Aromasin

AROMASIN is an aromatase inhibitor indicated for:

• •adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy (
  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)

  Parameter	Exemestane (N = 2352)	Tamoxifen (N = 2372)
  Age (years):
  Median age (range)	63.0 (38.0 – 96.0)	63.0 (31.0 – 90.0)
  Race, n (%):
  Caucasian	2315 (98.4)	2333 (98.4)
  Hispanic	13 (0.6)	13 (0.5)
  Asian	10 (0.4)	9 (0.4)
  Black	7 (0.3)	10 (0.4)
  Other/not reported	7 (0.3)	7 (0.3)
  Nodal status, n (%):
  Negative	1217 (51.7)	1228 (51.8)
  Positive	1051 (44.7)	1044 (44.0)
  1–3 Positive nodes	721 (30.7)	708 (29.8)
  4–9 Positive nodes	239 (10.2)	244 (10.3)
  >9 Positive nodes	88 (3.7)	86 (3.6)
  Not reported	3 (0.1)	6 (0.3)
  Unknown or missing	84 (3.6)	100 (4.2)
  Histologic type, n (%):
  Infiltrating ductal	1777 (75.6)	1830 (77.2)
  Infiltrating lobular	341 (14.5)	321 (13.5)
  Other	231 (9.8)	213 (9.0)
  Unknown or missing	3 (0.1)	8 (0.3)
  Receptor status Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization. , n (%):
  ER and PgR Positive	1331 (56.6)	1319 (55.6)
  ER Positive and PgR Negative/Unknown	677 (28.8)	692 (29.2)
  ER Unknown and PgR Positive Only one subject in the exemestane group had unknown ER status and positive PgR status. /Unknown	288 (12.2)	291 (12.3)
  ER Negative and PgR Positive	6 (0.3)	7 (0.3)
  ER Negative and PgR Negative/Unknown (none positive)	48 (2.0)	58 (2.4)
  Missing	2 (0.1)	5 (0.2)
  Tumor Size, n (%):
  ≤ 0.5 cm	58 (2.5)	46 (1.9)
  > 0.5 – 1.0 cm	315 (13.4)	302 (12.7)
  > 1.0 – 2 cm	1031 (43.8)	1033 (43.5)
  > 2.0 – 5.0 cm	833 (35.4)	883 (37.2)
  > 5.0 cm	62 (2.6)	59 (2.5)
  Not reported	53 (2.3)	49 (2.1)
  Tumor Grade, n (%):
  G1	397 (16.9)	393 (16.6)
  G2	977 (41.5)	1007 (42.5)
  G3	454 (19.3)	428 (18.0)
  G4	23 (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)

  Parameter	Exemestane (N = 2352)	Tamoxifen (N = 2372)
  Type of surgery, n (%):
  Mastectomy	1232 (52.4)	1242 (52.4)
  Breast-conserving	1116 (47.4)	1123 (47.3)
  Unknown or missing	4 (0.2)	7 (0.3)
  Radiotherapy to the breast, n (%):
  Yes	1524 (64.8)	1523 (64.2)
  No	824 (35.5)	843 (35.5)
  Not reported	4 (0.2)	6 (0.3)
  Prior therapy, n (%):
  Chemotherapy	774 (32.9)	769 (32.4)
  Hormone replacement therapy	567 (24.1)	561 (23.7)
  Bisphosphonates	43 (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 mg	2270 (96.5)	2287 (96.4)
  30 mg The 30 mg dose was used only in Denmark, where this dose was the standard of care.	78 (3.3)	75 (3.2)
  Not reported	4 (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)

  Event	First Events N (%)
  	Exemestane (N = 2352)	Tamoxifen (N = 2372)
  Loco-regional recurrence	34 (1.45)	45 (1.90)
  Distant recurrence	126 (5.36)	183 (7.72)
  Second primary – contralateral breast cancer	7 (0.30)	25 (1.05)
  Death – breast cancer	1 (0.04)	6 (0.25)
  Death – other reason	41 (1.74)	43 (1.81)
  Death – missing/unknown	3 (0.13)	5 (0.21)
  Ipsilateral breast cancer	1 (0.04)	0
  Total number of events	213 (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 Population	Hazard Ratio (95% CI)	p-value (log-rank test)
  Disease-free survival	0.69 (0.58–0.82)	0.00003
  Time to contralateral breast cancer	0.32 (0.15–0.72)	0.00340
  Distant recurrence-free survival	0.74 (0.62–0.90)	0.00207
  Overall survival	0.91 (0.81–1.04)	0.16 Not adjusted for multiple testing.
  ER and/or PgR positive
  Disease-free survival	0.65 (0.53–0.79)	0.00001
  Time to contralateral breast cancer	0.22 (0.08–0.57)	0.00069
  Distant recurrence-free survival	0.73 (0.59–0.90)	0.00367
  Overall survival	0.89 (0.78–1.02)	0.09065

  Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

  

  ).
• •treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (
  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

  Parameter	AROMASIN (N = 366)	Megestrol Acetate (N = 403)
  Median Age (range)	65 (35–89)	65 (30–91)
  ECOG Performance Status
  0	167 (46%)	187 (46%)
  1	162 (44%)	172 (43%)
  2	34 (9%)	42 (10%)
  Receptor Status
  ER and/or PgR +	246 (67%)	274 (68%)
  ER and PgR unknown	116 (32%)	128 (32%)
  Responders to prior tamoxifen	68 (19%)	85 (21%)
  NE for response to prior tamoxifen	46 (13%)	41 (10%)
  Site of Metastasis
  Visceral ± other sites	207 (57%)	239 (59%)
  Bone only	61 (17%)	73 (18%)
  Soft tissue only	54 (15%)	51 (13%)
  Bone & soft tissue	43 (12%)	38 (9%)
  Measurable Disease	287 (78%)	314 (78%)
  Prior Tamoxifen Therapy
  Adjuvant or Neoadjuvant	145 (40%)	152 (38%)
  Advanced Disease, Outcome
  CR, PR, or SD ≥ 6 months	179 (49%)	210 (52%)
  SD < 6 months, PD or NE	42 (12%)	41 (10%)
  Prior Chemotherapy
  For advanced disease ± adjuvant	58 (16%)	67 (17%)
  Adjuvant only	104 (28%)	108 (27%)
  No chemotherapy	203 (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 Characteristics	AROMASIN (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 (%)	15.0	12.4
  Difference in Response Rate (AR-MA)	2.6
  95% C.I.	7.5, -2.3
  CR (%)	2.2	1.2
  PR (%)	12.8	11.2
  SD ≥ 24 Weeks (%)	21.3	21.1
  Median Duration of Response (weeks)	76.1	71.0
  Median TTP (weeks)	20.3	16.6
  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

  

  ).

Recommended Dose: One 25 mg tablet once daily after a meal (

AROMASIN Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number "7663" in black.

Lactation: Advise not to breastfeed (

• •Reductions in bone mineral density (BMD) over time are seen with exemestane use (
  5.1 Reductions in Bone Mineral Density (BMD)

  Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed.

  Table 1. Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control¹

  	IES		027
  BMD	Exemestane N=29	Tamoxifen1 N=38	Exemestane N=59	Placebo1 N=65
  Lumbar spine (%)	-3.1	-0.2	-3.5	-2.4
  Femoral neck (%)	-4.2	-0.3	-4.6	-2.6

  During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate.
  ).
• •Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromata
  s
  e inhibitor treatment should be performed (
  5.2 Vitamin D Assessment

  Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D.
  ).
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception (
  5.6 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, AROMASIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions and embryo-fetal toxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the last dose

  [see Use in Specific Populations (8.1), (8.3)and Clinical Pharmacology (12.1)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings in animal studies and its mechanism of action

  ,

  AROMASIN can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . Limited human data from case reports are insufficient to inform a drug-associated risk. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions, embryo-fetal toxicity, and prolonged gestation with abnormal or difficult labor

  [see Data]

  . Advise pregnant women of the potential risk to a fetus.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Animal Data

  In animal reproduction studies in rats and rabbits, exemestane caused embryo-fetal toxicity, and was abortifacient. Radioactivity related to¹⁴C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m²basis). Increased resorptions, reduced number of live fetuses, decreased fetal weight, retarded ossification, prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day (approximately 7.5 times the recommended human daily dose on a mg/m²basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m²basis) and in the presence of maternal toxicity, abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. No malformations were noted when exemestane was administered to pregnant rats or rabbits during the organogenesis period at doses up to 810 and 270 mg/kg/day, respectively (approximately 320 and 210 times the recommended human dose on a mg/m²basis, respectively).
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating AROMASIN.

  Contraception

  Females

  AROMASIN can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  . Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the final dose.

  Infertility

  Based on findings in animals, male and female fertility may be impaired by treatment with AROMASIN

  [see Nonclinical Toxicology (13.1)]

  .
  ).