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Current Status and European Perspective on the Application of Actionable Biomarkers for Ovarian and Endometrial Cancers

Bernard Doger de Spéville, MD, PhD

Medical Oncology
START-Madrid, Early Phase Clinical Trials Unit
Hospital Fundación Jiménez Diaz
Madrid, Spain

Bernard Doger de Spéville, MD, PhD, has no relevant conflicts of interest to report.

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Prof Isabelle Ray-Coquard, MD, PhD

Professor of Department of Medical Oncology
Clinical Science Institute of the Léon Bérard Center
Lyon, France

Prof Isabelle Ray-Coquard, MD, PhD, has disclosed that she has received consulting fees from Amgen, AstraZeneca, Clovis, Deciphera, GlaxoSmithKline, Mersana, MSD, and Roche.

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Released: October 8, 2021

PARP inhibitors (eg, niraparib, olaparib with or without bevacizumab, and rucaparib) in ovarian cancer and anti–PD-1 immunotherapies (eg, dostarlimab and pembrolizumab) in endometrial cancer have shown significant improvement in responses and long-term survival outcomes based on data from large randomized clinical trials. Presently, BRCA and homologous recombination deficiency (HRD) status in ovarian cancer and DNA mismatch repair (MMR) and microsatellite instability (MSI) status in recurrent or advanced endometrial cancer are key to selecting PARP inhibitor–based and anti–PD-1–based therapies in these indications. In this commentary, Prof Isabelle Ray Coquard, MD, PhD, and Bernard Doger de Spéville, MD, PhD, discuss the European perspective on the use of actionable biomarkers for ovarian and endometrial cancers.

Ovarian Cancer

Isabelle Ray Coquard, MD, PhD:
At my institution, we have been using BRCA testing for several years now. In my current practice, we start with the BRCA somatic test and later move on to germline testing. But I know that some institutions have the possibility to do both tests in parallel. Consequently, there can be some variation from institution to institution for BRCA testing.

We now understand that HRD testing is essential for the selection of frontline maintenance therapy with olaparib plus bevacizumab based on data from the phase III PAOLA-1/ENGOT-ov25 trial, which compared olaparib plus bevacizumab vs placebo in patients including all comers. To learn more about the 2 subgroups of patients with HRD positive vs HRD-negative status, we have had free access to the Myriad myChoice test for close to 1 year now—until the end of 2021. In the near future, we anticipate that, with the European Network for Gynaecological Oncological Trial project, we will have access to other academic and commercial HRD tests as well. These tests will be validated on the PAOLA-1 tumor sample and I know that the same project is also anticipated with the PRIMA clinical trials tumor sample.

For you, Bernard, what is the current situation regarding molecular testing in Spain?

Bernard Doger de Spéville, MD, PhD:
Molecular testing for women with ovarian cancer in Spain is conducted very similarly to what you describe for France, but with a few variations. We also perform BRCA somatic testing for all patients at every institution. However, in some institutions like where I practice, BRCA germline testing is done in parallel with somatic testing, and other institutions do it sequentially. I am mostly dedicated to early phase clinical trials, and we are very lucky to also have access to next-generation sequencing, and all patients with good performance status may be considered for a clinical trial. Also at my institution, most patients will receive a FoundationOne medicine test, and we are able to capture results from loss of heterozygosity status (LOH) as well.

Prof Isabelle Ray Coquard, MD, PhD:
The big question for the future will be whether the LOH tests, or another like it, will be equivalent to what has been reported for the Myriad myChoice HRD testing in the PAOLA-1 and PRIMA trials. Based on the data presented at ESMO 2021 for the phase III NRG-GY004 study (NCT02446600) of olaparib with or without cediranib vs chemotherapy, LOH was not prognostic for progression-free survival benefit independent of BRCA status or predictive for activity for either experimental arm compared with chemotherapy. I think it will be important to look at the ATHENA trial (NCT03522246) of rucaparib and nivolumab as maintenance treatment following platinum-based chemotherapy to determine whether LOH could also be validated for first line. Presently, only Myriad myChoice HRD testing has validation to define the HRD positive population in first line.

Bernard Doger de Spéville, MD, PhD:
Yes, I agree with you. We don’t yet require these results to inform treatment for patients outside of a clinical trial. But we do need further information before we use it in daily practice.

Prof Isabelle Ray Coquard, MD, PhD:
A challenging question we currently face is what to do for patients who are resistant to PARP inhibitors, meaning patients experiencing disease progression while receiving a PARP inhibitor. Presently, our only options are to reintroduce chemotherapy in platinum sensitive relapse or to use surgery if the patient is a good candidate for surgery.

Bernard Doger de Spéville, MD, PhD:
In Spain, it is the same. We do not yet have any approved or reimbursed treatment beyond PARP inhibitor progression. Like in France, we do also need to rechallenge patients progressing on a PARP inhibitor with chemotherapy, surgery, or supportive care with radiation or ablation. We are eagerly waiting for the results from the phase III KEYLINK-001 trial of olaparib maintenance following carboplatin plus paclitaxel and pembrolizumab (NCT03740165); the phase III DUO-O trial of durvalumab plus chemotherapy and bevacizumab followed by maintenance durvalumab plus olaparib (NCT03737643); and the phase III NItCHE-MITO33 study of niraparib plus dostarlimab vs physician’s choice of chemotherapy in patients with recurrent, ovarian, fallopian tube, or primary peritoneal cancers who are not candidates for platinum retreatment (NCT04679064).

Prof Isabelle Ray Coquard, MD, PhD:
Important to note is the phase III OReO study evaluating olaparib rechallenge after ovarian cancer relapse to a PARP inhibitor. This trial opened an important door by showing positive results for reintroducing a PARP inhibitor in platinum-sensitive disease following relapse. This means that a number of these patients can experience benefit with PARP inhibitor reintroduction. The next challenge will be, for patients who respond to platinum based chemotherapy after PARP, to identify those who are the best candidate for a new maintenance with a PARP inhibitor because only between 15% and 20% of the patients who were rechallenged with olaparib in the OReO trial were progression free at 1 year.

Endometrial Cancer

Bernard Doger de Spéville, MD, PhD:
For advanced/recurrent MSI-stable endometrial cancer, the combination of pembrolizumab plus lenvatinib is not yet an option in daily practice in Spain. We are also limited by the lack of reimbursement for these therapies. For us, this is a very challenging population after we see progression after 1 previous line of platinum based chemotherapy. Our options are limited to rechallenging with other compounds of chemotherapy.

Prof Isabelle Ray Coquard, MD, PhD:
For us in France, we are in a similar situation as in Spain for advanced/recurrent MSI-stable endometrial cancer. However, we have the possibility to use dostarlimab in patients with MSI high/MMR-deficient recurrent or advanced endometrial cancer that has progressed on or after platinum-containing regimen. This has been very good news for our patients since the European Medicines Agency approved this agent in April 2021. And as you mention, the combination of lenvatinib plus pembrolizumab is not currently available to us, but we eagerly await for this combination to become available in Europe as well. I would say that, specifically, for the microsatellite-stable MMR-proficient population, where we know that immune therapy alone is not enough.

Bernard Doger de Spéville, MD, PhD:
Yes, I agree. And we will later have to consider MLF1 and novel combinations, such as PD 1 and 4 1BB, among others, that will enhance response to single-agent immunotherapy.

Your Thoughts
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