E.N.D.E.A.V.O.R.: An Exemestane Needed Dose Efficacy and Verification as an Ovulation Induction Regimen Study (ENDEAVOR)

Polycystic ovarian syndrome (PCOS/PMOS) is the leading cause of anovulation and infertility in reproductive age females in the United States with an overall incidence of 7-12%. The prevalence of subfertility ranges from 20-40% in women diagnosed with PCOS/PMOS. While the exact pathogenesis of PCOS/PMOS remains unknown, the symptoms of PCOS/PMOS are thought to be caused by abnormal elevated levels of androgens, which in turn interfere with the normal function of the ovaries. PCOS/PMOS is diagnosis of exclusion using the Rotterdam Criteria, which requires the presence of two out of the three from the following: oligomenorrhea/amenorrhea, polycystic ovaries on ultrasound, and clinical or biological hyperandrogenism (hirsutism or lab findings).

First-line treatment of infertility in women with PCOS/PMOS focuses on ovulation induction using different medications that target the hypothalamic-pituitary axis. Current available treatment options include clomiphene citrate, a selective estrogen receptor modulator, and letrozole, a third-generation aromatase inhibitor. A 2014 landmark study by Legro et al demonstrated that letrozole was associated with higher live-birth and ovulation rate compared to clomiphene citrate. The study found that ovulation rates with letrozole were around 60% compared to clomiphene citrate at 48%. Women who fail treatment with clomiphene citrate or letrozole are left with minimal options for ovulation induction, often requiring more expensive and invasive infertility treatments, such as ovarian drilling or IVF. A 2019 study by Mejia et al in 2019 compared letrozole and clomiphene for treating infertility in women with PCOS/PMOS, using progesterone levels as the primary outcome, consistent with the approach planned for this study.

From the literature review, no studies have examined exemestane- a relatively newer third generation aromatase inhibitor used to treat hormone responsive breast cancer in postmenopausal women - and its potential for ovulation induction. Aromatase inhibitors, including letrozole and exemestane, work by preventing aromatase from converting androgens into estrogen, resulting in overall decreased synthesis of endogenous estrogen. This results in inhibition of the negative feedback loop of estrogen on the hypothalamus resulting in increased gonadotropin releasing hormone (GnRH) pulses, which stimulates the pituitary to produce more follicle stimulating hormone (FSH) resulting in development of dominant follicles in the ovaries.

Letrozole, a triazole derivative, is a reversible non-steroidal aromatase inhibitor that binds to the cytochrome P-450 component of the aromatase enzyme and occupies its substrate-binding site. This is considered reversible because letrozole can be competitively displaced from this site by endogenous substrate. Exemestane, a androstenedione derivative, is an irreversible steroidal aromatase inhibitor. Exemestane is recognized by aromatase as an alternative substrate and converted into a reactive intermediate which binds irreversibly to the substrate-binding site, resulting in permanent inactivation of aromatase. This difference in interaction with aromatase has the potential to lead to divergent effects, with the potential for exemestane to provide an alternative ovulation induction therapy for women with PCOS/PMOS who have failed letrozole.

Letrozole is a reversible non-steroidal aromatase inhibitor, while exemestane is an irreversible steroidal aromatase inhibitor. Exemestane binds permanently to the aromatase enzyme, potentially leading to more sustained suppression of estrogen and a different hormonal profile than letrozole. Because of this mechanistic difference, direct dose equivalency is not established, and dose exploration is necessary.

To support the investigation of exemestane for ovulation induction in women with polycystic ovary syndrome/ polyendocrine metabolic ovarian syndrome (PCOS/PMOS), an Investigational New Drug (IND) application (#180400) has been submitted to and received by the U.S. Food and Drug Administration (FDA). Receipt of this IND permits the conduct of this clinical investigation under FDA oversight and confirms that the proposed study design, dosing strategy, and safety monitoring plan are acceptable for evaluation of exemestane in this investigational indication. All study procedures will be conducted in compliance with applicable FDA regulations, Good Clinical Practice (GCP) guidelines, and institutional review board (IRB) requirements.

This study looks to examine three exemestane dosing regimens:

• 25 mg for 5 days
• 25 mg for 10 days
• 50 mg for 5 days These doses are chosen to explore both dose intensity (25 vs. 50 mg) and duration of exposure (5 vs 10 days), similar to how letrozole is used in ovulation induction, typically 2.5-7.5 mg daily for 5 days.

Dose selection was constrained by the commercially available breast cancer formulations (25 mg and 50 mg), which necessitated evaluation at these dose levels. Within this framework, the study examines both dose intensity and duration of exposure, similar to established short course dosing strategies used with letrozole in ovulation induction. This study will use a randomized control trial to evaluate if exemestane will lead ovulation in women with infertility secondary to PCOS/PMOS. Using the Rotterdam Criteria, the study would include a small cohort of females aged 18-40 with a diagnosis of PCOS/PMOS with no other causes of infertility. Study participants would either undergo ovulation induction with exemestane at differing dose ranges or with placebo. The primary outcome would be ovulation, defined as midluteal serum progesterone concentration greater than or equal to 3 ng/mL. This pilot study will evaluate if exemestane leads to ovulation as measured by midluteal phase progesterone levels. Progesterone is a hormone produced by the corpus luteum following the release of an egg during ovulation. Its presence in the bloodstream, particularly at elevated levels, serves as a reliable indicator that ovulation has occurred. Measuring serum progesterone around day 21 of a typical menstrual cycle corresponds with the mid-luteal phase, when progesterone levels naturally peak. A threshold of ≥ 3 ng/mL is widely recognized in both clinical and research settings as a biochemical marker of ovulation. This method is minimally invasive, cost-effective, and broadly accessible, making it a practical and validated endpoint for evaluating the efficacy of ovulation induction agents.

Exemestane belongs to the class of medications known as aromatase inhibitors, the same class of medications as letrozole, and they prevent converting androgens into estrogen. This removes negative feedback on the hypothalamus resulting in increased GnRH pulses, which stimulates the pituitary to produce more FSH resulting in development of dominant follicles in the ovaries.

While letrozole is a reversible non-steroidal aromatase inhibitor that binds to the cytochrome P-450 component of the aromatase enzyme, exemestane is an irreversible steroidal aromatase inhibitor. Exemestane is recognized by aromatase as an alternative substrate and converted into a reactive intermediate which binds irreversibly to the substrate-binding site, resulting in permanent inactivation of aromatase. This difference in interaction with aromatase has the potential to lead to divergent effects, with the potential for exemestane to provide an alternative ovulation induction therapy for women with PCOS/PMOS who have failed letrozole.