Trials Open New Avenues of Endometrial Cancer Treatment

A new generation of drugs and drug combinations is changing the outlook for patients with endometrial cancer. The results of the first clinical trials of the new therapies were so promising that they’ve led researchers to launch follow-up trials to explore the potential for even better outcomes. 

The trials are geared to patients diagnosed with an advanced stage of the cancer and those whose cancer recurs. 

“Patients with early-stage disease can often be cured with standard therapy. For those with later-stage disease, we urgently need novel treatments,” says Panos Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology at Dana-Farber’s Susan F. Smith Center for Women’s Cancers. 

The new therapies represent a range of strategies for attacking cancer.  They include immunotherapies, which harness the cancer-fighting abilities of the immune system, targeted therapies that interfere with specific cancer-related proteins, and antibody-drug conjugates, which deliver powerful chemotherapy agents directly to tumor cells.   

Here are the results of four recent Dana-Farber-led clinical trials of endometrial cancer therapies – and a look at the newly opened trials that are building on those results. 

1. In a trial of a combination of the drug avelumab and talazoparib, 11% of patients responded to the regimen and 25% had a clinical benefit, researchers found. Avelumab is an immunotherapy agent known as an immune checkpoint inhibitor, which unleashes an immune system attack on cancer; talazoparib is a targeted therapy known as a PARP inhibitor, which impedes cancer cells’ ability to repair damaged DNA.  

–> Follow-up trial: Researchers are currently developing a trial of avelumab plus an inhibitor of the ATR protein, which helps cells sense and repair damaged DNA. 

2. A trial of the targeted drugs abemaciclib and letrozole plus hormonal therapy in patients with recurrent endometrial cancer driven by the hormone estrogen found that 30% of participants responded to the combination therapy. Letrozole decreases the amount of estrogen made by the body; abemaciclib interferes with a key phase of the cell cycle. The results of this study led to the addition of this regimen to the National Comprehensive Cancer Network treatment guidelines for uterine cancer. 

–> Follow-Up Trials:  A soon-to-open trial will compare the combination of abemaciclib and letrozole versus pembrolizumab as maintenance therapy after chemotherapy plus pembrolizumab in patients with advanced or recurrent endometrial cancer that is fueled by estrogen and is able to correct certain mistakes in DNA. Another trial that will open in 2024 will test the addition of the eIF4A inhibitor zotatin, which inhibits certain key proteins and may add to the anti-cancer activity of abemaciclib and letrozole. 

3. In a trial of the targeted therapy adavosertib in patients with recurrent uterine serous carcinoma, a subtype of endometrial cancer, 29% of patients responded to the treatment and 47% were free of cancer progression six months after being treated. Adavosertib targets an enzyme known as Wee1, which controls key aspects of cell division. 

–> Follow-Up Trials: A soon-to-open trial of a Wee1-inhibiting drug called azenosertib in women with recurrent or persistent uterine serous carcinoma. 

4. A trial of a combination of the checkpoint inhibitor pembrolizumab and mirvetuximab, an antibody-drug conjugate, found that the regimen was active in patients with a difficult-to-treat form of serous endometrial cancer known as folate receptor-α positive recurrent microsatellite stable/mismatch repair proficient. In a presentation at the 2024 Annual Meeting of the American Association for Cancer Research, investigators reported that tumors were reduced in six of the first 16 patients treated. 

More to come 

Dana-Farber investigators have opened or are about to open a range of other new trials for patients with endometrial cancer, including: 

• A trial (National Clinical Trial (NCT) 05579366) of an antibody-drug conjugate called PRO1184 that targets folate receptor alpha, a structure heavily expressed on many types of cancer cells, including endometrial. 
• A phase 1 trial (NCT 04585958) testing the antibody-drug conjugate trastuzumab deruxtecan plus the PARP inhibitor olaparib in endometrial and other cancers with high levels of the HER2 protein. This trial is temporarily closed but will reopen with higher dose levels of the agents. 
• The EndoMAP (NCT 04486352) trial, which is testing several targeted agents with or without the immune checkpoint inhibitor atezolizumab in patients with recurrent or persistent endometrial cancer. Participants have their tumor tissue genetically profiled and are then placed in a treatment group based on the profiling results. 
• The ARTIST trial (NCT 05798611) of ART0380, an agent that targets the cell protein ART, which helps detect DNA damage. It’s open to patients with recurrent endometrial cancer and some patients with advanced solid tumors or metastatic cancer. 
• A trial (NCT 06003231) of the antibody-drug conjugate disitamab vedotin in patients with endometrial cancer or certain other solid tumors that express the HER2 protein and have metastasized or cannot be surgically removed. 

Today’s standard treatment 

Treatment for endometrial cancer is determined by the stage of the disease (the extent of its development) at diagnosis and its grade and histology. Grade and histology are based on the tumor cells’ appearance under a microscope. High-grade tumors, which have highly abnormal-looking cells, tend to be more aggressive. Low-grade tumors, with more normal-looking cells, are usually less aggressive. 

Stage I endometrial cancers are confined to the main body of the uterus or have grown into the myometrium, the muscular wall of the uterus. Stage II cancers have spread to the connective tissue of the cervix but remain within the uterus. 

Patients with stage I endometrial cancer that are histologically low-risk are generally treated with surgery. If the tumor is high-risk, doctors are likely to recommend radiation therapy and/or chemotherapy after surgery. Certain histological types of endometrial cancer, such as clear cell, carcinosarcoma, and serous types, may require treatment after surgery even if diagnosed at an early stage. 

Treatment for stage II endometrial cancer involves surgery, including an examination of nearby lymph nodes for signs of cancer that has spread, plus radiation therapy. Chemotherapy may also be needed for certain aggressive histological subtypes, including serous, carcinosarcoma, and clear cell endometrial cancers. 

The extent and sequence of these therapies varies depending on the extent and grade of the cancer and the patient’s overall health. The use of radiation therapy, for example, depends on a variety of factors and is decided on a case-by-case basis. 

Treatment for stage III endometrial cancers, which have spread outside the uterus and cervix, may involve a radical hysterectomy plus the removal of both ovaries and fallopian tubes followed by radiation therapy and, if necessary, chemotherapy and sometimes immunotherapy. 

Most stage IV endometrial cancers, which have grown inside the bladder or bowel or outside the pelvis, have spread too far to be entirely removed by surgery. Patients may still undergo a hysterectomy and removal of the fallopian tubes and ovaries to prevent excessive bleeding. Radiation therapy may also be used for this purpose. The type of endometrial cancer and certain markers dictate the type of systemic therapy used. Hormone-blocking therapy may be used to stall the growth of cancer cells in other parts of the body, but aggressive cancers not driven by hormones are unlikely to respond to such drugs. Some patients with advanced endometrial cancer benefit from chemotherapy with or without immunotherapy for a time. 

For patients with stage III or IV endometrial serous cancer, treatment may also include trastuzumab, a drug that targets the HER2 protein on tumor cells. 

For patients whose cancer returns after initial therapy, treatment reflects the amount and location of the cancer. If the recurrence is local, such as in the pelvis, surgery, sometimes followed by radiation therapy, may be used.  For distant recurrences, surgery and/or radiation therapy may be used when the cancer is confined to a few small areas. Patients with more extensive recurrences are treated with the same approach as those with stage IV endometrial cancer. Systemic therapy is a very important part of treatment for relapsed or recurrent cancer, and the type of endometrial cancer, cell-surface biomarkers, and the genetics of the cancer all drive treatment decisions. 

Physician-researchers are currently exploring how best to integrate immunotherapy into endometrial cancer treatment for patients with more advanced forms of the disease, but these agents are very active against mismatch repair-deficient endometrial cancer. 

About the Medical Reviewer

Ursula A. Matulonis, MD is Chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. She is the first recipient of the Brock-Wilson Family Chair at the Dana-Farber Cancer Institute. She co-leads the Gynecologic Cancer Program within the Dana-Farber/Harvard Cancer Center and the Ovarian Cancer Specialized Program in Research Excellence (SPORE) grant from the National Cancer Institute. Her research focuses on developing new targeted therapies for gynecologic malignancies, with a specific interest in ovarian cancer and endometrial cancer.

Dr. Matulonis has led several PARP inhibitor, anti-angiogenic agent, immunotherapy, and combination trials for ovarian cancer in the United States and internationally. Dr. Matulonis serves on the Massachusetts Ovarian Cancer Task Force, chairs the Gyn subcommittee of the Alliance cooperative group, and the Scientific Advisory Board for the Ovarian Cancer Research Alliance, the Rivkin Foundation, the Clearity Foundation, and Overcome. She has received the Dana-Farber Dennis Thompson Compassionate Care Scholar award, the Lee M. Nadler "Extra Mile" Award, the Clearity Foundation award, the Zakim Award at Dana-Farber for patient advocacy, and recently in 2020, the Albany Medical College Alumni Association Distinguished Alumna Award. She has been named one of Boston's Best Physicians in Medical Oncology by Boston Magazine numerous times. Dr. Matulonis is also a recipient of grant funding from the Breast Cancer Research Foundation examining differences between ovarian cancer, endometrial cancer and breast cancer.

After receiving her MD from Albany Medical College, she completed an internship and residency at the University of Pittsburgh, followed by a medical oncology fellowship at Dana-Farber Cancer Institute in Boston, MA.