Orlistat Plus Progestin for Fertility-Sparing Treatment of Endometrial Cancer or Atypical Hyperplasia

Background and rationale:

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and 14% to 25% of cases occur in women of reproductive age, many of whom wish to preserve fertility. Progestin is the first-line agent for fertility-sparing treatment of grade 1-2 endometrioid EC and atypical endometrial hyperplasia (AEH), with reported complete response (CR) rates up to 84%. However, approximately 30% of patients show primary or secondary progestin resistance, and loss or down-regulation of the progesterone receptor (PR) is a key mechanism. Obesity is both an independent risk factor for EC and associated with poor progestin response, while progestin itself commonly causes weight gain, creating a vicious cycle of obesity, reduced efficacy, and further weight gain.

Orlistat is an FDA-approved oral gastrointestinal lipase inhibitor widely used for weight management. Beyond weight loss, preclinical studies have shown antitumor activity across several cancer types through inhibition of fatty acid synthase (FASN). The research team previously established a lipid metabolism-FOXA2-PR transcriptional regulatory axis in EC (Liu et al., Oncogene 2025), demonstrating that orlistat stabilizes FOXA2 by inhibiting AKT phosphorylation, thereby up-regulating PR transcription and restoring progestin sensitivity in xenograft models. This trial is the first prospective randomized controlled trial to evaluate orlistat as a transcriptional sensitizer in fertility-sparing treatment of EC/AEH.

Study design:

This is a single-center, prospective, randomized, open-label, parallel-controlled trial conducted at Peking University People's Hospital. Forty-eight eligible patients with G1-G2 endometrioid EC or AEH who have low PR expression (positive cells 25% or less) and have not achieved CR after at least 3 months of first-line progestin therapy are randomized in a 1:1 ratio to the experimental group (progestin plus oral orlistat 120 mg three times daily) or the control group (progestin alone). High-potency progestin (medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day) is individualized by the investigator according to body weight, liver function, and prior dose. Randomization uses a computer-generated sequence (SAS 9.4) concealed in sequentially numbered sealed opaque envelopes.

The treatment period is 3 months, followed by 24 months of follow-up. Endometrial biopsy by hysteroscopy is performed every 3 months to evaluate histopathologic response, with paired tissue sampling for translational endpoints (PR, FOXA2, and phospho-FOXA2 immunohistochemistry; bulk RNA sequencing; and peripheral blood lipid metabolomics). The primary endpoint is the relative change in PR expression from baseline at 3 months. A pre-planned interim futility analysis using an O'Brien-Fleming alpha-spending function is performed when 50% of participants are enrolled, overseen by a Data and Safety Monitoring Board.

Inclusion criteria

• Histologically confirmed grade 1-2 endometrioid endometrial adenocarcinoma or atypical endometrial hyperplasia (AEH), independently confirmed by two senior pathologists
• Lesion confined to the endometrium on MRI or transvaginal ultrasound; FIGO (2009) stage IA without myometrial invasion (for G1, superficial invasion less than one half is allowed; G2 must have no myometrial invasion)
• Age 45 years or younger
• Received first-line MPA 250-500 mg/day or MA 160-320 mg/day for at least 3 months, with hysteroscopy plus curettage confirming failure to achieve complete response (persistent EC/AEH lesion)
• PR-positive cell percentage 25% or less and intensity grade 1 or lower (0 negative, 1 weak, 2 moderate, 3 strong), independently judged by two senior pathologists with a third adjudicating any disagreement
• BMI 24 kg/m2 or higher; no severe comorbidity, specifically ALT/AST 2.5x ULN or lower, serum creatinine 1.5x ULN or lower, and no history of active gastrointestinal bleeding
• No contraindication to progestin therapy or to pregnancy
• No evidence of distant metastasis on pelvic MRI and chest/abdominal CT
• Clearly wishes to preserve fertility and provides signed informed consent
• No use of orlistat or other lipase inhibitors within the past 6 months
• Willing and able to comply with follow-up at this hospital

Exclusion criteria

• Tumor invading more than one half of the myometrium; FIGO (2009) stage IB or higher
• Grade G3 or non-endometrioid histology (serous, clear cell, carcinosarcoma, etc.)
• Coexisting other endometrial cancer or other reproductive-system malignancy; coexisting breast cancer or other hormone-dependent tumor precluding progestin use
• Allergy to orlistat or any formulation component, or prior severe adverse reaction (including severe hepatic injury) to orlistat
• Chronic malabsorption syndrome (Crohn disease, celiac disease, short bowel syndrome) or cholestasis
• Concurrent use of ciclosporin, warfarin, levothyroxine, antiepileptics (carbamazepine, phenytoin), or amiodarone that interact significantly with orlistat and cannot be replaced or dose-adjusted
• Planned bariatric surgery (gastric bypass, sleeve gastrectomy, etc.) during the study
• Pregnancy or lactation; unwilling to use reliable contraception during the study and for 3 months after study completion
• Poor compliance or unable to complete 24 months of follow-up