For patients with homologous relapse repair defect (HRD), PARP inhibitors may be an effective treatment for patients with ovarian cancer. PARP protectors such as olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) are all approved by the FDA and the European Medicines Agency as first-line maintenance treatments for patients with advanced ovarian cancer.
The PARP inhibitor olaparib was also approved in conjunction with the angiogenesis inhibitor bevacizumab (Avastin) as a first-line maintenance therapy in adult patients with ovarian cancer who are in full or partial response to first-line platinum-based chemotherapy and who have associated cancer. with homologous relapse deficiency (HRD), as defined by either malignant or suspicious BRCA mutation, and / or genomic instability. This indication was given based on the results of a phase 3 PAOLA-1 test (NCT02477644), which aimed to see if patients had any benefit from olaparib added to bevacizumab, regardless of BRCA inbhe mutation.
Participants in the trial were tested for tumor HRD status using the Myriad myChoice HRD Plus assay, which was subsequently approved by the FDA as a companion diagnosis for olaparib. And the study showed that patients with HRD had positivity, however BRCA mute status, which got the most benefit from the mixing regimen.1
In addition to HRD testing with the Myriad assay, however, HRD testing with gene panels is an alternative. However, according to Eric Pujade-Lauraine, MD, PhD, this method identifies fewer patients with advanced ovarian cancer who have mutations in genes of the homologous replication repair pathway (HRR) than the test Myriad.
In a presentation at the 2021 Annual Meeting of the Society of Gynecologic Oncology (SGO) on female cancer, Pujade-Lauraine et al showed data showing that these gene panels do not actually predict benefit from the combination of olaparib and bevacizumab in patients with ovarian cancer.2
Pujade-Lauraine, head of the Department of Medical Oncology at Hôpital Hôtel-Dieu in France, spoke about PARP defenders and the benefits of different test methods for HRD, in an interview with Targeted oncology ahead of SGO meeting.
ONCOLOGY TARGETED: Prior to these 3 studies, what outcomes were observed with platinum-based chemotherapy and debulking surgery alone for the facial treatment of patients with ovarian cancer?
PUJADE-LAURAINE: Until recently, advanced ovarian cancer treatment involved a combination of chemotherapy and debulking surgery – either facial debulking surgery or interim debulking surgery. But from the ESMO Congress [several years ago], 3 randomized phase 3 trials have shown that PARP inhibitor implantation significantly improves the progressive survival (PFS) of those patients with advanced ovarian cancer. And the surprising finding is that it is mostly those patients with HRD, tested with Myriad tests, who benefit from the PARP inhibitor. It is based on the PARP protector action mechanism. And this is new, why? To date, the population receiving the greatest benefit from PARP inhibitor has been the majority of those patients with BRCA mutation, and then it happens, [but now there is] a new subset of patients and a new population. [These are] the patients with HRD-positive test, who have a normal relapse repair deficit, however [do not] which is not a BRCA mutation. And we are targeting this population. How do you identify this patient who does not have the BRCA mutation, but HRD.
The main experiment used a specific genomic instability score. Therefore, it is a test that identifies the different genomic effects caused by HRD. And this test has some advantages, of course, but there are some limitations, I would say, as the test is much needed [amount of] DNA sample from the eardrum. That means that between 12% to 18% of the tests are noninvasive due to insufficient DNA samples. Therefore, we are trying to find other tests that could potentially increase this number of patients with advanced HRD who do not have BRCA mutation. And many laboratories around the world suggest that we may be able to replace this genomic instability score of the HRD test by identifying gene mutation in the HRR pathway. . Thus, only with a sign of genomic deficiencies but a mutation in some genes through following the next generation [NGS] and gene panel.
We therefore tested this idea in the PAOLA-1 trial, which is an experiment supported by the French group ARCAGY, which has studied the combination of olaparib plus bevacizumab in maintenance compared to placebo plus bevacizumab, and [the trial] has produced a dramatic increase in PFS, especially in the patients with HRD-positive. And what we found – and we studied 6 different gene panels, 3 previously published and 3 we took – and none of which predicted the activity of olaparib in the treatment and maintenance of first- this line. So that was a deception. Why these gene panels were ineffective for prediction occurs, and we have shown, that a mutation in some HRR pathway genes does not mean that it affects the efficiency of this pathway. And only a third and a half of those gene mutations promote HRD. So that was the first discovery. The second finding in the same line is that, according to the different gene panels, only 3.8% to 9.8% of patients with advanced ovarian cancer have mutations in these genes. Thus, gene panels identify very few patients compared to genomic instability scores, which identified nearly 20% of patients. Therefore, our conclusion is that, to date, there is no evidence that a gene panel for focusing on the HRR pathway can replace the genomic instability score determined by the Myriad test. And so, we need to further study other genomic instability and not focus, as we do in many countries, on the gene panel.
ONCOLOGY TARGETED: In terms of testing, how do you currently order exams? Do you prescribe a test before treatment, during treatment? What is your process?
PUJADE-LAURAINE: So I think the process is quite different by country, of course. In Europe, our Myriad test is available for just a few months. So, in France, our recommendation at diagnosing advanced ovarian cancer is to look for a Myriad HRD test. And in these experiments, both results of the BRCA mutation in the eardrum and the genomic instability score. Thus, you can, with these tests, identify those patients who are HRD positive and who get the most benefit from a PARP inhibitor, and those who are HRD negative, who [may not] benefit from PARP inhibitor. And then when you get the results of these tests, you can choose whether or not to give bevacizumab, as well as, of course, the prospect of offering a PARP inhibitor to the patient. So this is currently how we are doing it in Europe and especially in France, for all patients with advanced ovarian cancer and advanced disease.
TARGETED ONCOLOGY: In addition to HRD, what other prognostic types are you looking for in this test for these patients?
PUJADE-LAURAINE: So, in addition to the HRD test, we look, of course, for other prognostic factors. One important prognostic factor of FICO stage, especially at this advanced stage, is the difference between stage 4 and stage 3 disease. In fact, complete resection of all disease sites is more difficult when it is stage 4. .And the second most important prognostic feature is the ability to perform complete resection at the facial surgery. Therefore, there are various ways to assess this underlying potential of the disease when the disease is re-diagnosed. And if it is diagnosed, then it will be very difficult to get a complete surgical resection while we recommend the patient a cycle of intermittent chemotherapy and debulking surgery, followed by chemotherapy, and then maintenance with PARP inhibitor. And at any time you have to choose or not to add bevacizumab.
AFTERNOON PRAYER: What other things do we need to deal with in ongoing ovarian cancer testing?
PUJADE-LAURAINE: Therefore, one important point is that the HRD test is a predictive test. But within these tests, your knowledge is about tumors BRCA changes. And if the patient has a tumor BRCA mutation, this patient has a chance of having germinal as well BRCA mutation. And in this case, when a patient has a tumor BRCAmutation, it is important to refer this patient to [geneticist] look for germinal BRCA mutation, which may, in the end, be germinal BRCA mutation for the whole family. So it is also, of course, a test for the family.
The HRD test is a reversal in ovarian cancer. Why? Not just the HRD tests [able] to predict a new treatment, which is a PARP inhibitor, [but it also] allowing ovarian cancer to enter the field of precision treatment, which will provide a new perspective for the knowledge of ovarian cancer biology and future treatment. And in particular, what is extremely important, the 2 main priorities in ovarian cancer today are to understand how PARP works? That is, of course, for the HRD-positive patient, but also, who are these patients with HRD-negative tumors? What the specific biology of these HRD-negative tumors is and when we know that, we will find new targets and new treatments for our patients with ovarian cancer. New findings that are important to consider, such as different actions and tolerances of different PARPs.
REFERENCES:
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Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Inspectors. Olaparib plus Bevacizumab as a first-line maintenance in ovarian cancer. N Engl J Med. 2019; 381: 2416-2428. doi: 10.1056 / NEJMoa1911361
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Pujade-Lauraine E. Homologous recombinant repair mutation panels (except BRCA) are not predictive of maintenance of olaparib as well as efficacy of bevacizumab in the first-line PAOLA-1 / ENGOT-ov25 test. Presented at: 2021 Gynecologic Oncology Society Annual Meeting; March 19-25; Virtually.