Advanced Endometrial Carcinoma: Treatment Pipeline

Future opportunities being explored in clinical trials that show promise in treating advanced endometrial cancer.

Robert L. Coleman, MD, FACOG, FACS: The relationship of the molecular biology of endometrial cancer and the opportunities based on available compounds, which continues to grow every day, is very optimistic and exciting. We have several trials that are focused largely on the combination or addition of immune checkpoint inhibitors to a mostly chemotherapy backbone for patients who have either recurrent or primarily metastatic disease.

One of these trials, LEAP-001, is trying to take on combination paclitaxel-carboplatin in that line of therapy for patients with advanced-stage or first recurrent endometrial cancer. Pembrolizumab and lenvatinib are being compared with paclitaxel and carboplatin. In the patients with deficient MMR [mismatch repair], we’re looking at single-agent pembrolizumab against chemotherapy as well. We’re using or leveraging the biology to move the field along.

One of the other new and exciting targets in endometrial cancer has been to address the frequent TP53 mutation that we see in our copy number high or uterine serous type tumors. We’re focused on looking at compounds that can address that genetic finding. The SIENDO trial is looking at a nuclear export inhibitor to assess whether we can add to chemotherapy as a maintenance strategy for this cohort of patients. We’re excited to see this alternative to the immune checkpoint space.

There are a number of exciting targets in endometrial cancer. It’s been one of the most explosive new areas of evaluation in gynecology because of the frequency of alterations, particularly in the PI3 kinase and MAP kinase signaling pathways, as well as the integrin pathways, that has now opened up a large number of new trials and concepts to try to provide new therapies for our patients with this disease.

A question I get frequently is whether the PARP drug class works in endometrial cancer. It’s a good question. Many of you who treat gynecological cancers know that PARP inhibitors have basically revolutionized our approach to ovarian cancer, with the drugs now approved in recurrent treatment, recurrent maintenance after platinum, and in the front line as maintenance treatment after index therapy. It’s completely painted across the landscape of ovarian cancer.

Because of the similarities that we’re seeing with copy number high endometrial cancer, the question was raised on whether this would apply as a potential treatment alternative in women with endometrial cancer. There has been interest in looking at this, and certainly in TCGA [The Cancer Genome Atlas program] data, we know that these tumors are found, although infrequently, with mutations in many of the genes that govern homologous recombination, including BRCA1, BRCA2, PALB2, RAD51C, RAD51D, RIF1, and BARD1. We’ve seen these cases appear in our endometrial cancer landscape, so it makes sense to consider it. The relationships directly between these mutations, which are overall infrequent, and the loss of heterozygosity, which we also use in ovarian cancer, isn’t so cleanly differentiated. Nevertheless, we have seen several trials that are evaluating the role of PARP inhibitors either alone or in combination in patients with recurrent metastatic disease across multiple different histologies.

We’ve seen some signal of activity, and there’s at least 1 trial trying to combine the PARP inhibitor with immune checkpoint inhibitors as a maintenance strategy for patients who have responded to chemotherapy. This is part of an ongoing clinical trial. We’re excited to see this potential opportunity to evaluate another class of drug in patients with this particular disease, and hopefully we’ll rewrite the treatment landscape for our patients.

Transcript edited for clarity.

Initial Presentation

  • A 64-year-old postmenopausal woman presented with abnormal uterine bleeding for about 2 months. She has two grown children, underwent menopause at 57 years of age, has no known family history of cancer.
  • PMH: BMI is 32, and she has hypertension that is controlled with medication
  • PE: Notable for large uterus and right lower quadrant abdominal tenderness on palpation

Clinical work-up

  • Endometrial biopsy: endometrioid adenocarcinoma, FIGO grade 1
  • Surgery: ELAP TAH BSO with bilateral pelvic node dissection
  • Pathology: grade 2 endometrioid adenocarcinoma, 18 negative pelvic nodes, invasive 2.1 cm of 2.3 cm myometrium
  • Molecular testing shows MSS, MMR proficient, and HER2-


  • Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
  • 14 months after completing radiotherapy, she presented with new RLE edema and right hydroureter
  • She then was treated with carboplatin/paclitaxel chemotherapy which was well tolerated
  • Nine months later the patient has disease relapse with metastases to the paraaortic lymph nodes and lung
  • She is now treated with lenvatinib/pembrolizumab
Related Videos
John Allan, MD, an expert on chronic lymphocytic leukemia