitumor action of MA is not known; several hormonal effects have been proposed, including suppression of circulating estrogens.³⁰ In the present study, we found that the inhibitory effect of MA on estrogens was less marked and of shorter duration than that observed with EXE. In fact, by week 48, MA suppressed circulating estrogens by only 50% to 70%. Lundgren et al³¹ demonstrated that the estrogen suppression caused by MA is not a result of aromatase inhibition but rather a profound suppression at the hypothalamic-pituitary level, which in turn causes a reduction in the circulating levels of the aromatase enzyme substrates androstenedione and testosterone. Furthermore, in an in vitro study with human placental aromatase, MA, up to a concentration of 30,000 nmol/L, did not inhibit aromatase enzyme activity, whereas EXE inhibited 50% of enzyme activity at a concentration of only 38 nmol/L (E. di Salle, unpublished data, 1999). Therefore, unlike EXE, which is highly specific in causing estrogen suppression through aromatase inactivation,¹⁴ the effect of MA is highly nonspecific and less marked.

In our study, both EXE and MA were well tolerated. Women treated with MA experienced more adverse events, including weight gain, that were drug-related or of indeterminate cause and withdrew from treatment because of adverse events more often than did women treated with EXE. As seen in previous reports,^15,16,18,19 the most frequent adverse reactions in women who received EXE were low-grade hot flashes, nausea, and fatigue; these events are consistent with the estrogen suppressive effect of EXE. Tolerability was confirmed by the greater than 80% compliance by most patients treated with EXE and the improvement in QOL on a number of subscales (global health, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, constipation, appetite loss, and pain) during EXE treatment. In general, this improvement was superior to that reported by women treated with MA.

Weight gain was significantly more common with MA, particularly in women who were overweight at baseline. More than 20% of overweight patients treated with MA had a 10% or greater weight gain compared with only 4% of overweight women treated with EXE.

In summary, the results of this prospective, controlled study demonstrate significantly improved overall duration of success, longer TTP and TTF, and improved survival with the aromatase inactivator EXE when compared with MA in the second-line therapy of metastatic breast cancer. These data establish EXE as a new treatment option for postmenopausal women with progressive advanced breast cancer after therapy with TAM. Trials are currently underway to evaluate EXE in women with earlier stages of breast cancer.

	APPENDIX Principal Investigators for the Exemestane Study Group

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Principal Investigators... REFERENCES

 
Argentina: C.A. Delfino, Hospital Privado de la Comunidad; E. Mickiewicz, Instituto de Oncologia Angel H. Roffo; R.C. Wainstain, Hospital Pasadas; R. Testa, Hospital Italiano, Buenos Aires; S.B. Zunino, Instituto Privado de Radioterapia, Nueva Cordoba; and E.A. Richardet, Hospital Italiano de Cordoba, Cordoba.

Australia: E.T. Walpole, Princess Alexandra Hospital, Brisbane, Queensland; P.G. Gill, Royal Adelaide Hospital, Adelaide, South Australia; R.M.L. Murray, Peter MacCallum Cancer Institute, East Melbourne, Victoria; J.P. Collins, The Royal Melbourne Hospital, Parkville, Victoria; and P. De Souza, The St George Hospital, Kogarah, New South Wales.

Austria: G.G. Steger, Universitatsklinik fur Innere, Wien, and H. Samonnig, Medizinische Universitatsklinik, Graz.

Belgium: A.T. Van Oosterom and A.M. Pové, Universitair Ziekenhuis Antwerpen, Edegem; M.J. Piccart, Institut Jules Bordet; J. Longueville, Universite Catholique de Louvain Saint-Luc; J.L.P. De Grève, Akademisch Ziekenhuis Vrije Universiteit, Brussels; L.Y. Dirix, Sint-Augustinus Ziekenhuis, Wilrijk (Antwerpen); M. Beauduin, Hôpital de Jolimont; J. Michel, Centre Hospitalier Universitaire de Tivoli, La Louviere; J.L. Canon, Clinique Notre Dame et Reine Fabiola, Charleroi; F.J.M.L. Maisin, Clinique Sainte-Elisabeth, Namur; S.J.P. Van Belle, Universitair Ziekenhuis Gent, Gent; D.C.M. Becquart, Akademisch Ziekenhuis Middelheim, Antwerpen; D. Verhoeven, KLINA Campus St Jozef, Kapellen; C. Focan, Centre Hospitalier St Joseph Espérance, Liège; and R.J.H. Paridaens, Universitair Ziekenhuis Gasthuisberg, Leuven.

Brazil: A.M. Murad, Hospital das Clinicas, Horizonte, Minas Gerais; C. Tosello de Oliveira, Brazilian Institute of Cancer Control, Sãn Paulo; and C.H. Barrios, Hospital Sao Lucas, Porto Alegre, Rio Grande do Sul.

France: J. P. Guastalla, Center Léon Bérard, Lyon; M. Namer, Center Antoine Lacassagne, Nice; D. Serin, Clinique Sainte-Catherine, Avignon; and P. Chinet-Charrot, Centre Henri Becquerel, Rouen.

Germany: R. Engelhardt, Medizinische Universitätsklinik; N. Marschner, Klinik für Tumorbiologie, Freiburg; H.-G. Meerpohl, St Vincentius Krankenhaus, Karlsruhe; M. Kaufmann, Universitätsklinik Frankfurt, Frankfurt; U.R. Kleeberg, Praxis für Innere Medizin Labormedizin und Hämatologie; A. Mohr, Praxis für Hämatologie und Onkologie, Hamburg; W. Eiermann, Frauenklinik vom Roten Kreuz; M. Untch, Klinikum GroBhadern; F.-J. Tigges, Onkologische Gemeinschaftspraxis, München; A.E. Schindler, Universitätsklinik Essen, Essen; B. Conrad, Städtische Kliniken Kassel, Kassel; I. Schrader, Henriettenstift, Hannover; W. Jäger, Universitätsklinik, Erlangen; C.M. Kurbacher, Universitäts-Frauenklinik, Köln; and W. Lichtenegger, Universitätsklinikum Charité, Berlin.

Ireland: T.N. Walsh and H.P. Redmond, Beaumont Hospital, and N. O’Higgins, St Vincent’s Hospital, Dublin.

Italy: M.S. Aapro, Istituto Europeo di Oncologia, Milano; F. Boccardo, Istituto Nazionale per la Ricerca sul Cancro, Genova; and P. Pozzi, Instituto Nazionale Tumori, Milano.

Mexico: T.R. Ugalde, Instituto Nacional de Cancerologia, Tlalpan; J. Cardenas Sanchez, Centro Estatal de Cancerologia, Colima, Col; and J.F. Alexander Meza, Hospital General de Occidente, Zapopan, Jalisco.

the Netherlands: G.H. Blijham, Academisch Ziekenhuis Utrecht; J.W.R. Nortier, Diakonessenhuis, Utrecht; C.J. Robenburg, Algemeen Christelijk Ziekenhuis Eemland–Lokatie De Lichtenberg, Amersfoort; P.H.Th.J. Slee, Sint Antonius Ziekenhuis, Nieuwegein; H.van Veelen, Medisch Centrum Leeuwarden–Locatie Zuid, Leeuwarden; F.L.G. Erdkamp, Maaslandziekenhuis Sittard Afdeling Inwendige, Sittard; J. Wals, Ziekenhuis De Wever en Gregorius–Lokatie Gregorius, Brunssum; J.A.J.M. Wils, Sint Laurentius Zienkenhuis, Roermond; A. van Bochove, St Ziekenhuis "De Heel," Zaandam; H. Piersma, Martini Ziekenhuis Groningen–Lokatie Van Swieten, Groningen; J.Th.P. Janssen, Ziekenhuis Sint Franciscus, Roosendaal; and G. Vreugdenhil, St Joseph Ziekenhuis, Veldhoven.

Poland: T.J. Piénkowski, Maria Sklodowska-Curie Memorial Cancer Institute, Warsaw; J. Jassem, Medical Academy in Gdansk, Gdansk; and C. Ramlau, Medical Academy, Cracow.

Portugal: J. Carmo-Pereira, Instituto Portgues de Oncologia Francisco Gentil de Lisboa, Lisboa.

South Africa: W.R. Bezwoda, Johannesburg General Hospital, Parktown; J.P. Jordaan, Addington Hospital, Durban; L. Goedhals, National Hospital, Bloemfontein; and J.A. Van Zyl, Tygerberg Hospital, Parow.

Spain: M. Martin, Hospital Universitario San Carlos, Madrid; E. Aranda Aguilar, Hospital Universitario Reina Sofia de Córdoba, Córdoba; A. Anton Torres, Hospital Miguel servet, Zaragoza; C. Jara Sanchez, Hospital General de Albacete, Albacete; A. Barnadas, Hospital Germans, Barcelona; C.C. Picó Navarro, Hospital General Universitario de Alicante, Alicante; A. Carrato, Hospital General de Elche, Elche-Alicante; R. Pérez Carrión, Hospital La Princesa; C. Mendiola Fernández, Hospital Universitario 12 de Octubre de Madrid, Madrid; A. Arcusa Lanza, Consorci Sanitari de Terrassa, Terrassa; and M.J. Godes Sanz de Bremond, Hospital General Universitario, Valencia.

Turkey: D. Firat, Hacettepe Universitesi; F. Icli, Ankara Universitesi Tip Fakültesi Medikal Onkoloji Bilim Dali; N. Günel, Gazi Universitesi, Ankara; S. Serdengeçti and E. Topuz, Istanbul Universitesi, Istanbul; and M. Kinay, Dokuz Eylül Universitesi Tip Fakultesi Radyasyon, Izmir.

United Kingdom: R.E. Mansel, University of Wales College of Medicine, Cardiff; M.B. McIllmurray, Royal Lancaster Infirmary, Lancaster; J.L. Mansi, St George’s Hospital; R.C.D.S. Coombes, Charing Cross Hospital; M.F. Spittle, The Middlesex Hospital, London; T.J. Perren, St James’s University Hospital, Leeds; A.L. Stewart, Christie Hospital National Health Service Trust, Manchester; D.W. Rea and H.M. Earl, Selly Oak Hospital, Birmingham; P.A. Murray, Essex County Hospital, Essex; F. Roberts, Cookridge Hospital, West Yorkshire; and N.P. Rowell, Wycombe General Hospital, Buckinghamshire.

United States: M.Ellis, The Georgetown University Medical Center, Washington, DC; A.G. Glass, Kaiser Permanente, Portland, OR; P.D. Eisenberg, Marin Oncology Associates, Greenbrae; I. Royston, T. Campbell, and J. Gutheil, Sharp HealthCare, San Diego; D. Prager, University of California at Los Angeles, Los Angeles; S. George, Cancer & Blood Institute of the Desert, Rancho Mirage, CA; L.R. Laufman, Hematology Oncology Consultants, Inc, Worthington; B. Cooper, University Hospitals of Cleveland, Cleveland; H. Ritter, Toledo Clinic, Toledo, OH; E. Lester, Mercy Memorial Medical Center, St Joseph; N.V. Dimitrov, Michigan State Department of Medicine, East Lansing, MI; M. Moore, Georgia Cancer Specialists Clinical Studies Limited, Decatur, GA; D. Merkel, Evanston Hospital, Evanston; J.M. Wolter, Rush Presbyterian–St Lukes Medical Center, Chicago; J. Kugler, Oncology Hematology Association, Peoria, IL; M. Thant, Franklin Square Hospital Center, Baltimore, MD; J.M. Bennett, University of Rochester Cancer Center; A.Y.C. Chang, Interlakes Oncology & Hematology, Inc, Rocherster, NY; C.L. Vogel, Parkway Regional Medical Center, North Miami; M. Martinez-Rio, Mt Sinai Medical Center, North Miami Beach; J.A. Reeves, Lee Coast Research Center, Inc, Fort Myers; H.B. Sher, Jacksonville Oncology Group, Jacksonville; J. Otoya, Regional Oncology Hematology Association, Kissimmee; L.A. Kalman, Oncology/Hematology Group of South Florida, Miami; C.L. Vogel, Columbia Cancer Research Network, Aventura, FL; J.A. Mailliard, Creighton Cancer Center, Omaha, NE; E.P. Winer and L. Sutton, Duke University Medical Center, Durham, NC; A.M. Desai, Medical Oncology Hematology Association, Philadelphia, PA; P.T. Silberstein, North Iowa Mercy Health Center, Mason City; D. Zenk, Oncology Associates, Cedar Rapids, IA; G. Grana, Cooper Hospital, Camden; R.E. Isaacs and R. Rosenbluth, Hackensack University Medical Center, Hackensack, NJ; J.R. Crews, Raleigh Internal Medicine Association, Raleigh, NC; J.R. Eckardt, St John’s Mercy Medical Center, St Louis, MO; L.L. Stolbach, St Vincent’s Hospital, Worcester, MA; D.C. Osborn, Western Washington Cancer Treatment Center, Olymia, WA; V.C. Baker, Oklahoma Oncology, Inc, Tulsa, OK; and R. Blachly, Northeast Arkansas Clinic, Jonesboro, AR.

	ACKNOWLEDGMENTS

 
Supported in part by a grant-in-aid from Pharmacia & Upjohn.

We thank Antonello Abbattista for data management and analysis, Alessandra Consonni and Silvana Lanzalone for study and data management, Ornella Mariani, Shari Gaylor, Paola di Nicolò, Maria Luisa Bonanomi, Marco Eisel, Giulia Perna, and Laura Caprari for data management, Giorgio Ornati for pharmacodynamic assays, and all study monitors worldwide.

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Submitted June 1, 1999; accepted December 8, 1999.

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