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Exm4.9
Exemestane Research
Mostly mechanism / observationalLimited safety
7 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Exemestane studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 2003–2022 with a typical study size of 7,030 participants.
Based on 7 studies · 2 meta-analyses · 5 RCTs · 33,699 total participants
Confidence
High
By outcome
Breast cancer (approved)
Mostly mechanism / observational7 studies
Testosterone & estradiol (off-label, men)
Mostly mechanism / observational4 studies
Bone health (trade-off)
Mostly mechanism / observational3 studies
Safety profile
Too few graded studies1 study
Steady research
1 study in the last 5 years · Latest meta-analysis: 2022
200320122022
1RCTn=4,742 · very large study2004
Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al.; Intergroup Exemestane Study. · The New England journal of medicine (2004)
The pivotal IES double-blind RCT (n=4742): switch to exemestane after 2-3 years of tamoxifen vs continue tamoxifen, in postmenopausal HR-positive breast cancer
Switching to exemestane reduced first events with a hazard ratio of 0.68 (95% CI 0.56-0.82, P<0.001) — a 32% risk reduction and 4.7% absolute disease-free-survival benefit at 3 years
Overall survival was not significantly different between groups; contralateral breast cancer was less frequent on exemestane
Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer.
Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, et al.; NCIC CTG MAP.3 Study Investigators. · The New England journal of medicine (2011)
MAP.3 randomized, placebo-controlled, double-blind prevention trial (n=4560) in higher-risk postmenopausal women
Exemestane reduced the annual incidence of invasive breast cancer by 65% (0.19% vs 0.55%; HR 0.35, 95% CI 0.18-0.70, P=0.002)
At a median 3-year follow-up there were no significant differences in skeletal fractures, cardiovascular events, or other cancers, with only minimal quality-of-life changes
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy.
Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, et al. · Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013)
MA.27 open-label phase III RCT (n=7576): exemestane vs anastrozole as up-front 5-year adjuvant therapy in postmenopausal breast cancer
4-year event-free survival was 91% with exemestane vs 91.2% with anastrozole (HR 1.02, 95% CI 0.87-1.18, P=0.85) — neither AI superior
Osteoporosis/osteopenia, hypertriglyceridemia, and hypercholesterolemia were less frequent on exemestane, consistent with its steroidal/androgenic profile, but the difference required confirmation
Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer.
van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, et al. · Lancet (London, England) (2011)
TEAM phase 3 RCT (n=9779): exemestane monotherapy vs tamoxifen-then-exemestane sequential treatment over 5 years
5-year disease-free survival was equivalent between the two regimens (85% vs 86%; HR 0.97, 95% CI 0.88-1.08, P=0.60)
Exemestane monotherapy carried more musculoskeletal adverse events, hypertension, and hyperlipidaemia, while sequential treatment had more gynaecological and thrombotic events
There were more bone fractures with aromatase inhibitor than with tamoxifen (227 [6.4%] vs 180 [5.1%]; RR 1.27 [95% CI 1.04-1.54]; p=0.017).
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). · The Lancet. Oncology (2022)
EBCTCG patient-level meta-analysis of four RCTs (n=7030; aromatase inhibitors including exemestane vs tamoxifen) in premenopausal women receiving ovarian suppression
Aromatase inhibitors lowered breast-cancer recurrence (RR 0.79, 95% CI 0.69-0.90, P=0.0005), mainly in years 0-4, with no difference in breast-cancer or all-cause mortality
Significantly MORE bone fractures occurred on aromatase inhibitors than tamoxifen (RR 1.27, 95% CI 1.04-1.54, P=0.017)
Patients receiving exemestane showed a mean decrease from baseline [in lumbar spine BMD] of 2.6% after 12 months and 3.5% after 24 months... Exemestane resulted in decreases in BMD and increases in bone turnover markers.
Hadji P, Asmar L, van Nes JG, Menschik T, Hasenburg A, Kuck J, Nortier JW, van de Velde CJ, Jones SE, Ziller M. · Journal of cancer research and clinical oncology (2011)
Meta-analysis of four TEAM bone sub-studies comparing exemestane vs tamoxifen on bone-mineral density and turnover markers
Exemestane DECREASED lumbar-spine BMD by 2.6% at 12 months and 3.5% at 24 months, whereas tamoxifen INCREASED it (significant difference, P<0.0001 at both time points)
Bone turnover markers rose with exemestane and fell with tamoxifen — the steroidal/androgenic metabolite did NOT prevent bone loss
Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38%; 50 mg, 32%], with a reciprocal increase in testosterone concentrations (60% and 56%).
Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B. · The Journal of clinical endocrinology and metabolism (2003)
Randomized crossover dose-finding study in healthy eugonadal young males (n=12) comparing exemestane 25 mg and 50 mg daily
Exemestane lowered estradiol by ~38% (25 mg) with a reciprocal ~60% rise in testosterone — the direct evidence for the off-label male hormonal effect
Plasma lipids and IGF-I were unaffected over the short course and the drug was well tolerated