When diagnosed and treated in its early stages, endometrial cancer is largely curable. However, for the 10 to 15 percent of patients diagnosed with late-stage disease, standard therapy does not lead to a cure.
Researchers at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) are seeking to improve outcomes for these patients through a series of clinical trials they are leading. The trials are among the first in the country to target the advanced form of the cancer that develops in the lining of the uterus.
“Patients with late-stage endometrial cancer have few, if any, options,” said Panos Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology. “They typically have exhausted multiple prior lines of standard treatments and need novel therapies.”
According to Dr. Konstantinopoulos, recent advances in understanding both the genetic drivers behind endometrial cancer and the disease’s progression are allowing researchers to specifically target the appropriate genes and repair pathways with novel agents. He added that immunotherapies hold particular promise, given their good results in treating patients with melanoma, lung cancer and kidney cancer.
One of the trials led by Dr. Konstantinopoulos is studying a therapy that combines an immune checkpoint inhibitor called avelumab and a PARP inhibitor called talazoparib. In a previous trial, avelumab was found to be effective in patients with endometrial cancer with “microsatellite instability” (MSI), or a high tendency to mutate. However, it was largely inactive in the much more common “microsatellite stable” (MSS) form of the disease.
The current trial will explore whether pairing avelumab with a PARP inhibitor is more effective in patients with MSS disease. It is the first time a combination of PARP inhibitors and immunotherapy is being used to treat endometrial cancer.
Another trial led by Dr. 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. 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.
Two additional Phase II trials, either recently opened or opening shortly at DF/BWCC include:
- A trial that combines the checkpoint inhibitor pembrolizumab with an antibody-drug conjugate called mirvetuximab. The trial, led by Jennifer L. Veneris, MD, PhD, of the Gynecologic Oncology program at DF/BWCC, will examine the effectiveness of the combination in patients with MSS endometrial cancer whose tumor cells have a folate receptor α on their surface.
- A trial led by Joyce F. Liu, MD, MPH, director of clinical research for DF/BWCC’s Gynecologic Oncology program, of the targeted therapy AZD1775 in patients with high-grade serous uterine cancer, which accounts for 10 to 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 Dr. Liu and Ursula Matulonis, MD, chief of the Gynecologic Oncology program, 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.
The clinical trials are collaborative and bring together various centers of expertise throughout the organization.
“Dana-Farber faculty are working closely with the Brigham and Women’s Hospital Department of Pathology and Division of Surgical Oncology throughout these trials,” Dr. Konstantinopoulos noted. “We also are taking advantage of the Brigham’s oncology panel in studying DNA molecular profiles to help us better understand the genetic mutations that exist in endometrial cancer.”
“These trials are attracting patients from across the United States, and they’re great examples of DF/BWCC’s leadership in the development of gynecologic-oncology approaches that don’t exist anywhere else,” Dr. Konstantinopoulos concluded. “Our goal is for these new regimens to gain FDA approval so they can become the standard of care available to all patients with late-stage endometrial cancer.”