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AROMASIN® (exemestane) Clinical Studies

14 CLINICAL STUDIES

14.1 Adjuvant Treatment in Early Breast Cancer

The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to AROMASIN rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to AROMASIN (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.

Table 5. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane
(N = 2352)
Tamoxifen
(N = 2372)
*
Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization.
Only one subject in the exemestane group had unknown ER status and positive PgR status.
Age (years):
Median age (range)63.0 (38.0 – 96.0)63.0 (31.0 – 90.0)
Race, n (%):
Caucasian2315 (98.4)2333 (98.4)
Hispanic13 (0.6)13 (0.5)
Asian10 (0.4)9 (0.4)
Black 7 (0.3)10 (0.4)
Other/not reported 7 (0.3)7 (0.3)
Nodal status, n (%):
Negative1217 (51.7)1228 (51.8)
Positive1051 (44.7)1044 (44.0)
  1–3 Positive nodes721 (30.7)708 (29.8)
  4–9 Positive nodes239 (10.2)244 (10.3)
  >9 Positive nodes88 (3.7)86 (3.6)
  Not reported3 (0.1)6 (0.3)
Unknown or missing84 (3.6)100 (4.2)
Histologic type, n (%):
Infiltrating ductal1777 (75.6)1830 (77.2)
Infiltrating lobular341 (14.5)321 (13.5)
Other231 (9.8)213 (9.0)
Unknown or missing3 (0.1)8 (0.3)
Receptor status*, n (%):
ER and PgR Positive1331 (56.6)1319 (55.6)
ER Positive and PgR Negative/Unknown677 (28.8)692 (29.2)
ER Unknown and PgR Positive/Unknown288 (12.2)291 (12.3)
ER Negative and PgR Positive6 (0.3)7 (0.3)
ER Negative and PgR Negative/Unknown (none positive)48 (2.0)58 (2.4)
Missing2 (0.1)5 (0.2)
Tumor Size, n (%):
≤ 0.5 cm58 (2.5) 46 (1.9)
> 0.5 – 1.0 cm315 (13.4)302 (12.7)
> 1.0 – 2 cm1031 (43.8)1033 (43.5)
> 2.0 – 5.0 cm833 (35.4)883 (37.2)
> 5.0 cm62 (2.6)59 (2.5)
Not reported53 (2.3)49 (2.1)
Tumor Grade, n (%):
G1397 (16.9)393 (16.6)
G2977 (41.5)1007 (42.5)
G3454 (19.3)428 (18.0)
G423 (1.0)19 (0.8)
Unknown/Not Assessed/Not reported 501 (21.3)525 (22.1)
Table 6. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane
(N = 2352)
Tamoxifen
(N = 2372)
*
The 30 mg dose was used only in Denmark, where this dose was the standard of care.
Type of surgery, n (%):
Mastectomy1232 (52.4)1242 (52.4)
Breast-conserving1116 (47.4)1123 (47.3)
Unknown or missing4 (0.2)7 (0.3)
Radiotherapy to the breast, n (%):
Yes1524 (64.8)1523 (64.2)
No824 (35.5)843 (35.5)
Not reported4 (0.2)6 (0.3)
Prior therapy, n (%):
Chemotherapy774 (32.9)769 (32.4)
Hormone replacement therapy567 (24.1)561 (23.7)
Bisphosphonates43 (1.8)34 (1.4)
Duration of tamoxifen therapy at randomization (months):
Median (range)28.5 (15.8 – 52.2)28.4 (15.6 – 63.0)
Tamoxifen dose, n (%):
20 mg2270 (96.5)2287 (96.4)
30 mg*78 (3.3)75 (3.2)
Not reported4 (0.2)10 (0.4)

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the AROMASIN group and 307 in the tamoxifen group (Table 7).

Table 7. Primary Endpoint Events (ITT Population)
EventFirst Events
N (%)
Exemestane
(N = 2352)
Tamoxifen
(N = 2372)
Loco-regional recurrence34 (1.45)45 (1.90)
Distant recurrence126 (5.36)183 (7.72)
Second primary – contralateral breast cancer7 (0.30)25 (1.05)
Death – breast cancer1 (0.04)6 (0.25)
Death – other reason41 (1.74)43 (1.81)
Death – missing/unknown3 (0.13)5 (0.21)
Ipsilateral breast cancer1 (0.04)0
Total number of events213 (9.06)307 (12.94)

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the AROMASIN arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the AROMASIN arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy.

An overall survival update at 119 months median follow-up showed no significant difference between the two groups, with 467 deaths (19.9%) occurring in the AROMASIN group and 510 deaths (21.5%) in the tamoxifen group.

Table 8. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer
ITT PopulationHazard Ratio
(95% CI)
p-value
(log-rank test)
*
Not adjusted for multiple testing.
Disease-free survival0.69 (0.58–0.82)0.00003
Time to contralateral breast cancer0.32 (0.15–0.72)0.00340
Distant recurrence-free survival0.74 (0.62–0.90)0.00207
Overall survival0.91 (0.81–1.04)0.16*
ER and/or PgR positive
Disease-free survival0.65 (0.53–0.79)0.00001
Time to contralateral breast cancer0.22 (0.08–0.57)0.00069
Distant recurrence-free survival0.73 (0.59–0.90)0.00367
Overall survival0.89 (0.78–1.02)0.09065*
Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
Figure 1

14.2 Treatment of Advanced Breast Cancer

Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive AROMASIN (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.

Table 9. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
ParameterAROMASIN
(N = 366)
Megestrol Acetate
(N = 403)
Median Age (range)65 (35–89)65 (30–91)
ECOG Performance Status
  0167 (46%)187 (46%)
  1162 (44%)172 (43%)
  234 (9%)42 (10%)
Receptor Status
  ER and/or PgR +246 (67%)274 (68%)
  ER and PgR unknown116 (32%)128 (32%)
    Responders to prior tamoxifen68 (19%)85 (21%)
    NE for response to prior tamoxifen46 (13%)41 (10%)
Site of Metastasis
  Visceral ± other sites207 (57%)239 (59%)
  Bone only61 (17%)73 (18%)
  Soft tissue only54 (15%)51 (13%)
  Bone & soft tissue43 (12%)38 (9%)
Measurable Disease287 (78%)314 (78%)
Prior Tamoxifen Therapy
  Adjuvant or Neoadjuvant145 (40%)152 (38%)
  Advanced Disease, Outcome
    CR, PR, or SD ≥ 6 months179 (49%)210 (52%)
    SD < 6 months, PD or NE42 (12%)41 (10%)
Prior Chemotherapy
  For advanced disease ± adjuvant58 (16%)67 (17%)
  Adjuvant only104 (28%)108 (27%)
  No chemotherapy203 (56%)226 (56%)

The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that AROMASIN was not different from megestrol acetate. Response rates for AROMASIN from the two single-arm trials were 23.4% and 28.1%.

Table 10. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
Response CharacteristicsAROMASIN
(N=366)
Megestrol Acetate
(N=403)
Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = time to tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN
Objective Response Rate = CR + PR (%)15.012.4
    Difference in Response Rate (AR-MA)
2.6
    95% C.I.7.5, -2.3
CR (%)2.21.2
PR (%)12.811.2
  SD ≥ 24 Weeks (%)21.321.1
Median Duration of Response (weeks)76.171.0
Median TTP (weeks)20.316.6
    Hazard Ratio (AR-MA)0.84

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

Figure 2. Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy
Figure 2
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