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Current Challenges in the Management of Endometrial and Ovarian Cancers

Jubilee Brown, MD

Professor and Division Director
Gynecologic Oncology
Levine Cancer Institute, Atrium Health
Charlotte, North Carolina

Jubilee Brown, MD, has disclosed that she has received funds for research support from GlaxoSmithKline, Olympus, and Tesaro.

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Ursula Matulonis, MD

Chief, Division of Gynecologic Oncology
Brock-Wilson Faculty Chair
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Boston, Massachusetts

Ursula Matulonis, MD, has disclosed that she has received consulting fees from GlaxoSmithKline, Merck, NextCure, and Novartis.

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Released: May 3, 2021

Endometrial and ovarian cancers are 2 common gynecologic malignancies affecting women worldwide. Despite progress in the past decade, challenges remain when managing these diseases. In this commentary, Jubilee Brown, MD, and Ursula Matulonis, MD, discuss some of the key challenges regarding the use of immunotherapy in endometrial cancer and the use of PARP inhibitors for ovarian cancer, including strategies on how to address them.

Endometrial Cancer

Jubilee Brown, MD:
Historically, we have had a dearth of available treatments for patients with endometrial cancer. Until recently, we basically only had platinum-based chemotherapy with carboplatin and paclitaxel. Now we are able to reclassify endometrial tumors into microsatellite instability (MSI)–high tumors and DNA mismatch repair–deficient (dMMR) tumors and identify patients likely to respond to single-agent immunotherapy or immunotherapy in combination other agents. Studies like KEYNOTE‑775, evaluating lenvatinib plus pembrolizumab vs single-agent chemotherapy, and the phase I GARNET trial, evaluating dostarlimab, an anti–PD-1 monoclonal antibody, in advanced endometrial cancer are really going to inform how we treat patients with endometrial cancer, especially now that dostarlimab is approved by the FDA for dMMR recurrent or advanced endometrial cancers, adding to available options for our patients.

Ursula Matulonis, MD:
Dr. Brown, in patients with MSI-high tumors receiving single-agent pembrolizumab, based on data from the KEYNOTE-158 clinical trial, after receiving 2 years of treatment, do you stop or do you continue?

Jubilee Brown, MD:
I have continued pembrolizumab after the 2 years as long as the patient can tolerate it. Do you?

Ursula Matulonis, MD:
I think it depends, but I think that is not an unreasonable answer, especially if she is doing well and she may have disease that is still present. I usually talk to my patients about the KEYNOTE-158 trial and the cutoff at 2 years and sometimes they want to stop. However, I continue to check their CT every 3‑6 months or so.

Data from the KEYNOTE‑775 trial was recently presented at the virtual SGO 2021 meeting and investigators showed improved responses (overall response rate: 31.9% vs 14.7%) and median progression-free survival (6.6 vs 3.8 months) for lenvatinib plus pembrolizumab compared with single-agent chemotherapy (doxorubicin or paclitaxel) in patients with advanced/recurrent endometrial cancer without MSI-high or dMMR status. However, lenvatinib plus pembrolizumab was associated with increased toxicity including grade ≥3 hypertension (37.9% vs 2.3%) and diarrhea (7.6% vs 2.1%).

Dr. Brown, would you care to comment on some of the challenges from the KEYNOTE‑775 study, including with the lenvatinib dosing?

Jubilee Brown, MD:
The adverse events associated with the lenvatinib plus pembrolizumab combination in KEYNOTE-775 merit some special considerations. With this regimen, it is important to educate patients to monitor their blood pressures at home and to know when to take antihypertensive medication (hydralazine) and when to call their healthcare provider. Many of our patients may already have underlying hypertension, which adds to the challenge of administering this treatment. And we also have to manage their ensuing hypertension as well. It is not always an easy combination to give and further experience with this regimen will help guide us on the appropriate starting dose of lenvatinib.

Ursula Matulonis, MD:
That makes sense. And for patients who progress with lenvatinib plus pembrolizumab, how do you treat them at that point?

Jubilee Brown, MD:
It depends on where the tumor is located, and if you have an isolated pulmonary metastasis, you can even consider surgery or potentially hormonal therapy for small-volume pulmonary metastases. Another option would be a clinical trial and potentially also looking at molecular profiling to further explore the possibility for targeted therapy.

Estrogen Receptor–Positive Tumors

Ursula Matulonis, MD:
Let’s switch things over to estrogen receptor (ER)–positive endometrial cancer.

For this group of patients, I use megestrol acetate alone or tamoxifen alternating with megestrol acetate or an aromatase inhibitor, depending on the individual patient. Aromatase inhibitors are probably my least favorite choice because of the lack of data. Moreover, giving megestrol acetate can be a challenge because it makes patients eat more and they gain weight, it can increase hypertension, and it may also worsen diabetes. CDK4/6 inhibitors are some of the emerging treatments that we may be able to offer to patients with ER-positive endometrial cancer, and a phase II trial of abemaciclib plus letrozole is currently recruiting (NCT03675893). I am excited to see what the data will show in patients with ER-positive disease from that study.

Jubilee Brown, MD:
Dr. Matulonis, what do you think are the current challenges in HER2‑positive serous endometrial cancer?

Ursula Matulonis, MD:
For patients with advanced serous endometrial cancer who are HER2-positive by immunohistochemistry, I would add trastuzumab to carboplatin and paclitaxel, and once cycles of carboplatin and paclitaxel are completed, I continue with trastuzumab maintenance until progression. The key thing there is to check echocardiograms every 3 months because of the risk of cardiac toxicity with this treatment.

Jubilee Brown, MD:
I also think those patients with serous endometrial cancer could potentially benefit from immunotherapy. However, since that is not how it has been evaluated and approved, like you, I also proceed with combination chemotherapy, but if it doesn’t work all the way, I hold out great hope for immunotherapy.

Ovarian Cancer

Ursula Matulonis, MD:
Dr. Brown, what are some of the current challenges in the management of ovarian cancer?

Jubilee Brown, MD:
For patients who have confirmed germline and/or somatic mutations on DNA repair genes, we have good treatment options with platinum-based chemotherapy and PARP inhibitors as frontline maintenance based on data from the PRIMA, SOLO-1, and PAOLA-1 trials. I think an unmet need exists in patients who relapse while receiving PARP inhibitors and those with BRCA mutations where upfront chemotherapy and PARP inhibitor do not work. What to do there and why is that the case? Is it always a reversion mutation or is there something else and how do we exploit that therapeutically?

Ursula Matulonis, MD:
I agree that for newly diagnosed patients with BRCA mutations, the use of a PARP inhibitor is critical, but for the patients with homologous recombination–proficient disease, there is clearly an unmet need. In patients with recurrent disease, I think immunotherapy has been disappointing both as single agents or in combinations (JAVELIN Ovarian 200) and in frontline in combination with chemotherapy (JAVELIN Ovarian 100) and bevacizumab containing therapy (IMagyn050), all of which have been negative studies.

I think another challenge in relapsed/recurrent ovarian cancer is lack of useful biomarkers for patients who do not have a BRCA1/2 mutation and who currently have limited treatment options.

Jubilee Brown, MD:
I agree. An illustrative example of that are patients with clear‑cell carcinomas who may have a great response with immunotherapy, but where PD-L1 testing is not really predictive. The lack of correlation between PD-1/PD-L1–positive status in ovarian cancer can be very frustrating.

Ursula Matulonis, MD:
I agree. In KEYNOTE‑100, evaluating pembrolizumab monotherapy in recurrent ovarian cancer, we also looked at potential biomarkers of tumor mutation burden and response with immunotherapy and results were inconclusive.

Jubilee Brown, MD:
Looking at all these challenges that we face with ovarian cancer, what is your opinion of the phase II OPAL trial evaluating bevacizumab, dostarlimab, and niraparib in recurrent ovarian cancer (which is taking all of our most exciting drugs and using them together)?

Ursula Matulonis, MD:
The study enrolled patients with high‑grade serous recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were also platinum resistant after ≥4 cycles of therapy and most were BRCA wild type. The response rate was 17.9%. I am also an investigator on that study and I have had 2 patients who are still on study. One of my patients has been on for more than 1 year, and another patient with stable disease recently had to come off trial because of arthritic problems and weight loss related to dostarlimab. So, I have rose‑colored glasses looking at this trial because of my own 2 patients, but the bottom line is 18% response rate. And that is using 3 different drugs, which shows you that these patients are a true challenge.

Jubilee Brown, MD:
I agree, and I think that if we can get to stable disease, that is also a good thing. Considering the number of patients who achieved stable disease, the clinical benefit rate in OPAL was approximately 77%.

Ursula Matulonis, MD:
I think that another ongoing challenge with these treatments in ovarian cancer are adverse events, particularly in the combination of bevacizumab and niraparib, both of which can cause hypertension. We saw this in the OPAL and OVARIO trials presented by Hardesty and colleagues at SGO 2021. In OVARIO, hypertension was significant, with grade ≥3 hypertension reported in 27% of patients. In addition, patients have to be diligent about checking their blood pressure.

Financial Toxicities

Jubilee Brown, MD:
Finally, cost toxicity is really important for our patients, particularly for PARP inhibitors, and many of the manufacturers have great patient resources to help patients along the way. But the cost of these novel therapies remains a challenge when caring for patients with ovarian cancer.

Ursula Matulonis, MD:
I agree. I think with the 3 PARP inhibitors, there is market competition, which helps reduce some of the cost, and as you said, manufacturers really do have quite robust patient assistance programs.

Your Thoughts?
How do you currently address treatment challenges in patients with endometrial and/or ovarian cancer? Do you currently use novel immunotherapy as single agents or in combinations for endometrial cancer and PARP inhibitors for ovarian cancer? Answer the polling question and join the conversation by posting a comment in the discussion section below.

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