In recent years, there has been a dearth of clinical trials studying new approaches to how endometrial cancer, which forms in the lining of the uterus, is treated. That is changing rapidly, however, as basic research into the disease spurs the testing of novel drugs and drug combinations. A host of clinical trials—including four led by Dana-Farber investigators—are now being launched.
The trials are especially geared to the 10 to 15 percent of patients with endometrial cancer who are diagnosed with an advanced stage of the disease. These patients almost always relapse after receiving standard therapy, at which point the disease generally can’t be cured with existing drugs.
“For the 90 percent of patients with early-stage disease, standard therapy is curative. For patients 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.
Dana-Farber research into the biology of endometrial cancer suggested potentially promising new ways of attacking the disease with targeted therapies as well as immunotherapies. The four new phase II trials, either recently opened or opening shortly, include:
- A trial led by Konstantinopoulos that combines an immune checkpoint inhibitor called avelumab and a PARP inhibitor called talazoparib. (Checkpoint inhibitors clear the way for an immune system attack on cancer; PARP inhibitors undermine cancer cells by impeding their ability to repair damaged DNA.) In a previous trial, avelumab was very effective in patients with endometrial cancer with “microsatellite instability” (MSI)—a high tendency to mutate—but was largely inactive in the much more common “microsatellite stable” (MSS) form of the disease. The trial will explore whether pairing avelumab with a PARP inhibitor is more effective in patients with MSS disease.
- A trial that combines the checkpoint inhibitor pembrolizumab with an antibody-drug conjugate called mirvetuximab. (Pembrolizumab targets an immune checkpoint protein called PD-1; mirvetuximab joins an antibody to a drug molecule that targets a key structure in fast-dividing cancer cells.) The trial, led by Jennifer Veneris, MD, PhD, of the Gynecologic Oncology program at Dana-Farber, will examine the effectiveness of the combination in patients with MSS endometrial cancer whose tumor cells have a folate receptor α on their surface.
- Another trial, led by Konstantinopoulos, will test a combination of the targeted drug abemaciclib, a new drug compound called LY3023414, and hormonal therapy in patients with high-risk endometrial cancer. (LY3023414 targets a cancer cell enzyme called PI 3-kinase; abemaciclib interferes with a key phase of the cell cycle.) Between 70 and 90 percent of endometrial cancers are fueled by the hormone estrogen and initially respond to hormone-blocking therapy, but eventually relapse. By adding abemaciclib and LY3023414, which strike two parts of the same molecular pathway, to hormone-blocking therapy, investigators hope to overcome the problem of drug resistance.
- A trial led by Joyce Liu, MD, MPH, director of clinical research in the Division of Gynecologic Oncology at Dana-Farber, of the targeted therapy AZD1775 inpatients with high-grade serous uterine cancer, which accounts for 10-15 percent of endometrial cancers. Such cancers are aggressive and usually recur after standard therapy. The trial, which recently opened, is based on research led by Liu and Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber, showing that AZD1775 has activity in patient-derived models of high-grade serous ovarian cancer that share several genetic features with high-grade serous endometrial cancer.
Each of the trials addresses a shortcoming of standard therapy or a problem identified in previous trials of novel drugs. The first two trials, for example, seek to overcome the fact that immunotherapies haven’t worked well in patients with MSS disease. The third tackles the problem of resistance to hormone therapies, and the fourth targets a specific subtype of endothelial cancer.
Today’s Standard Treatment
Treatment for endometrial cancer is determined by the stage of the disease—the extent of its development—when diagnosed and by other health conditions that patients may have.
Women with stage I cancers, which haven’t spread beyond the uterus, are generally treated with surgery. If the tumor is high-grade, or aggressive, doctors are likely to recommend radiation therapy and/or chemotherapy after surgery.
Treatment for stage II endometrial cancer, which has spread to the connective tissue of the cervix but remains within the uterus, involves surgery—including an examination of nearby lymph nodes for signs of cancer that has spread—and radiation therapy. Chemotherapy may also be needed for certain aggressive subtypes of endometrial cancer.
The extent and sequence of these therapies varies depending on the extent and grade of the cancer and the patient’s overall health.
Treatment for stage III endometrial cancers, which have spread outside the uterus, may involve a radical hysterectomy plus the removal of both ovaries and fallopian tubes plus radiation therapy and/or chemotherapy depending on where and how far the cancer has spread. More aggressive tumors may entail more extensive surgeries.
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. 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 for a time.
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. Women with more extensive recurrences are treated with the same approach as those with stage IV endometrial cancer.