Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor–Positive Breast Cancer

Abstract

ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.ObjectiveTo compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor–positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of −6%.Design, Setting, and ParticipantsThis multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor–positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.InterventionsExemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.Main Outcomes and MeasuresSerum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.ResultsA total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was −89%, −85%, and −60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was −3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, −5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of −7.5%, −5.0%, and −4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and −17.0%, −9.0%, and −7.0% for progesterone receptor, respectively. Sex hormone–binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.Conclusions and RelevanceIn this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.Trial RegistrationClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16

Reduced-Frequency Endocrine Therapy and Challenges of Noninferiority Study Designs

“…Ingle et al, in a case-control study of postmenopausal women with early breast cancer, found that those with 0.5 pg/mL or higher serum estradiol after 6 months of adjuvant exemestane had a statistically significant 2.2-fold increase in early breast cancer–related events. Note that 0.5 pg/mL is below the 1-pg/mL limit of detection for the solid-phase extraction assay used for the primary analysis of the present study . In total, 69% of women in the daily-dose arm and 65% in the 3-times-weekly arm, but only 17% in the once-weekly arm, had estradiol suppressed below the 1-pg/mL detection limit.…”

“…The authors suggest that the 3-times-weekly regimen should be studied further in longer-duration primary prevention and adjuvant therapy trials . Should we take their advice, given the inability to demonstrate noninferiority in the ITT analysis of the primary efficacy biomarker or difference in adverse events between the standard and 3-times-weekly arms?…”

“…Generally, for small noninferiority margins and high confidence intervals, a greater sample size is recommended. For this trial, the sample size may not have been sufficient to overcome the predefined noninferiority margin plus the 97.5% CI . The primary analysis of superiority trials usually assesses data on an ITT basis, which is considered the most conservative.…”

“…In this issue of JAMA Oncology , Serrano et al present results of a phase 2b trial of postmenopausal women with early-stage breast cancer assessing change in serum estradiol levels and breast tumor Ki-67 after 4 to 6 weeks of 3-times-weekly or once-weekly exemestane reduced-frequency regimens vs the standard 25 mg daily . The primary end point was the noninferiority of change in serum estradiol between the reduced-frequency and standard-frequency arms when estradiol was measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry.…”

“…For women who were compliant with prescribed dosing, the mean relative change in estradiol was −91% for the 3-times-weekly regimen vs −92% for daily exemestane . Noninferiority was defined as having 97.5% confidence that the reduced-frequency regimens did not differ from the daily regimen in estradiol suppression by more than a relative 6%.…”