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Molecularly targeted therapy is proving promising for endometrial cancer.

Not only are molecular tests able to group or split endometrial cancers into specific molecular groups, but the tests can also be utilized as biomarkers for other therapies, said Casey Cosgrove, MD, of the Ohio State University Comprehensive Cancer Center in Columbus.

For instance, he explained, the p53-mutated group of ovarian cancer has a higher percentage of HER2 amplifications, for which there is a new "exciting therapeutic option" with the antibody-drug conjugate trastuzumab deruxtecan (Enhertu).

In the DESTINY-PanTumor02 trial, trastuzumab deruxtecan had what Cosgrove called an "extraordinarily high" overall response rate of 85% in endometrial cancers that had HER2 3+ immunohistochemistry (IHC) and a "quite high" response rate of 58% in HER2-positive patients overall.

In April, the drug gained FDA approval for all solid tumors with IHC 3+ staining. "And so now not only are we able to have our endometrial cancers where we can classify the tumors better based off molecular features to provide more precise prognostic counseling for patients, but we're actually able to start translating some of these findings also to better therapeutic options," Cosgrove said.

Trastuzumab deruxtecan is now recommended in the National Comprehensive Cancer Network guidelines for HER2 IHC 2+ or 3+ endometrial cancer.

Immunotherapy

Immunotherapy has generally worked less well for the p53, or copy number, altered group, which has had the poorest outcomes of the four molecular groups, he noted. However, exploratory data from the showed that the addition of dostarlimab (Jemperli) to chemotherapy in the p53-mutated group actually had a hazard ratio for overall survival that was similar to that of the mismatch repair-deficient (dMMR) group. "So these patients are doing worse, but they are potentially getting a benefit from immunotherapy for reasons that we're still trying to identify and figure out," Cosgrove said.

RUBY led to the approval of dostarlimab in combination with chemotherapy as a frontline option for patients with advanced or recurrent endometrial cancer and dMMR or microsatellite instability-high tumors. Two other immune checkpoint inhibitors -- durvalumab (Imfinzi) and pembrolizumab (Keytruda) -- are also now approved with chemotherapy for treating advanced endometrial cancer. (Editor’s Note: In August, the to include use in combination with chemotherapy followed by use as monotherapy for adults with primary advanced or recurrent endometrial cancer regardless of dMMR or microsatellite instability status.)

With time, it will need to be sorted out how to mitigate immunotherapy complications, how to be able to predict better who's going to get an immunotherapy complication, and then how to best treat patients who progress through an immunotherapy, said Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute in Boston.

"How do we figure out for patients with mismatch repair-proficient cancers who's really going to benefit the most from the addition of an immunotherapy? Because checkpoint inhibitors are not non-toxic," Matulonis noted. "Most of the time the toxicities are manageable, but there are certain circumstances where the toxicities are life altering, and that can be adrenaline insufficiency, autoimmune-induced hepatitis, cardiac toxicities, pneumonitis, anything to do with the GI tract or colitis."

PARP Inhibitors

Gynecologic oncologists have gained experience with PARP inhibitors in ovarian cancer over the last several years, as the approximately 15% of epithelial ovarian cancer patients with a germline mutation in BRCA1 or 2 "by far, have the biggest and best responses to PARP inhibitors," Cosgrove noted, and the large group of tumors that have homologous recombination deficiency (HRD) also benefit.

"While endometrial and ovarian cancer are very different diseases, there are some molecular overlaps and there's some histologic overlap that made the community excited about maybe having the opportunity to utilize these PARP inhibitors for our endometrial cancer patients," Cosgrove said.

In the phase III DUO-E trial among advanced endometrial cancer patients getting chemotherapy, adding the immunotherapy agent durvalumab with or without the PARP inhibitor olaparib (Lynparza) showed significant progression-free survival benefit (HR 0.55 and 0.71, respectively, vs control).

"There seemed to be potentially some additive benefit for a PARP inhibitor," Cosgrove noted -- adding, though, that the trial "wasn't designed in a way where we can definitively say whether or not PARP inhibitors, or the immunotherapy, or the combination of those two are the main drivers of this."

FDA's recent approval of durvalumab did not include the addition of the PARP inhibitor.

In a small phase II trial, maintenance with the PARP inhibitor rucaparib (Rubraca) after first- or second-line chemotherapy improved progression-free survival (PFS) in patients with metastatic or recurrent endometrial cancer without immunotherapy.

However, while ovarian cancer has biomarkers of BRCA mutation and HRD to help sort out which patients have the best chance of benefiting from PARP inhibitors, the same has not yet been sorted out in endometrial cancer, Matulonis noted.

"And frankly, we've learned from ovarian cancer that PARP inhibitors have toxicities," she added. "They have toxicities of drop in blood counts, fatigue, and then importantly, risks of secondary leukemias and myelodysplastic syndrome. And then also what we've learned from ovarian cancer is that there may be resistance mechanisms set up by the PARP inhibitor to make that cancer less responsive to future therapy. Not 100% worked out, but certainly the phase III trials may suggest this."

"There's a lot to learn about the use of PARP inhibitors in endometrial cancer," said Matulonis. "I think the use of PARP inhibitors outside the context of a clinical trial is premature at this time in endometrial cancer."

Novel Avenues for Targeted Therapy

Novel antibody-drug conjugates are being developed beyond HER2 as well, Matulonis noted. Folate receptor alpha which is targeted in ovarian cancer by mirvetuximab soravtansine (Elahere), is a target that's also present on endometrial cancers.

"We're learning more about which histologic subtypes have it, which don't. But the bottom line is eventually we'll be able to check for these markers," Matulonis said. "So this is a very early field, but I think a very exciting one that will definitely benefit patients."

Wee1 inhibitors targeting cell cycle derangement are also being tried. Early phase studies have been promising in ovarian cancer. And because "replication stress is an entity that is really quite profound in endometrial cancers, there are trials ongoing of single-agent Wee1 inhibitors or in combinations," Matulonis said.

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