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2022 ESGO Congress: Experts Discuss HRD Testing, PARP Inhibitors in Recurrent Ovarian Cancer, and QoL in Nonepithelial Ovarian Cancer

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: consultant/advisor/speaker: AstraZeneca, Clovis, GlaxoSmithKline, MSD.

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Ignace Vergote, MD, PhD

Professor Em. of Department of Obstetrics and Gynecologic Oncology
University Hospitals Leuven Belgium

Ignace Vergote, MD, PhD: consultant/advisor/speaker: Agenus, Akesobio, AstraZeneca, Bristol-Myers Squibb, Deciphera, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Immunogen, Jazz, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis; researcher: Amgen, Roche, Oncoinvent AS.

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Released: December 2, 2022

Key Takeaways

  • Three academic-developed homologous repair deficiency tests are now available in Europe with high concordance with Myriad myChoice and lower failure rates: Geneva, NOGGO-GIS, and Leuven.
  • In ARIEL3, an overall survival benefit was not observed with maintenance rucaparib vs placebo following response to platinum-based chemotherapy, but progression-free survival benefit from primary analyses was maintained through subsequent lines of therapy.
  • In the GINECO VIVROVAIRE study, nonepithelial ovarian cancer survivors reported similar fatigue and global quality-of-life scores 6 years after treatment with bleomycin, etoposide, and platinum chemotherapy vs healthy volunteers but reported more premature menopause, late-onset adverse events of cognition, neurotoxicity, and sexual difficulties.

In this commentary, Ignace Vergote, MD, PhD, from University Hospitals Leuven in Leuven, Belgium, and Isabelle Ray-Coquard, MD, PhD, from the Clinical Science Institute of the Léon Bérard Center in Lyon, France, discuss studies presented at the European Society of Gynaecological Oncology (ESGO) 2022 Congress in Berlin, Germany, including findings from new laboratory-developed tests for homologous repair deficiency (HRD) in ovarian cancer, emerging data for PARP inhibitors in recurrent ovarian cancer, and quality-of-life (QoL) outcomes for women with nonepithelial ovarian cancer following treatment with bleomycin, etoposide, and platinum (BEP) chemotherapy for germ-cell tumors (GCTs) and sex cord–stromal tumors (SCSTs).

The Geneva Test

Ignace Vergote, MD, PhD:
HRD testing is increasingly required to guide the use of PARP inhibitors in treating patients with ovarian cancer, especially in the first-line setting. However, current testing modalities are plagued by high failure rates and limited accessibility. The ENGOT HRD European Initiative is developing new HRD tests based on samples from the phase III PAOLA-1 trial, which randomized patients with advanced ovarian cancer to receive frontline therapy with bevacizumab plus either the PARP inhibitor olaparib or a placebo. In this study, a genomic instability score (GIS) was generated for all patients using the Myriad myChoice next-generation sequencing (NGS) assay for HRD. Remaining samples were sufficient to develop additional academic-developed HRD tests, and 2 of these tests were presented at the 2022 ESGO Congress.

Christinat and colleagues presented results from a study of the Geneva HRD test, which used DNA samples and the Geneva University Hospitals OncoScan assay to determine copy number variation. This test does not use loss of heterozygosity (LOH) or telomeric allelic imbalance (TAI) like the Myriad myChoice assay and instead focuses solely on large-scale state transitions in chromosomes. The Geneva test is far less costly than Myriad myChoice (~€350 vs ~€5000), but does not detect BRCA mutations or other homologous recombination repair (HRR) mutations. In this presentation, there was quite good concordance for both positivity and negativity compared with the Myriad myChoice GIS, including similar progression-free survival (PFS) HRs for olaparib vs placebo (HR: 0.41). Of note, even after patients with BRCA mutations were excluded, the HR for HRD positive vs negative in the BRCA wild-type group remained very similar to the Myriad myChoice results. In addition, there was a higher positivity rate and lower failure rate for the Geneva test, particularly in BRCA wild-type tumors. A caveat is that although these are very promising data, further clinical testing is warranted to fully validate this assay.


Ignace Vergote, MD, PhD:
The second new academic HRD test based on PAOLA-1 samples is the NOGGO-GIS assay. Unlike the Geneva test, the NOGGO-GIS HRD assay uses NGS to detect HRR genes (eg, RAD51, PALB) and relevant mutations for patients who are HRD positive (eg, HER2 amplification, mutations in KRAS, BRAF, PIK3C, EGFR) and can evaluate LOH. Also this HRD test is robust with a low failure rate. As discussed, the Myriad myChoice assay determines the HRD phenotype using LOH, TAI, and large-scale transitions to generate a GIS, whereas the NOGGO-GIS test generates a score based on partial LOH and proliferating cell nuclear antigen. Like the Geneva test, the overall survival (OS) curves and HRs with NOGGO-GIS were similar to those seen with the Myriad myChoice test in both the HRD-positive and HRD-unknown groups.

A third new HRD test is the “Leuven” test, which also was developed as part of the ENGOT HRD initiative and was already presented during the Society of Gynecologic Oncology meeting in March 2022. This assay uses capture-based targeted resequencing of approximately 90,000 genome-wide small nucleotide polymorphisms and coding exons of BRCA1, BRCA2, RAD51C, RAD51D, PALB2, BLM, BARD1, BRIP1, and TP53. Like the Geneva and NOGGO-GIS assays, results are similar to those with Myriad myChoice and less expensive. I am encouraged that there are now multiple tests available that can predict PFS and OS with PARP inhibitors in first-line ovarian cancer like the Myriad myChoice test.

Maintenance Therapy

Isabelle Ray-Coquard, MD, PhD:
In PAOLA-1, olaparib was given in combination with bevacizumab as maintenance treatment. Do you think that in the future we should determine if these tests also are useful to guide ovarian cancer maintenance/treatment with PARP inhibitor monotherapy?

Ignace Vergote, MD, PhD:
Yes. In other trials, such as PRIMA, VELIA, and ATHENA, there was a clearer benefit for maintenance with PARP inhibitor monotherapy in patients with HRD-positive ovarian cancer vs HRD-negative cancer, regardless of whether a BRCA mutation was present. As demonstrated in PAOLA-1, the late OS survival data make me concerned about giving patients who are HRD negative a PARP inhibitor. I feel it is important to know a patient’s current HRD status, both at diagnosis and then during first-line treatment. One question I encounter is whether to use a first-line PARP inhibitor in patients with HRD-negative ovarian cancer who do not require bevacizumab. Going forward, it will be important to improve all 3 of these newer tests. We know that not all patients who are HRD positive will respond to PARP inhibition and that some patients who are HRD negative will respond to PARP inhibition. Through academic collaboration, we can improve these tests to better identify these patients.


Isabelle Ray-Coquard, MD, PhD:
Other important data presented at the 2022 ESGO Congress include ARIEL3, a randomized phase III trial that compared maintenance therapy with the PARP inhibitor rucaparib vs placebo in more than 500 patients with platinum-sensitive, recurrent ovarian cancer who responded to their most recent platinum regimen. Previously, it was reported that the primary endpoint of PFS was improved with rucaparib. At the 2022 ESGO Congress, Coleman and colleagues presented updated OS results from ARIEL3. In this analysis, 72% of patients with a BRCA mutation and 76% of patients with HRD had received subsequent therapy vs approximately 90% of patients receiving placebo. In the cohort of patients with a BRCA mutation, median OS was similar between maintenance rucaparib and placebo (~46 months; HR: 0.83). Disappointingly, no OS benefit was seen in the HRD-positive cohort, where the placebo arm had slightly longer median OS (HR: 1.005). However, PFS on the subsequent line of therapy (PFS2) was improved with rucaparib across the intention-to-treat population (HR: 0.70), including patients with a BRCA mutation (HR: 0.67) and patients with HRD (HR: 0.72). Unsurprisingly, 46% of those in the placebo arm received subsequent PARP inhibitor therapy. There were no unexpected safety issues in this final analysis, including grade 3 adverse events and deaths from adverse events. That said, the development of myelodysplastic syndromes or acute myeloid leukemia was reported in 3.8% of the rucaparib group and 3.2% of the placebo group.

Ignace Vergote, MD, PhD:
These are intriguing results. In your opinion, should PARP inhibitors be used in patients with HRD-negative ovarian cancer in platinum-sensitive relapse?

Isabelle Ray-Coquard, MD, PhD:
Currently, I think this is an option that could be considered. However, ARIEL3 was not powered to detect an OS difference, and the patients who progressed on the rucaparib and placebo arm had differences. In general, I do favor PARP inhibitor maintenance in patients with ovarian cancer who responded to first-line platinum chemotherapy and have not yet received a PARP inhibitor.


Isabelle Ray-Coquard, MD, PhD:
Nonepithelial ovarian cancers are rare and include GCTs and SCSTs. In the retrospective GINECO VIVROVAIRE tumor study, 144 patients with GCT or SCST ovarian cancer received treatment with at least surgery plus chemotherapy (BEP). After at least 2 years of follow-up, they were age matched with a control group of 144 women without cancer, and all patients were given questionnaires to capture fatigue, QoL, and long-term adverse events (neurotoxicity, cognition, day-to-day life, anxiety/depression, and insomnia). Results showed that these measures were largely similar between groups, with the exception of social well-being scores, which were higher in patients with cancer vs the control group (5.5% vs 4.9%, respectively; P <.01). Of note, significantly more patients with cancer had entered menopause (mean: 38.6 years) vs the control group (mean: 50.4 years); also, a BMI >30 kg/m2 was seen in 17% of patients with cancer vs 5% in the control group (P <.001). More individuals in the control group had a high level of education (78% vs 55% of patients with cancer; P <.001).  

Of importance, significantly more patients with cancer reported early menopause (20%) compared with the control group (0%; P <.001). Likewise, sexual worries and concerns were significantly more common in patients with cancer (eg, being afraid of never having children). Moreover, patients with cancer saw a much worse impact of their health condition on daily life, including daily activities, leisure activities, and sports. Severe neuropathy was reported in 23% of patients with cancer vs 5% of the control group, and cognitive complaints were noted in 31% vs 14%, respectively. Overall, it is clear that although chemotherapy can cure patients with rare nonepithelial ovarian cancers, it comes at a price of substantial toxicity and long-term sequelae that must be managed.

Ignace Vergote, MD, PhD:
There have been very few studies of QoL in nonepithelial ovarian cancer. As seen in VIVROVAIRE, there were notable differences in cognitive complaints and sexual health with BEP chemotherapy, which is important, as many of the patients with these cancers are younger. I am curious whether the differences seen with BEP in this study will persist in longer follow-up.

Isabelle Ray-Coquard, MD, PhD:
I am curious as well and expect that these differences will actually increase over time. Such extended follow-up has been conducted for testicular GCTs but not in women with rare ovarian cancers.

Ignace Vergote, MD, PhD:
Intense chemotherapy such as BEP should negatively affect patient-reported outcomes such as anxiety and fatigue. However, in this study, those were not significantly increased. This might be due to the low patient numbers (which represent a relatively large trial in this rare cancer), but I still would have expected to see effects on anxiety and fatigue.

Isabelle Ray-Coquard, MD, PhD:
We discussed this question with Dr Florence Joly, who led the VIVROVAIRE study. Her group feels the answer (based in part on breast cancer studies) is not that the patient numbers are too low, but that the healthy controls may not be as healthy as expected.

Your Thoughts?
What are the challenges you experience in treating patients with ovarian cancer in your practice? Answer the polling question and join the conversation in the discussion box below.

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