Panagiotis Konstantinopoulos, MD, PhD

Developing new therapeutic strategies for breast and gynecologic cancers.

Impact

There is significant unmet therapeutic need for the two most common gynecologic cancers in the United States, ovarian and endometrial. These cancers have genetic overlap with certain types of breast cancer driven by mutations in the BRCA genes. Breast cancer survivors are at risk for these cancers because of inherited high-risk BRCA mutations, rising incidence of endometrial cancer in the United States, and increased risk of endometrial cancer caused by certain breast cancer treatments such as tamoxifen. Poly (ADP-ribose) polymerase (PARP) inhibitors, which are approved for BRCA-induced cancer, are not beneficial to all patients and tumors that do eventually develop resistant to the treatment. Drs. Konstantinopoulos and Matulonis are developing combination therapies that may act synergistically to provide better treatment outcomes for patients with breast or ovarian cancers.

Progress Thus Far

Drs. Konstantinopoulos and Matulonis have multiple clinical trials in progress testing new treatment strategies. During the past year, the team reported several important clinical trial findings in gynecologic cancers. A phase 2 trial, RESOLVE, testing a three-drug combination (abemaciclib, letrozole, and metformin) in women with recurrent endometrial cancer showed promising results, with about one-third of patients responding to treatment, including some experiencing a complete response. A large phase 3 trial, EPIK-O, tested a combination of two targeted drugs, olaparib and alpelisib, in ovarian cancer that had stopped responding to chemotherapy. While the trial overall did not show a benefit compared to standard options, a subset of patients whose tumors had specific genetic changes did seem to benefit, pointing to future precision medicine approaches. Finally, results from a trial of the Wee1 inhibitor adavosertib in aggressive uterine serous cancer, ADAGIO, showed some anti-tumor activity, though side effects limited its tolerability.

What’s next

In the upcoming year, Drs. Konstantinopoulos and Matulonis will build from these findings to better personalize treatment for women with gynecologic cancers. Follow-up studies of the RESOLVE trial will explore how best to use the three-drug combination and identify which patients are most likely to benefit. Building on the results from the EPIK-O trial, the researchers will dig deeper into genetic testing to confirm which tumor subtypes respond to the olaparib and alpelisib combination, with the goal of designing future precision medicine trials. The team will continue to refine strategies for targeting Wee1 while reducing side effects for uterine serous cancer, as well as exploring new drug combinations.