Insights From: Oliver Dorigo, MD, PhD, Stanford University Medical Center; Whitney Graybill, MD, MS, Medical University of South Carolina; Matthew Powell, MD, Washington University School of Medicine
Whitney S. Graybill, MD, MS: In 2014, the SGO (Society of Gynecologic Oncology) came out with a statement that all patients with ovarian cancer should be tested for both BRCA1 and BRCA2 germline mutations. This is really important, because we know that about 30% of patients with ovarian cancer do not have a first-degree relative or someone close in their family with a cancer history, and approximately 35% of patients with germline mutations don’t develop ovarian cancer until after the age of 60. It’s really important that patients undergo this testing, because it helps to inform relatives and other family members so that they can undergo testing themselves. It allows for patients to undergo risk reduction surgery, if appropriate, and it also opens up new therapies for patients.
In terms of HRD (homologous repair deficiency) testing, we know that patients who receive PARP inhibitors tend to have a greater response if they have a germline BRCA mutation. The efficacy decreases somewhat as you go to somatic mutations, then tumors that are BRCA negative but HRD positive, followed by wild-type tumors that are HRD negative. So, HRD testing allows us to, in some instances, better inform groups of patients as to what kind of a response they may have while on therapy.
If we look at the NOVA trial, which evaluated niraparib versus placebo in patients with platinum-sensitive recurrent disease, patients who received niraparib in the maintenance setting had a significantly increased progression-free survival as compared to patients who received placebo.
Now the improvement, or the PFS, was greatest for patients who had a germline mutation and a somatic BRCA mutation. However, all subgroups evaluated, including patients that BRCA wild-type and HRD negative disease, had a significant improvement in progression-free survival. So, this really opened the door and allowed a broad label for PARP inhibitors in the maintenance setting so that patients who want this drug in the maintenance setting don’t have to undergo germline or somatic testing, or HRD testing, to be eligible to receive it.
I think there are a couple of places for HRD testing clinically. The first, again, is to inform patients of what kind of a response they may have while on the drug. In addition, it helps in the treatment setting for clinicians to be able to know which patients will qualify for a drug. In the treatment setting, patients are eligible for olaparib if they’ve had greater than or equal to 3 lines of treatment and have a germline BRCA mutation.
The indications are a little bit different for rucaparib. Rucaparib is FDA approved for patients with greater than or equal to 2 lines of previous treatment, and they can have a germline or a somatic BRCA mutation. So, if a patient is germline negative and you want to put them on a PARP inhibitor for treatment, then testing their tumor for a somatic mutation or HRD positivity would make sense to see if they qualify for the rucaparib agent. In the maintenance setting, it’s not necessary for patients to undergo HRD testing, but it can inform patients what to expect regarding outcome.
Now, HRD is really good at giving us an idea of how a group of patients is going to respond to a PARP inhibitor, but it’s really not aggregately sensitive to inform an individual patient as to how they’re going to respond. So, it’s just really important to keep that in mind. In terms of coverage, I think it’s important to try to get coverage through insurance for these tests off of clinical trials. But if that’s not possible, companies such as Myriad have programs to help cover the cost for patients who aren’t able to afford the testing when insurance doesn’t cover it.