BRCA, HRD Testing Are Essential in Up-front Advanced Ovarian Cancer Management

Thomas C. Krivak, MD

The first decision in newly diagnosed, advanced ovarian cancer is whether to pursue primary debulking or neoadjuvant chemotherapy, determined in part by the presence of pleural effusion, significant ascites, and diffusely metastatic disease. However, providers should also take the time to order molecular testing, said Thomas C. Krivak, MD, because the results will have important implications on subsequent recommendations for maintenance therapy.

“In thinking about the optimal strategy for up-front treatment, [we have to consider] clinical biomarkers. We’ll be thinking about PARP inhibition in patients who have HRD [homologous recombination deficiency] or a germline [BRCA] mutation,” said Krivak, the director of the Ovarian Cancer Center of Excellence and co-chair of the Society of Gynecologic Oncology Research Institute, Allegheny Health Network.

In an interview with OncLive^®, Krivak discussed his approach to up-front treatment for women with newly diagnosed advanced ovarian cancer.

OncLive^®: How have the FDA approvals of PARP inhibitors as frontline maintenance therapy affected how you think about surgery and the use of bevacizumab (Avastin) in a patient with newly diagnosed ovarian cancer?

Krivak: We all grapple [with] that [question] every day. The results of the maintenance trials in up-front ovarian cancer and recurrent ovarian cancer have shown that maintenance is very important. In thinking about a patient with newly diagnosed ovarian cancer, the goal is making sure that I can get that patient through chemotherapy and surgery with minimal toxicity so they can be treated with maintenance therapy, whether that’s with a PARP inhibitor alone or a combination of a PARP inhibitor and bevacizumab. When I look at caring for a patient, a good-quality surgery is important. Getting the patient to have a complete response is very important, [as is] trying to minimize toxicity so that patients can tolerate an oral agent.

The results of SOLO-1 [NCT01844986] and PRIMA [(NCT02655016), as well as PAOLA-1 (NCT02477644)], are very important. Veliparib is not FDA approved, but all of those data show that maintenance therapy is tremendously important.

How does biomarker testing now factor into the equation for you?

Everybody will debate the use of biomarkers. Biomarkers are prognostic and predictive. Patients with a BRCA-mutated tumor, whether it’s somatic or germline, or with a tumor that has HRD are the patients who I want to make sure get through treatment with minimal toxicity. Patients can undergo PARP-directed therapy for 2 to 3 years. Having these medications available [for a few years now], we’re starting to see patients doing very well with no evidence of disease 2 and 3 years out, and having them come off therapy is at times stressful.

Patients have done very well with some of the adverse effects [AEs], learning how to manage the AEs themselves: how to change their diet, how to take their medications, [etc]. I think they find some reassurance and they feel like they’re doing something [by adhering to the medication], and there’s no doubt [that they are]. The HRs that we saw in SOLO-1, PAOLA-1, and PRIMA really are tremendous and showed that maintenance therapy is important. We’re thinking about [the possibility of getting patients on PARP inhibitors] day 1.

We basket everything out: Let’s get a good diagnosis. Let’s get the treatment plan going. Let’s get a good surgery. The goal is to achieve remission, then once we achieve remission and we finish therapy, we ask: What maintenance therapy will we use? We try to use a biomarker strategy as well as clinical factors [to answer that question].

What other clinical and disease factors do you use to inform treatment decisions in the up-front setting?

The first decision tree we face is deciding whether we are going to recommend neoadjuvant chemotherapy or primary debulking. I don’t like using age as a determining factor, but if somebody is in their 80s, then surgery may be less likely, and we may want to do neoadjuvant chemotherapy [instead]. Clinical factors—such as pleural effusions, diffuse metastatic disease, looking at a CT scan, not thinking that we can get this patient to microscopic residual [disease]—[make it more likely that] patients will get a CT-guided biopsy or drainage of fluid and initiate chemotherapy. In patients with pleural effusion, significant ascites, and diffusely metastatic disease, we will utilize bevacizumab before surgery as well as after surgery. Functional status and disease status will help [us decide whether we’ll] want to pursue surgery or chemotherapy. There is no perfect way to assess in whom you want to do surgery first vs neoadjuvant [chemotherapy], but that’s the first decision tree analysis that we need to look at.

In terms of clinical factors, I consider ovarian cancer to be a high-risk disease. Some patients have more poor prognostic factors than others. I also look at HRD. Myriad has an excellent test, but numerous tests are out there, including from Foundation [Medicine], Caris, and Tempus. The most clinically validated tests are from Foundation [Medicine] and Myriad, so I rely on those.

It may be a clinical feature that [determines whether] we put somebody on bevacizumab followed by a PARP inhibitor: age, functional status, distribution of disease, significant ascites, pleural effusions, prealbumin, or albumin. I look at those factors and try to determine how those patients will tolerate up-front therapy and then neoadjuvant chemotherapy vs primary debulking.

How we’ll [approach] maintenance therapy depends on some clinical features. Do these patients tolerate their chemotherapy? Are they fit? Are their platelets OK? Is their hemoglobin OK? Are they clinically fit to initiate maintenance therapy? We will factor all that in as we go along.

To what do you attribute the barriers to biomarker testing?

Biomarkers are really confusing. Sometimes, as physicians, we want everything to be black and white. We want a perfect test, but there’s really no perfect test in medicine. CA-125 is not perfect and CT scans aren’t perfect. A lot of what we do is based on our clinical intuition as well as science. A lot of the hesitancy [with regard to biomarker testing] is that it’s not a perfect test and may miss some patients [who are eligible for certain medications].

[It’s also hard because] with BRCA testing, patients are at increased risk, but it’s not like 100% of women with a BRCA mutation will develop cancer. [Approximately] 80% [of these women] will develop breast cancer and 40% [will] develop ovarian cancer. Technically, you could say you’re operating on 10 women to benefit 4. It’s a very lethal disease; you can’t screen for it. But still, we want to have this perfect test. That’s one of the barriers to testing for HRD.

We’re also all very busy clinically. I’ve been practicing out of fellowship for 20 years now, [and in that time], the history and physical [evaluation] really haven’t changed, surgery hasn’t really changed, we do a little bit of neoadjuvant chemotherapy [now]. [What is different is that] we have so many more clinical trials, so many more options, and so many more molecular data to interrogate and convey to the patient. [Consequently], our office time has increased [tremendously]. It takes a lot of [work] to be prepared for these patients when they come in, to have [all the necessary] information, and it does take a lot of follow-up phone calls.

I can still remember when our system released information to patients, so they could see the results in real time. The Foundation Medicine report has a [combined positive score] related to lung cancer. Patients with ovarian cancer were seeing this [result tied to] lung cancer and were calling the practitioner, saying, “Now I have lung cancer and ovarian cancer.”

We try to explain all this to patients, and it takes a lot of time. Ordering the test takes time. I’m very lucky in that I have a good [team] who works with me, and they will have the charts prepped. They know how I practice. They know that we’re going to order biomarker testing here, we’re going to have [things done a certain way there], etc, and they’ll help communicate this information to patients. Clinicians are time constrained with all these new molecular data, and it’s not just molecular data—it’s all these new clinical trials. I have no idea how a medical oncologist who treats breast cancer, lung cancer, liquid tumors, and then ovarian, endometrial, and cervical cancer [as well keeps up].

So many new studies have come out in the past 3 to 5 years. We really have to do our homework to make sure that we’re prepared. Biomarker testing adds to some of the complexity in counseling our patients, so if you can get away with not doing it, it will save you a lot of time—although I don’t know whether that’s best for our patients. We have to find time to prepare the charts and we have to find time, if we need to talk offline to patients, to communicate [about the details] with them.

Patients are getting smarter. They are all on Facebook, and a lot of them will come in knowing a lot about HRD testing or BRCA testing or panel testing, which does help [in a way. Still], one of the biggest barriers is clinician understanding of the test and making the right decision [for treatment] in the time that it takes to interpret the test, as well as explain it to the patients. I’m in favor of [testing] because it’s a huge prognostic factor. It really does affect how I’m going to make decisions clinically. It’s worth the extra effort and time.

Which clinical trials on the horizon could potentially inform or change your practice in the coming years?

We have been really spoiled these past few years. In the first 10 years after [my] fellowship, we had bevacizumab and made baby steps. Then, [all of the positive data with] PARP inhibitors [came out]. It’s exciting for up-front ovarian cancer as well as recurrent ovarian cancer. For up-front ovarian cancer, ATHENA [NCT03522246] will hopefully read out [soon]. A lot of us are looking forward to not necessarily the interpretation of the BRCA-mutated patients or the patients who have HRD, but the group with homologous recombination proficient [HRP] tumors. ATHENA is evaluating the combination of rucaparib [Rubraca] and nivolumab [Opdivo]. It’ll be interesting to see whether [the combination] has a significant impact in the 50% of women whose tumors are HRP. That’s going to be very exciting.

Another trial, DUO-O [NCT03737643], is looking at adding additional medications to maintenance therapy to help improve progression-free survival and overall survival. KEYLINK[-001 (NCT03740165)] will read out [soon] as well.

Novel compounds such as WEE1 inhibitors and ATR inhibitors [are being evaluated to] help combat platinum resistance and PARP resistance. Those [approaches] will be [under study in] fascinating phase 1 and phase 2 trials. Antibody-drug conjugates [ADCs] are also fascinating, and one, tisotumab vedotin-tftv [Tivdak], is approved for cervical cancer. ADCs will be important in ovarian cancer. We have had some clinical trials open and have seen some excellent responses with [ADCs in patients with] platinum-resistant disease. ADCs as single agents and in combination with other already approved agents will also be very interesting. Hopefully, we will get some more analyses from some of these large trials that will provide better data and additional molecular information to help tailor these treatments. Looking at [those approaches in] the recurrent as well as up-front ovarian cancer settings is very important.

OReO [NCT03106987] is another exciting trial. The study evaluated PARP after PARP, and [it was clearly] a great trial with strong HRs. The deltas were kind of small, but these are patients who were heavily pretreated with platinum and had received a PARP inhibitor for a prolonged period. The trial was positive in the patients who had platinum-sensitive disease, regardless of BRCA status or HRD status. The results also showed the safety of PARP after PARP. We weren’t seeing a whole lot of signals with respect to myelodysplastic syndromes and acute myeloid leukemia. PARP after PARP is going to be a very interesting approach. [I’m sure investigators will] take it to a next step [and evaluate] PARP and then PARP with some combination after progression. A lot of novel combinations are out there. [The ovarian cancer space is] amazing, with all the medications that are being developed. It’s a fascinating time and it will only get better in the next 5 to 10 years—not just ovarian cancer, but cervical and endometrial cancer as well.

Would you like to emphasize anything else?

It’s important to highlight that what’s making [us] all successful is the interaction of academic medicine, community medicine, and pharmaceutical companies. One can’t succeed without the other. Because of what [OncLive^® does], clinicians and patients are getting educated and more patients want to participate in clinical trials. In our institution, we had tremendous trial enrollment over the past year. This is a positive for women with gynecologic malignancies. It’s everybody working together.

There is a lot of negativity in the world right now with COVID-19, but even with that going on, we still had all these positive data [emerge]. We had all these great clinical trials, we still enrolled patients, we’re still developing concepts, and you still see this great interaction among patients and clinicians and pharmaceutical companies and academics, as well as community medicine. Even though there are a lot of challenges in medicine, this [interview] really highlights some tremendous successes within the Gynecologic Oncology Group Foundation, NRG Oncology, and pharmaceutical companies in general.