(Z)-endoxifen Reduces MBD, Is Well Tolerated in Premenopausal Women Screened for Breast Cancer

Steven C. Quay, MD, PhD

Low doses of (Z)-endoxifen significantly reduced mammographic breast density (MBD) and was generally well tolerated compared with placebo in premenopausal women being screened for breast cancer, according to topline data from the phase 2 KARISMA-Endoxifen trial (NCT05068388), which was conducted through the Karolinska Institute in Stockholm, Sweden.¹

Findings showed that patients administered (Z)-endoxifen at doses of 1 mg and 2 mg experienced a MBD change of –19.3% and –26.5%, respectively, compared with those given placebo. There was not a significant difference in MBD change when comparing 2 (Z)-endoxifen arms.

Furthermore, the mean endoxifen plasma concentration was 5.18 ng/mL and 10.87 ng/mL in the 1 mg and 2 mg arms, respectively, after 1 month of therapy; plasma concentrations stayed the same at 3 and 6 months.

“We are thrilled with the topline results from the KARISMA-Endoxifen phase 2 trial with [Z]-endoxifen and heartened by the idea that this work may someday lead us to a preventative approach to breast cancer,” Steven C. Quay, MD, PhD, chief executive officer of Atossa Therapeutics, stated in a news release. “Although further analysis of this study is required, the potential that 1 mg of [Z]-endoxifen may significantly reduce breast density as well as, if not better than currently available therapies, potentially without many of the intolerable [adverse] effects [AEs], is extremely encouraging and a significant step toward a solution for millions of women with dense breasts.”

(Z)-endoxifen is a potent selective estrogen receptor modulator (SERM) for estrogen receptor inhibition and may cause estrogen receptor degradation. Additionally, the SERM has demonstrated efficacy in the setting of patients with tumor resistance to other hormonal treatments. (Z)-endoxifen has been shown to target the known oncogenic protein PKCβ1 at clinically attainable blood concentrations, and it appears to deliver similar or better bone agonistic effects; this comes with little or no endometrial proliferative effects compared with standard-of-care approaches, such as tamoxifen.

The phase 2 trial evaluated (Z)-endoxifen in healthy premenopausal women 40 to 55 years of age.² Women were required to receive a mammogram within 3 months of study inclusion, and they needed to have a mammographic density score of B, C, or D per BI-RADS. Those with a BI-RADS malignancy code of 3 or higher at baseline were not allowed to enroll. Other key exclusion criteria consisted of any previous diagnosis of breast cancer; a history of breast surgery that could affect density measurements; a body mass index (BMI) of more than 30; and a history of thromboembolic disease.

Enrolled patients were randomly assigned to 1 mg of (Z)-endoxifen, 2 mg of (Z)-endoxifen, or matching placebo once per day.¹ There were 80 women in each study arm, and the study lasted 6 months.

Change in mammographic density at 6 months per iCAD software assessment served as the trial’s primary end point.² Secondary end points included mammographic density changes at 3 months per iCAD software; mammographic density changes at 3 and 6 months per Stratus software; change from baseline responses to the Breast Cancer Prevention Trial Eight Symptom Scale; and safety.

There were no differences in age, BMI, or other background factors between randomization arms.¹

Investigators utilized a validated questionnaire including 36 questions, and a 5-graded Likert scale was used for self-assessment of symptoms. Only vasomotor symptoms, such as night/cold sweats and hot flushes, increased during the study period in the experimental arms, but these increases were not substantial. The mean was reported at 1.4 on a 10-point scale.

There were no changes in hematological safety tests or vital signs during the trial period. However, AEs related to treatment led to discontinuation in 4 patients in the placebo arm, 5 patients in the 1-mg arm, and 12 patients in the 2-mg arm. Vasomotor symptoms were not reported as a reason for discontinuation.

References

1. Atossa Therapeutics reports positive KARISMA-Endoxifen trial results. Atossa Therapeutics. November 4, 2024. Accessed November 5, 2024. https://investors.atossatherapeutics.com/node/11296/pdf
2. Effect of oral (Z)-endoxifen in premenopausal women with measurable breast density. ClinicalTrials.gov. Updated April 26, 2024. Accessed November 5, 2024. https://clinicaltrials.gov/study/NCT05068388