Specific HRD Testing Helps to Clarify the Role for PARP Inhibition in Ovarian Cancer

For patients with homologous recombination repair deficiency (HRD), PARP inhibitors can be an effective treatment for patients with ovarian cancer. PARP inhibitors such as olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) have all been approved by the FDA and the European Medicines Agency as first-line maintenance therapies for patients with advanced ovarian cancer.

The PARP inhibitor olaparib was also approved in combination with the angiogenesis inhibitor bevacizumab (Avastin) as a first-line maintenance therapy in adult patients with ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD), as defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. This indication was granted based off of findings from the phase 3 PAOLA-1 trial (NCT02477644), which aimed to see if patients received any benefit from olaparib added to bevacizumab, regardless of BRCA mutation status.

Participants in the trial were tested for tumor HRD status using the Myriad myChoice HRD Plus assay, which was later approved by the FDA as a companion diagnostic for olaparib. And the study demonstrated that patients with HRD positivity, regardless of BRCA mutation status, benefited most from the combination regimen.¹

In addition to HRD testing with the Myriad assay, though, HRD testing with gene panels is another approach. However, according to Eric Pujade-Lauraine, MD, PhD, this method identifies fewer patients with high-grade ovarian cancer who have mutations in homologous recombination repair (HRR) pathway genes than the Myriad test. 

In a presentation during the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer, Pujade-Lauraine et al demonstrated data showing that these gene panels are not truly predictive of benefit from the combination of olaparib and bevacizumab in patients with ovarian cancer.² 

Pujade-Lauraine, head of the Medical Oncology Department at Hôpital Hôtel-Dieu in France, discussed PARP inhibitors and the benefits of various testing methods for HRD, in an interview with Targeted Oncology ahead of the SGO meeting.

TARGETED ONCOLOGY: Prior to these 3 studies, what outcomes were observed with platinum-based chemotherapy and debulking surgery alone for the frontline treatment of patients with ovarian cancer?

PUJADE-LAURAINE: Until recently, the treatment of advanced ovarian cancer consisted of the combination of chemotherapy and debulking surgery—either upfront debulking surgery or interval debulking surgery. But since the ESMO Congress [several years ago], 3 randomized phase 3 trials have shown that the addition of a PARP inhibitor prolongs significantly the progression-free survival (PFS) of these patients who have high-grade ovarian cancer. And the remarkable finding is that it’s mainly those patients with HRD, tested by the Myriad tests, who benefit from the PARP inhibitor. It is in line with the mechanism of action of a PARP inhibitor. And this is new, why? Because until now, the population that benefits most from a PARP inhibitor was mainly those patients with a BRCA mutation, and there, it happens, [but now there is] a new subset of patients and new population. [These are] the patients who have an HRD-positive test, who has a normal reverse recombination repair deficiency, but [do not] have not a BRCA mutation. And we are focusing on this population. How to recognize this patient who do not have the BRCA mutation, but HRD.

The main test used a specific genomic instability score. So, it is a test that recognizes the different genomic abnormalities induced by HRD. And this test has some advantages, of course, but has some, I would say, limitations, such as the test needs quite a significant [amount of] DNA sample from the tumor. That means that between 12% to 18% of the tests are non-informative because of insufficient DNA samples. So, we are trying to find other tests which could identify this population of HRD-positive patients who do not have a BRCA mutation. And many labs throughout the world suggest that perhaps we could substitute this genomic instability score of the HRD test with the identification of mutation of a gene in the HRR pathway. So, just having a sign of genomic abnormalities but mutation in some genes through next-generation sequencing [NGS] and a gene panel.

So, we have tested this hypothesis in the PAOLA-1 trial, which is a trial sponsored by the French group ARCAGY, who have explored the combination of olaparib plus bevacizumab in maintenance compared to placebo plus bevacizumab, and [the trial] has shown very striking prolongation of PFS, particularly in the HRD-positive patients. And what we found—and we explored 6 different gene panels, 3 were previously published and 3 that we have built—and none of these were predictive of olaparib activity in this first-line treatment and maintenance. So that was a deception. Why these gene panels were ineffective to predict happens, and we have shown, that mutation in some of the genes of the HRR pathway doesn't mean that it impacts the effectiveness of this pathway. And only a third to half of these gene mutations induce HRD. So that was the first finding. The second finding is in the same line is that according to the different gene panels, only 3.8% to 9.8% of the patients with high-grade ovarian cancer have a mutation in these genes. So, gene panels recognize only a small proportion of patients compared to genomic instability scores, which identified almost 20% of the patients. So, our conclusion is that until now, there is no evidence that a gene panel for focus on the HRR pathway can substitute the genomic instability score tested with the Myriad test. And thus, we have to explore further other genomic instability and not focus, as we do in many countries, on the gene panel. 

TARGETED ONCOLOGY: Regarding testing, how are you currently ordering testing? Are you ordering testing prior to treatment, during treatment? What is your process?

PUJADE-LAURAINE: So, I think the process is quite different according to countries, of course. In Europe, we have the Myriad test available for only a few months. So, in France, what we propose is at diagnosis of a high-grade ovarian cancer, to look for Myriad HRD test. And in these tests, you have both the results of the BRCA mutation in the tumor and the genomic instability score. So, you can, with these tests, recognize those patients who are HRD positive and can benefit the most from a PARP inhibitor, and those who are HRD negative, who [may not] benefit from a PARP inhibitor. And then when you have the results of these tests, you can choose if you want to give bevacizumab or not, in addition to, of course, the perspective of offering the patient a PARP inhibitor. So, this is currently the way we are doing it in Europe and particularly in France, for all patients with high-grade ovarian cancer and advanced disease.

TARGETED ONCOLOGY: Aside from HRD, what other kind of prognostic factors are you looking for in this testing for these patients?

PUJADE-LAURAINE: So, in addition to the HRD testing, we look, of course, for other prognostic factors. One important prognostic factor is FICO stage, particularly in this advanced stage, the difference between stage 4 and stage 3 disease Of course, it's more difficult to get a complete resection of all the sites of disease when it is a stage 4. And the second most important prognostic factor is the possibility to achieve a complete resection at the upfront surgery. So, there are different methods to assess this basic capability of the disease when the disease is newly diagnosed. And if it is considered, then that it will be very difficult to get a complete surgical resection while we propose to the patient a cycle of a chemotherapy and interval debulking surgery, followed by chemotherapy, and then maintenance with PARP inhibitor. And at any point you have to choose or not to add bevacizumab.

TARGETED ONCOLOGY: What other things do we have to address with testing in ovarian cancer going forward?

PUJADE-LAURAINE: So, one important point is that the HRD test is a predictive test. But inside these tests, you have the information about tumor BRCA mutations. And if the patient has a tumor BRCA mutation, this patient has a chance to also have a germinal BRCA mutation. And in this case, when a patient has a discovered tumor BRCAmutation, it is important to send this patient to the [geneticist] to look for a germinal BRCA mutation, which may, at the end, be a germinal BRCA mutation for the whole family. So, it is also, of course, a test for the family.

The HRD test is a revolution in ovarian cancer. Why? Not only are the HRD tests [able] to predict a new treatment, which is a PARP inhibitor, [but it also] allows ovarian cancer to enter the precision medicine area, which gives a new perspective for the knowledge of ovarian cancer biology and future treatment. And particularly, what is highly important, the 2 main priorities in ovarian cancer today is first to understand what is the mechanism of resistance of PARP? That's of course, for the HRD-positive patient, but also, who are these patients with an HRD-negative tumor? What is the specific biology of these HRD-negative tumors and when we will know that, we will find new targets and new treatments for our patients with ovarian cancer. It is new findings which are important to consider, such as the different activities and tolerance of the different PARPs.

_^REFERENCES:

1. _{^{Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019;381:2416-2428. doi:10.1056/NEJMoa1911361}}

2. _{^{Pujade-Lauraine E. Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial. Presented at: 2021 Society of Gynecologic Oncology Annual Meeting; March 19-25; Virtual.}}