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Randomized Phase II Trial of Ridaforolimus in Advanced Endometrial Carcinoma
Amit M Oza1, Sandro Pignata2, Andres Poveda2
1Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA. amit.oza@uhn.ca.
Purpose:
The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR inhibitors show clinical activity in endometrial cancer.
Patients And Methods:
An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review.
Results:
One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021).
Conclusion:
Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
Insights
Ridaforolimus demonstrated improved progression-free survival in advanced endometrial cancer patients but caused significant toxicity. Targeting the PI3K/Akt/mTOR pathway shows promise for future endometrial cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Endometrial cancer with recurrence or metastasis has a poor prognosis, necessitating novel therapeutic strategies.
- The mammalian target of rapamycin (mTOR) pathway is implicated in endometrial cancer progression and represents a potential therapeutic target.
- mTOR inhibitors have demonstrated clinical efficacy in endometrial cancer, warranting further investigation.
Purpose of the Study:
- To evaluate the efficacy and safety of oral ridaforolimus compared to standard treatments in patients with advanced endometrial cancer.
- To assess progression-free survival (PFS) as the primary endpoint in a phase II clinical trial.
Main Methods:
- An open-label, multicenter, randomized phase II trial compared oral ridaforolimus with progestin or investigator's choice chemotherapy.
- The study included 130 patients with metastatic or recurrent endometrial cancer who had progressed after prior chemotherapy.
- Progression-free survival (PFS) was assessed by independent radiologic review.
Main Results:
- Ridaforolimus showed a median PFS of 3.6 months versus 1.9 months for the comparator (hazard ratio, 0.53; P = .008).
- Higher rates of treatment discontinuation due to adverse events were observed with ridaforolimus (33%) compared to the comparator (6%).
- Stable disease was achieved in 35% of patients on ridaforolimus versus 17% on the comparator (P = .021).
Conclusions:
- Oral ridaforolimus exhibits encouraging activity in advanced endometrial cancer.
- Significant toxicity associated with ridaforolimus necessitates careful patient selection and monitoring.
- Inhibition of the PI3K/Akt/mTOR pathway is a promising therapeutic strategy for advanced endometrial cancer.
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