Exemestane is an orally active, steroidal aromatase inhibitor approved for the treatment of estrogen receptor-positive breast cancer in postmenopausal women.[1] It functions as an irreversible inactivator of the aromatase enzyme, which catalyzes the final step in estrogen biosynthesis, thereby substantially reducing circulating estrogen levels and inhibiting the growth of hormone-dependent tumors.[1] First approved by the U.S. Food and Drug Administration in 1999 under the brand name Aromasin, it is administered as a 25 mg tablet once daily and has demonstrated efficacy in both adjuvant and advanced disease settings.[2]In clinical practice, exemestane is primarily indicated as adjuvant therapy for early-stage breast cancer following 2–3 years of tamoxifen treatment to complete a total of 5 years of endocrine therapy, where it has shown a significant reduction in the risk of recurrence.[1] It is also used for advanced breast cancer that has progressed after tamoxifen therapy, offering benefits such as slowed disease progression and improved symptom control.[1] Key trials, including the Intergroup Exemestane Study (IES), have reported a 24% relative reduction in the risk of recurrence or death compared to continued tamoxifen, with an absolute benefit of 3.3% in disease-free survival after a median follow-up of 55.7 months.[3]Pharmacologically, exemestane exhibits approximately 42% oral bioavailability, a plasmahalf-life of about 27 hours, and achieves steady-state concentrations within 7 days of dosing, leading to up to 90% suppression of plasma estrogens in postmenopausal women.[3] While generally well-tolerated, common adverse effects include hot flushes (up to 21%), fatigue (16%), and arthralgia (15%), along with risks of decreased bone mineral density and osteoporosis; it is contraindicated in cases of hypersensitivity and requires precautions during pregnancy due to potential fetal harm.[1][4]
Clinical Use
Medical Uses
Exemestane is approved by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of estrogen receptor-positive (ER+) early breast cancer in postmenopausal women who have received 2 to 3 years of tamoxifentherapy and are switched to exemestane to complete a total of 5 consecutive years of adjuvant hormonal therapy.[1][5] This indication was expanded in 2005 based on clinical evidence demonstrating improved disease-free survival in this sequential therapy approach.[5] The recommended dosage for this use is 25 mg orally once daily after a meal.[1]Exemestane is also FDA-approved for the treatment of advanced ER+ breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.[1] This indication received initial approval in 1999, targeting patients with metastatic disease after antiestrogen failure.[2] The same 25 mg daily oral dosage is used, administered after a meal.[1]In premenopausal women with early-stage ER+ breast cancer at higher risk of recurrence, exemestane combined with ovarian function suppression (such as via gonadotropin-releasing hormone agonists) has been shown to reduce the risk of disease recurrence compared to tamoxifen with ovarian suppression. This is based on the combined analysis of the SOFT and TEXT trials, including 15-year follow-up data presented in 2025 showing sustained benefits in disease-free survival and freedom from distant recurrence with exemestane plus suppression.[6][7] Although not FDA-approved for premenopausal use, this regimen is recommended by ASCO and NCCN guidelines for select high-risk patients as of 2025.[8][9]
Contraindications
Exemestane is contraindicated in patients with known hypersensitivity to the drug or any of its excipients, as severe allergic reactions may occur.[1][10]Exemestane is not indicated for use in premenopausal women without ovarian function suppression, due to insufficient efficacy against endogenous estrogen production. However, it may be used off-label with suppression in high-risk cases per clinical guidelines.[1][10]Exemestane can cause fetal harm when administered to pregnant women based on its mechanism of action and findings in animal reproduction studies; effective contraception should be used during treatment and for 1 month after the last dose.[1][10][11]Women should be advised not to breastfeed during treatment with exemestane and for 1 month after the final dose, due to potential excretion into breast milk and risk of adverse effects on the nursinginfant.[10][11]Use exemestane with caution in patients with severe hepatic impairment (Child-Pugh class C), as exposure may be substantially increased; no dose adjustment is required, but close monitoring is recommended.[10][1]Use exemestane with caution in patients with severe renal impairment (creatinine clearance <30 mL/min), as systemic exposure may be approximately twofold higher; no dose adjustment is required.[10][1]Exemestane may decrease bone mineral density, increasing the risk of osteoporosis and fractures; assess bone mineral density prior to initiation and monitor periodically, particularly in patients with risk factors or history of osteoporotic fractures. Consider use of bone-modifying agents as appropriate.[1][11][12]
Safety Profile
Side Effects
Exemestane, a steroidal aromatase inhibitor, is associated with a range of adverse reactions primarily stemming from estrogen suppression, with most being mild to moderate in severity.[1] Common side effects occurring in more than 10% of patients in clinical trials include hot flushes (13-21%), arthralgia or joint pain (up to 15%), fatigue (8-16%), and insomnia (12%).[1] Other frequently reported effects at rates of 5-10% encompass nausea (9%), increased sweating (4-12%), and headache (13%).[1]Serious adverse effects, observed in 1-10% of users, include an increased risk of osteoporosis and bone fractures due to estrogen depletion, with clinical fractures reported in approximately 4% of patients compared to 3% on tamoxifen.[1] Hypercholesterolemia occurs in about 10% of patients, potentially linked to alterations in lipid profiles such as elevated LDL cholesterol.[1] Lymphopenia, though rare and often preexisting, requires monitoring, with grade 3 or 4 events noted in up to 20% but mostly in those with prior lower-grade reductions.[1] Cardiac ischemic events, including myocardial infarction and angina, have an incidence of 1.6%, higher than with tamoxifen (0.6%).[1]As a steroidal aromatase inhibitor, exemestane exhibits mild androgenic activity, leading to effects such as acne, hair loss, or hirsutism, typically at therapeutic doses of 25 mg daily.[13]Long-term use may elevate cardiovascular event risks in certain cohorts, alongside persistent bone density loss and lipid changes.[14] Management strategies include regular bone mineral density assessments, supplementation with calcium and vitamin D, and consideration of bisphosphonates to mitigate osteoporosis risk.[1] Lipid profiles should be monitored, with interventions for hypercholesterolemia as needed.[15]Post-marketing reports include hypersensitivity reactions, hepatitis, paresthesia, tendon disorders (such as tendon rupture, tendonitis, and tenosynovitis), acute generalized exanthematous pustulosis, urticaria, and pruritus.[1][16]Discontinuation rates due to intolerable side effects, such as joint pain, range from 2-6% across studies.[1]
Overdose
Limited human data exist on exemestane overdose, primarily derived from clinical trials and isolated case reports. In studies, single oral doses of up to 800 mg in healthy female volunteers and daily doses of up to 600 mg for 12 weeks in postmenopausal women with advanced breast cancer were generally well tolerated, with no life-threatening effects observed.[1] Toxicity in overdose is expected to manifest as an extension of known adverse effects, potentially including intensified nausea, vomiting, fatigue, and hot flashes, which typically resolve within days.[17] One reported case involved a male child who accidentally ingested a single 25 mg tablet; the patient exhibited transient leucocytosis (white blood cell count of 25,000/mm³ with 90% neutrophils) one hour post-ingestion, which normalized within four days without specific treatment.[1]There is no specific antidote for exemestane overdose, and management focuses on supportive and symptomatic care. For recent ingestion, gastric lavage or administration of activated charcoal may be considered to reduce absorption, particularly if within one hour of exposure and the patient can protect their airway.[18][19] Vital signs, electrolytes, complete blood count, and liver function should be monitored closely, with general supportive measures provided as needed. Hemodialysis is not expected to be effective due to exemestane's high plasma protein binding (approximately 90%) and extensive tissue distribution.[17][20]Animal studies indicate acute toxicity at extremely high doses, with mortality observed in mice at 3,200 mg/kg (approximately 640 times the recommended human dose on a mg/m² basis), rats at 5,000 mg/kg (approximately 2,000 times the human dose), and dogs at 3,000 mg/kg (approximately 4,000 times the human dose); convulsions were noted in mice at 400 mg/kg and in dogs at 3,000 mg/kg.[1] High doses in reproductive toxicity studies also caused reduced fertility in rats and embryo-fetal toxicity in rats and rabbits, though these effects relate more to prolonged exposure than acute overdose. No data are available on chronic overdose in humans, but extended high-level exposure would likely exacerbate severe estrogen suppression, leading to amplified effects similar to those seen in therapeutic use but at greater intensity.[1]
Drug Interactions
Pharmacokinetic Interactions
Exemestane undergoes primary metabolism in the liver via the cytochrome P450 3A4 (CYP3A4) enzyme, with less than 10% of the administered dose excreted as unchanged drug in urine and feces.[21]Strong CYP3A4 inducers, such as rifampin, significantly decrease exemestane exposure by approximately 54% in terms of area under the curve (AUC), potentially reducing its efficacy; therefore, the recommended dose is increased to 50 mg daily when coadministered with such agents.[21][22] In contrast, potent CYP3A4 inhibitors like ketoconazole have no significant impact on exemestane pharmacokinetics, as demonstrated in clinical studies.[21]The absolute bioavailability of exemestane is approximately 42%, and its pharmacokinetics are influenced by food intake.[21] Administration after a high-fat meal increases the AUC by 59% and maximum plasma concentration (Cmax) by 39% compared to the fasted state, with a slight delay in time to Cmax (Tmax), though exemestane should be taken after a meal to optimize absorption.[21]Exemestane is approximately 90% bound to plasma proteins, primarily albumin and α1-acid glycoprotein.[21] Although highly protein-bound drugs like warfarin and diazepam could theoretically displace exemestane, clinical monitoring of INR is recommended when coadministered with warfarin due to reports of increased anticoagulant effect.[23][24]
Clinical Interactions
Exemestane's therapeutic effects can be antagonized by concomitant use of estrogens, such as those found in hormone replacement therapy (HRT) or oral contraceptives, which reduce aromatase inhibition and are contraindicated in patients receiving exemestane for breast cancer treatment.[25] This interaction underscores the need to avoid estrogen-containing products to maintain the drug's efficacy in hormone-dependent malignancies.[26]The combination of exemestane with everolimus is FDA-approved for postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer previously treated with nonsteroidal aromatase inhibitors; this regimen demonstrated a significant improvement in progression-free survival (median 10.6 months versus 4.1 months with exemestane alone) in the phase III BOLERO-2 trial. The addition of everolimus enhances clinical outcomes without compromising exemestane's core mechanism, offering a viable option for endocrine-resistant disease.[27]Bone-modifying agents like denosumab are commonly co-administered with exemestane to counteract aromatase inhibitor-associated bone loss and reduce fracture risk in postmenopausal breast cancer patients, without evidence of diminished exemestane efficacy.[28] Clinical guidelines support this approach for managing osteoporosis in long-term therapy, preserving overall treatment benefits.[29]Exemestane exhibits no significant clinical interactions with tamoxifen, supporting its standard sequential use after 2 to 3 years of tamoxifen in adjuvant settings, which improves disease-free survival compared to continued tamoxifen alone. However, concurrent administration with other antiestrogens should be avoided to prevent potential overlap in estrogen suppression that could increase toxicity without added benefit.[30]
Pharmacology
Pharmacodynamics
Exemestane is an irreversible, steroidal aromatase inhibitor that functions as a suicide substrate for the enzyme cytochrome P450 19A1 (aromatase), covalently binding to it and permanently inactivating the enzyme.[21] This mechanism prevents the conversion of androgens to estrogens in peripheral tissues, thereby substantially reducing circulating estrogen levels in postmenopausal women, where estrogen production primarily occurs extragonadally via aromatase.[31] Unlike nonsteroidal aromatase inhibitors, exemestane's steroidal structure allows it to mimic the natural substrate androstenedione, leading to irreversible inhibition without affecting other steroidogenic enzymes at clinically relevant concentrations.[21]At the standard dose of 25 mg daily, exemestane suppresses plasma levels of estradiol, estrone, and estrone sulfate by 85-95% in postmenopausal women, achieving near-maximal inhibition within 2-3 days and reducing whole-body aromatization by approximately 98%.[21][32] This profound estrogen deprivation has no significant impact on adrenal corticosteroid synthesis, aldosterone production, or thyroid function, preserving these pathways despite the enzyme's role in broader steroidogenesis.[21] Exemestane exhibits no direct antiestrogenic activity at the estrogen receptor (ER); its therapeutic effects are mediated exclusively through the reduction of endogenous estrogen levels.[33]Exemestane possesses mild androgenic properties due to its weak affinity for the androgen receptor, approximately 0.2-0.28% that of dihydrotestosterone (DHT), which may contribute to subtle virilizing effects observed in some patients.[21][34] One of its metabolites, 17-dihydroexemestane, demonstrates substantially higher androgen receptor affinity, up to 100-fold greater than the parent compound, potentially enhancing this activity.[21]Because the inhibition is irreversible, recovery of aromatase activity depends on the synthesis of new enzyme protein, with the functional half-life of inhibition estimated at around 24 hours under chronic dosing conditions.[21][23]
Pharmacokinetics
Exemestane is administered orally and exhibits approximately 42% bioavailability following absorption from the gastrointestinal tract.[21] Absorption is rapid, with a mean time to maximum plasma concentration (Tmax) of 1.2 hours in breast cancer patients, and pharmacokinetics are linear at the standard 25 mg dose.[21]The drug is extensively distributed into tissues, with an apparent volume of distribution (V/F) of approximately 20,000 L.[35] Exemestane is approximately 90% bound to plasma proteins, primarily albumin and α1-acid glycoprotein.[21]Exemestane undergoes extensive hepatic metabolism, primarily via cytochrome P450 3A4 (CYP3A4) oxidation and reduction by aldo-keto reductases, with less than 10% of the parent drug circulating unchanged in plasma.[21] The major metabolite is the inactive 17β-dihydroexemestane (17-hydro derivative), accounting for a substantial portion of circulating compounds, alongside minor oxidation products that are also inactive or of low potency.[36]Elimination occurs with a mean terminal half-life of about 24 hours.[21] Approximately 42% of the dose is excreted in urine and 42% in feces over one week, predominantly as metabolites, with less than 1% as unchanged drug in urine; apparent oral clearance is lower in breast cancer patients compared to healthy volunteers.[21]Steady-state plasma concentrations are achieved within 7 days of daily dosing, with approximately 15% accumulation due to the elimination half-life.[37] No dose adjustment is required for patients with mild to moderate hepatic or renal impairment.[21]
Chemical Properties
Structure and Synthesis
Exemestane possesses the molecular formula C_{20}H_{24}O_{2} and a molecular weight of 296.41 g/mol.[31] Its IUPAC name is 6-methylideneandrosta-1,4-diene-3,17-dione.[31] As a steroidal compound, exemestane is structurally derived from androstenedione (androsta-4-ene-3,17-dione), with key modifications including an exocyclic methylene group (=CH_{2}) at the C6 position and an α,β-unsaturated ketone system in the A-ring (Δ^{1,4}).[31] These structural features enable the molecule to act as a mechanism-based inhibitor, where the methylene group at C6 undergoes oxidation to form a reactive intermediate that covalently binds to the target enzyme.[38]The synthesis of exemestane starts from androst-4-ene-3,17-dione as the primary precursor.[38] The exocyclic methylene group at the C6 position is introduced using formaldehyde diethylacetal and phosphoryl chloride. The final step involves dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to establish the 1,4-diene system in the A-ring. This synthetic route was developed and patented by Farmitalia Carlo Erba (later Pharmacia & Upjohn) in the late 1980s, as detailed in US Patent 4,808,616.[38]The stereochemistry of exemestane follows the standard androstane configuration with absolute configurations at five chiral centers (8R, 9S, 10R, 13S, 14S).[39] This stereospecificity is essential for maintaining the molecule's binding affinity and inhibitory potency, as alterations would disrupt the spatial arrangement required for enzymeinteraction, distinguishing exemestane from inactive stereoisomers.[40]
Physical and Stability Characteristics
Exemestane appears as a white to off-white crystalline powder.[31][41]The compound exhibits low aqueous solubility, being practically insoluble in water at less than 0.1 mg/mL, while it is soluble in organic solvents such as ethanol (approximately 20 mg/mL) and acetone.[31][41][42] Its lipophilicity is reflected in a logP value of 3.7.[23] This profile of solubility influences its oral bioavailability, as noted in pharmacokinetic studies.[23]Exemestane has a melting point ranging from 191°C to 196°C.[43] The compound is stable under normal storage conditions at 25°C but degrades primarily through oxidation when exposed to oxidative stress.[44][45] It shows no significant polymorphism issues in its standard crystalline form, supporting consistent formulation properties.[46]In pharmaceutical formulations, exemestane is available as 25 mg tablets containing excipients such as mannitol, crospovidone, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate to aid disintegration and compression.[21] These tablets have a shelf life of 3 years when stored at 25°C in controlled room temperature conditions.[47]
History and Society
Development and Approval
Exemestane was discovered and entered preclinical development in 1986 by Pharmacia, an Italian pharmaceutical company, as part of research into steroidal aromatase inhibitors aimed at treating hormone-dependent breast cancer through irreversible enzyme inactivation.[48] Initial preclinical studies focused on its mechanism as an orally active, steroidal compound that acts as a suicide substrate for aromatase, leading to permanent inhibition and suppression of estrogen biosynthesis in postmenopausal women.[48]Clinical development progressed through the 1990s, with Phase III trials evaluating its efficacy in breast cancer treatment. The Intergroup Exemestane Study (IES), a pivotal randomized trial initiated in February 1998, demonstrated exemestane's superiority over continued tamoxifen in the adjuvant setting for postmenopausal women with primary breast cancer after 2 to 3 years of tamoxifen therapy, showing disease-free survival rates of 91.5% versus 86.8% at 3 years (hazard ratio 0.68; 95% CI, 0.56 to 0.82; P<0.001).[49]Regulatory approval began in Europe in December 1998 for the treatment of advanced breast cancer in postmenopausal women whose disease had progressed following tamoxifen therapy.[50] The U.S. Food and Drug Administration (FDA) granted approval on October 21, 1999, for the same indication of advanced breast cancer after tamoxifen failure.[2] In October 2005, the FDA expanded approval to include adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women, following 2 to 3 years of tamoxifen to complete a total of 5 years of adjuvant hormonal therapy.[50]Generic versions of exemestane became available in the European Union starting in 2010, with approvals such as in Denmark for Sandoz's formulation, and in the United States in April 2011 following the expiration of the original U.S. patent for Aromasin in April 2011, enabling multiple manufacturers to produce equivalents.[51][52]
Non-Medical Uses
Exemestane is misused in bodybuilding and post-cycle therapy regimens to counteract estrogen rebound associated with anabolic-androgenic steroid (AAS) use, typically at doses of 12.5–25 mg per day.[53] In a cross-sectional study of 50 male AAS users engaging in doping practices, exemestane was the most commonly used aromatase inhibitor, administered at a mean daily dose of 10.5 ± 5.4 mg during 80% of AAS cycles (median duration 84 days), often to prevent estrogen-related side effects like gynecomastia.[54]As an aromatase inhibitor, exemestane has been prohibited by the World Anti-Doping Agency (WADA) since 2001 for male athletes and since 2005 for female athletes, under the category of hormone and metabolic modulators.[55][56] Its detection in doping controls has resulted in athlete suspensions, including multiple cases reported in the 2010s through anti-doping agencies like USADA.[57]Off-label, exemestane has been explored for gynecomastia prevention in men, particularly those on AAS, but clinical evidence for efficacy is limited, with studies showing inconsistent results in reducing breast tissue growth and highlighting risks of androgenic side effects due to its steroidal nature.[58]Exemestane is classified as a prescription-only medication in countries like the United States and those in the European Union, with non-medical use regulated under anti-doping and controlled substance laws; however, it remains widely available through online black markets targeting performance enhancement enthusiasts.[59]Unmonitored non-medical use of exemestane heightens risks of osteoporosis from accelerated bone mineral density loss and cardiovascular events from prolonged estrogen suppression, as these effects lack the mitigation provided by medical oversight such as bone density monitoring or cardioprotective interventions.[60][61]
Research Directions
Key Clinical Trials
The Intergroup Exemestane Study (IES), a pivotal phase III trial conducted in postmenopausal women with hormone receptor-positive early breast cancer, enrolled 4,724 participants who had received 2 to 3 years of adjuvant tamoxifen therapy. Patients were randomized to switch to exemestane (25 mg daily) or continue tamoxifen until completing 5 years of endocrine treatment. The primary endpoint of disease-free survival (DFS) was significantly improved with exemestane, with a hazard ratio (HR) of 0.68 (95% CI, 0.56-0.82; P<0.001), translating to a 3-year DFS rate of 91.5% versus 86.8%. Longer-term follow-up confirmed an overall survival (OS) benefit, with an HR of 0.81 (95% CI, 0.72-0.92), establishing exemestane as a superior sequential therapy option after initial tamoxifen.[49][62]Comparisons from the ATAC trial subgroup analyses in 2005 highlighted exemestane's role relative to anastrozole in adjuvant therapy for postmenopausal women with early breast cancer. While the ATAC trial primarily evaluated anastrozole versus tamoxifen, indirect assessments and early cross-trial data indicated similar efficacy between exemestane and anastrozole in reducing recurrence risk, with exemestane demonstrating better tolerability in metrics such as reduced incidence of certain cardiovascular events and improved lipid profiles compared to non-steroidal inhibitors like anastrozole.[63]The BOLERO-2 trial, a phase III study in 2012, assessed exemestane combined with everolimus in 724 postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer refractory to non-steroidal aromatase inhibitors. Participants were randomized to exemestane (25 mg daily) plus everolimus (10 mg daily) or exemestane plus placebo. The combination significantly prolonged progression-free survival (PFS) to a median of 7.8 months versus 3.2 months with exemestane alone (HR 0.43; 95% CI, 0.35-0.54; P<0.0001), with benefits most pronounced in patients without prior chemotherapy exposure, underscoring the role of mTOR inhibition in overcoming endocrine resistance. Safety data showed increased rates of stomatitis, fatigue, and hyperglycemia with the combination, but no new OS signals at the time.[64]The SOFT and TEXT trials, combined in a 2014 analysis, evaluated exemestane with ovarian function suppression (OFS) in premenopausal women with hormone receptor-positive early breast cancer. Involving 5,708 participants across both studies, women at higher risk of recurrence were randomized to tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS for 5 years. Exemestane plus OFS reduced the risk of DFS events by 30% compared to tamoxifen alone (HR 0.70; 95% CI, 0.58-0.85; P<0.001), with absolute improvements in 5-year DFS of 7.6% in higher-risk subgroups, supporting its use in premenopausal settings with adequate suppression of ovarian estrogen production.[6]A 2024 real-world study compared exemestane plus OFS with toremifene in premenopausal women with hormone receptor-positive breast cancer, focusing on patient-reported outcomes (PROs). In a cohort of 392 patients, the toremifene group showed advantages in some PRO domains (e.g., higher SF-36 role physical and mental health scores, lower anxiety/depression), with no significant differences in DFS (5-year rates 96.5% vs 91.9%; p=0.39) at longer follow-up, validating exemestane's tolerability in routine clinical practice akin to selective estrogen receptor modulators like toremifene.[65]
Emerging Applications
Recent reviews from 2023 to 2025 have explored extending exemestane use beyond five years as adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer, aiming to further diminish late recurrence risks observed after initial endocrine treatment. These investigations build on evidence that prolonging aromatase inhibitor therapy to seven to ten years yields superior outcomes in reducing distant recurrences compared to five years alone, with relative risk reductions of approximately 27% in select cohorts. For instance, analyses indicate that extended exemestane following tamoxifen can improve four-year disease-free survival to 91% versus 89% in placebo groups, though benefits vary by patient risk profile and adherence challenges.[66][67][68]Emerging combinations of exemestane with CDK4/6 inhibitors, such as abemaciclib, are under evaluation for high-risk early breast cancer, particularly in adjuvant settings to enhance progression-free survival. In the monarchE trial, abemaciclib paired with endocrine therapy—including aromatase inhibitors like exemestane—demonstrated sustained benefits in node-positive, hormone receptor-positive cases, with 2023 analyses confirming reduced invasive disease recurrence at longer follow-up. For relapsemanagement after prior CDK4/6 inhibitor exposure, 2025 studies suggest potential utility of exemestane in sequencing strategies to overcome resistance, though optimal integration remains investigational.[69][70][71]Beyond breast cancer, phase II trials have assessed exemestane in estrogen-driven endometrial carcinoma, showing modest activity with a 10% response rate in advanced or recurrent cases, prompting ongoing interest in its role for hormone-sensitive gynecologic malignancies. A 2023 case report highlighted risks of exemestane in male patients with concurrent breast and prostate cancers, noting increased testosterone and PSA levels that could accelerate prostate disease progression, limiting its clinical translation despite potential estrogen pathway modulation.[72][73]For breast cancer risk reduction, the MAP.3 trial established exemestane as an effective agent in high-risk postmenopausal women, achieving a 65% relative reduction in invasive breast cancer incidence compared to placebo over 3.6 years of follow-up. Analogous applications continue to be explored in prevention strategies, emphasizing its tolerability profile over selective estrogen receptor modulators in this population.[74][75]Data on exemestane combined with immunotherapy remain sparse in 2024-2025 publications, with no large-scale trials confirming synergistic effects in breast cancer subtypes. Ongoing studies, such as NCT03695341 evaluating everolimus plus exemestane versus fulvestrant in aromatase inhibitor-resistant metastatic breast cancer, and a phase II trial of ruxolitinib with exemestane for estrogen receptor-positive, AI-resistant advanced disease, address resistance mechanisms and inform future expansions in targeted therapy combinations.[76][77][78]