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 [

] 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.

, Krivak discussed his approach to up-front treatment for women with newly diagnosed advanced ovarian cancer.

: 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?

: 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 

-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].

 testing, patients are at increased risk, but it’s not like 100% of women with a 

 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 

 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 

-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 

 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 [

 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.

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Thomas C. Krivak, MD, discusses his approach to up-front treatment for women with newly diagnosed advanced ovarian cancer.

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

To stay on top of 2 of the most common adverse effects (AEs) of PARP inhibitors in advanced ovarian cancer—cytopenias and fatigue—patients should undergo weekly monitoring of their blood counts and increase their physical activity, according to Angela Jain, MD.

“Common AEs of PARP inhibitors include cytopenias, like neutropenia, anemia, and thrombocytopenia. [Also], fighting fatigue can be quite difficult for some patients, but I recommend something that’s maybe counterintuitive: trying to increase physical activity and strength training, as I find that many patients have lost some stamina after surgery and chemotherapy,” said Jain.

, Jain, an assistant professor in the Department of Hematology/ Oncology at Fox Chase Cancer Center, provided perspective on the use of PARP inhibitors in the treatment of patients with advanced ovarian cancer.

How have the indications for PARP inhibitors in the frontline maintenance setting affected their use in ovarian cancer?

: The use of PARP inhibitors in frontline maintenance therapy is relatively new, but several great trials show that there are some opportunities for this [class of agents].

 mutation do benefit from PARP maintenance therapy, [specifically with] the combination of olaparib [Lynparza] and bevacizumab [Avastin]. Olaparib plus bevacizumab is given for 2 years after initial chemotherapy and surgery. Bevacizumab is also usually started at the time of treatment during that paradigm, and then olaparib is added as maintenance after it’s all over. Niraparib [Zejula] has been given an indication for frontline maintenance regardless of a 

 mutation, which has really changed how we think about maintenance therapy for all our patients with ovarian cancer.

In terms of dosing, do you tend to start patients on the full dose? In what scenarios would you consider starting patients on a lower dose?

[Excellent] guidelines have been set in terms of dosing the PARP inhibitors. Usually, I try to start patients at their full recommended dose unless there is a good reason not to, because that is the most effective dose. Niraparib has a “weights and plates” dosing, so if a patient’s weight is under 150 pounds, or their platelet count is under 150,000 at the time of starting therapy, [you can] reduce the dose at the start of therapy to 200 mg to reduce the chances of cytopenias, but otherwise, there is no other recommendation at the start of therapy to dose reduce.

How do you manage the cytopenias and fatigue that are associated with PARP inhibitors?

Some patients will talk about having some nausea [and/or] fatigue with the PARP inhibitors. I make sure that patients have antiemetics at home in case they’re needed. [We also have to] monitor blood counts. I usually monitor them weekly for the first month or two to look out for those changes, then make dose modifications as necessary. Patients also have to work at rebuilding the stamina [they lost after surgery and chemotherapy]. Plus, with niraparib, you do have to worry about patients developing some hypertension and headaches. That’s something to look out for and monitor a little bit more closely as well at home.

This will [likely] be the first time that patients are on an oral [cancer] therapy. Some patients may assume that these drugs don’t have AEs that need to be monitored, but I do recommend, for the first month or two, scheduling an every-other-week phone call or office visit to confirm that they’re tolerating the medication well. This can help look out for cytopenias and hypertension, and it reminds patients that AEs [are possible] and that they should call if they’re having any trouble.

How does knowing that PARP inhibitors are available in the frontline and recurrent settings affect your treatment recommendations?

PARP inhibitors are now approved in multiple settings: We can treat patients in the frontline maintenance setting; in the second-line, platinum-sensitive setting; and in the recurrent setting, for patients with a 

 mutation or [homologous recombination deficiency]–positive loss of heterozygosity. Being cognizant of potential AEs and potentially thinking about when we would want to use a PARP inhibitor in those settings is [key], especially considering that there is a rare risk of leukemia and [myelodysplastic syndrome] in the future. Giving thought to when to use these drugs can sometimes be a little tricky, and having that honest conversation with our patients is important.

What are your thoughts on rechallenging patients with a PARP inhibitor based on the data from the OReO trial (NCT03106987)?

We reuse platinum with recurrence, and we have to ask if we can reuse PARP inhibitors. If we have a patient who can receive a PARP inhibitor as frontline maintenance, should we use it again in second-line maintenance? The OReO study looked at that question and found a progression-free survival benefit, regardless of a 

 mutation, for rechallenge with a PARP inhibitor. Other studies are coming, but it is promising that we can still hold this option again for patients if the setting is right.

What trials with PARP inhibitors are you watching?

The space of PARP inhibitors in ovarian cancer is still very much evolving, especially as newer therapies arise or [are being combined] with older therapies. We know that there might be benefits in combining [PARP inhibitors] with bevacizumab [or] with immunotherapy. These trials are ongoing and I’m looking forward to their results [in the future].

Angela Jain, MD, provides perspective on use of PARP inhibitors in the treatment of patients with advanced ovarian cancer.

Frequent Blood Count Monitoring and Increased Physicality Are Important in PARP-Treated Ovarian Cancer

Switch maintenance therapy with bevacizumab (Avastin) or PARP inhibitors, such as olaparib (Lynparza), niraparib (Zejula), or rucaparib (Rubraca), has improved outcomes for patients with platinum-sensitive recurrent ovarian cancer, said Richard Penson, MD, MBBS. He added that the field is continuing to move the needle forward with novel targets like WEE1 and ATR, and with combination strategies of PARP inhibitors plus PI3K inhibitors or immunotherapy.

“With maintenance therapy, we have flipped the old concept that palliative chemotherapy compromises quality of life with no advantage to overall survival [OS]. The new antiangiogenic agent bevacizumab [and] PARP inhibitor switch maintenance therapy [represent] the standard,” Penson said. “[In the up-front setting of] platinum-sensitive recurrent ovarian cancer, we have to decide about surgery and which platinum-based combination of chemotherapy to choose. However, from the get-go, we must educate patients about the natural transition to switch maintenance therapy.”

, Penson discussed how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer. He is clinical director of medical gynecologic oncology at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School.

: Platinum-sensitivity status informs treatment selection for patients with recurrent ovarian cancer. Does it also inform maintenance therapy selection or should other factors be considered?

: In ovarian cancer, most patients—about two-thirds—will have what we arbitrarily call a potentially platinum-sensitive recurrence, which means that their recurrence happens more than 6 months [after platinum-based treatment]. We treat [platinum-sensitive vs platinum-resistant] disease very differently.

It is true that because of the incorporation of some of the newer, more exciting therapies into our armamentarium, we don’t solely rely on platinum-sensitive vs platinum-resistant [status to guide treatment decisions]. We think about the genotype of the patient and the tumor. We think about the platinum-free interval as a continual variable rather than 2 distinct groups. We also think about the histology and how the patient responded to previous treatments.

For platinum-sensitive recurrent ovarian cancer, patients will go on to combination platinum-based therapy. We preferentially choose pegylated liposomal doxorubicin with carboplatin, and pretty much everybody gets it with bevacizumab based on an [Society of Gynecologic Oncology] Study Group trial that showed superior progression-free survival and OS with that combination. However, some clinicians, particularly for patients with a shorter, 6- to 12-month platinum-free interval, prefer gemcitabine/ carboplatin. That is very popular and [the regimens] are similar in lots of ways. The fabulous thing [with both is that patients] have no hair loss, little neuropathy, and good tolerability.

The question about whether we choose switch maintenance therapy with a PARP inhibitor or continue with bevacizumab is [dependent] on clinician and patient preference. The data suggest that PARP inhibitors have a greater impact compared with bevacizumab in platinum-sensitive recurrent ovarian cancer.

The OReO study [NCT03106987], which looked at the response to rechallenging, was a little disappointing in that the data were a sobering reminder that when patients had previous switch maintenance PARP inhibitor therapy, they had a 2- or 2.5-month time to progression on placebo. [Olaparib] doubled that, but it is still not very long.

The push is to try other avenues, but rechallenging with PARP inhibitors with subsequent lines of therapy is still a popular option. The OReO trial showed that, in contrast to the NOVA [NCT01847274], ARIEL3 [NCT01968213], and SOLO-1 [NCT01874353] trials, at least one-third of patients who likely had reversion mutations got no benefit from PARP inhibitors. A small group of patients, 5% to 10%, got incredibly durable benefit from rechallenge with PARP inhibitors. Currently, our molecular diagnostics are helpful. The ARIEL4 trial [NCT02855944] showed how powerful the molecular diagnostics were. However, picking out the patients who will be long-term survivors with these new therapies remains challenging.

When a patient with recurrent ovarian cancer sits in front of you requiring switch maintenance therapy, what patient- or disease-related factors 

do you consider that could play into treatment selection?

For patients with mucinous or clear cell cancers, we will shift them to bevacizumab as their switch maintenance therapy. In patients with stage IV disease, in whom there is a demonstrated OS benefit with up-front bevacizumab, bevacizumab becomes an essential part of the armamentarium. In certain clinical situations, such as patients who have ascites or pleural effusions, the serous effusions reflect the vascular permeability factors that drive leaky vessels and cause accumulation of serous, fluid-filled effusions in the chest or abdomen.

At the other end of the spectrum are patients who will get more benefit from a PARP inhibitor: those with great responses to chemotherapy; with high-grade serous cancers; with homologous recombination deficiency [HRD] or a highly penetrant HRD gene like 

What rationale do you use for selecting among the 3 available PARP inhibitors?

We have 3 FDA-approved PARP inhibitors for switch maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer that has responded to combination platinum-based therapy. The original [PARP inhibitor] was olaparib in 2014. It was approved as therapy, but the data were [not] available at that time. The following approvals were for niraparib and rucaparib. They are all very similar [in terms of efficacy].

If we use the 200-mg dose of niraparib, the agents are similar in terms of adverse effect profile as well. We have to be careful about nausea and fatigue. Patients must be informed about the small risk of myelodysplastic syndrome and acute myeloid leukemia. These treatments impact survival and are an essential part of the armamentarium.

What unmet needs regarding patients with homologous recombination proficient (HRP) tumors need to be addressed? Do any emerging agents, combinations, or targets look promising?

When we think about maintenance therapy in the recurrent setting, the patients who have HRP tumors or those who are not likely to benefit from PARP inhibitors are the ones of the biggest need and the ones nearest to developing platinumresistant disease. That is a huge unmet need.

There is a lot of excitement about the different avenues [being explored], such as PI3K inhibitors or immunotherapy in combination with PARP inhibitors, or other approaches to attacking the DNA damage response. The more proficient a tumor is at repairing DNA damage, the harder it is to get a better outcome. If [that proficiency] is compromised, patients will respond better to chemotherapy and PARP inhibitors.

We are interested in WEE1 and ATR, as well as lots of other targets. The best cocktail is not known at the moment, and the challenge is that many of these agents have overlapping toxicities. Therefore, getting the right cocktail of therapies without excess hematologic toxicities is difficult. 

It’s true to say there are many fans of antiangiogenic agents or immunotherapeutics with PARP inhibitors. PI3K inhibitors in combination with PARP inhibitors, for example, are now in phase 3 trials. We are in exciting times, but the next generation of studies that report on these outcomes will help us define the new frontier, [allowing us] to help those who do not sufficiently [benefit from] single-agent PARP inhibitor switch maintenance therapy.

Although these advances with switch maintenance therapy options are welcome for patients with recurrent ovarian cancer, disparities in terms of access to care remain. How can clinicians begin to bridge those gaps?

Perhaps [emerging] out of the COVID-19 pandemic, something important that [is getting attention] in the United States is access to care. [For instance], a friend of mine looked at his disadvantaged minority patients and found that they got a PARP inhibitor as switch maintenance therapy only a quarter as often [as nonminority patients]. There is tragic injustice in terms of effective therapies that aren’t getting to everyone. 

Raising awareness and doing educational efforts like this interview with 

 [is key] to making sure people know how to identify the patients who benefit from these drugs and how to best use these drugs against this terrible disease. Getting these new and effective therapies to everyone who can benefit is just as important as driving the next scientific advance.

Richard Penson, MD, MBBS, discusses how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

Penson Provides a Snapshot View of Switch Maintenance Therapy Selection in Recurrent Ovarian Cancer

Although niraparib (Zejula) is approved as frontline maintenance therapy for women with advanced ovarian cancer regardless of biomarker status, the agent should be reserved for women with homologous recombination–deficient (HRD) tumors, explained Anil K. Sood, MD. He added that bevacizumab (Avastin) alone should be a consideration for women with homologous recombination–proficient (HRP) disease.

“Once we have all [the genetic] information, if there is a 

 mutation, either a germline or somatic [mutation], or HRD, then we consider using a PARP inhibitor for maintenance once the up-front treatment is completed. If there is no such defect, then we consider using bevacizumab or no treatment in the maintenance setting,” said Sood.

Such recommendations are based, in part, on f indings from the phase 3 PRIMA trial (NCT02655016), which randomized 733 patients with newly diagnosed, advanced ovarian cancer who responded to frontline platinumbased chemotherapy 2:1 to receive niraparib (n = 487) or placebo (n = 246).

The results showed that among patients with a 

 mutation, the median progression-free survival (PFS) was 22.1 months with niraparib vs 10.9 months with placebo (HR, 0.40; 95% CI, 0.27-0.62). In those with HRD-positive tumors who were negative for 

 mutations, the median PFS was 19.6 vs 8.2 months, respectively (HR, 0.50; 95% CI, 0.31-0.83).

In patients with HRD-negative tumors, the median PFS was 8.1 months with niraparib vs 5.4 months with placebo (HR, 0.68; 95% CI, 0.49-0.94).

, Sood provided insight into his approach toward the frontline maintenance treatment of women with advanced ovarian cancer. He is professor and vice chair for translational research in the Departments of Gynecologic Oncology and Cancer Biology; co-director of the Center for RNA Interference and Non-Coding RNA; director of the multidisciplinary Blanton-Davis Ovarian Cancer Research Program; and co-director of the Ovarian Cancer Moonshot Program, all at The University of Texas MD Anderson Cancer Center.

: How have the approvals of PARP inhibitors as frontline maintenance shaped your initial discussions with patients with newly diagnosed advanced ovarian cancer?

: It’s been a remarkable development for patients in a lot of ways. The options are becoming more and more complex. From the very beginning, we really try to discuss with patients what their whole treatment plan may look like, so they’re prepared as they get to different aspects of their treatment. [Those options] include personalizing their treatment in the up-front setting toward surgery vs using neoadjuvant chemotherapy. That’s when we start the discussions about what possible maintenance strategies may look like and how we would make good decisions around those [options].

What is unique to your practice when it comes to frontline maintenance therapy?

We have a number of ongoing studies looking at novel drugs in this setting. Also, we have a second-look assessment study; this was done quite a bit in the past but was stopped in the late 1990s. In the current setting of new drugs, etc, the group here is testing the utility of second-look assessment using laparoscopy.

What is the single most important aspect of care for you when it comes to frontline maintenance therapy?

In my view, genetic testing is the single most important aspect, since that helps to personalize [treatment] approaches. In some parts of the country, the testing rates are still quite low.

How does genetic testing influence the type of maintenance treatments you offer?

Ovarian cancer is an incredibly diverse disease. For all patients with high-grade serous and endometrioid disease, we offer up-front germline genetic testing, especially around 

 genes. About 15% to 20% of women will have a germline mutation. Now, if they don’t have a germline mutation, then we also do tumor testing or somatic testing for

Do any distinguishable features among niraparib, olaparib (Lynparza) alone, and olaparib plus bevacizumab help with your treatment recommendations?

The PARP inhibitors overall seem to have comparable efficacy, [with] some differences in their adverse effect profiles and in the duration of the maintenance therapy. In our group, there is some variation [in what is recommended]. In the up-front maintenance setting, either olaparib or niraparib can be used, and our practitioners have used [both].

Are patients more drawn to one PARP inhibitor over another?

It’s worth having a conversation [with patients about this]. Either [niraparib or olaparib] is a valid option. Patients are incredibly empowered these days; they come well informed. Typically, [we will have] a conversation weighing the pros and cons of either of the PARP inhibitors, the duration of treatment, and so on.

In what situations would you add bevacizumab to frontline maintenance therapy vs not adding it?

In patients with high-risk disease—such as those with distant metastases, residual disease after surgery, etc— we would consider adding bevacizumab and then using it in maintenance.

Might certain toxicities sway you away from a particular agent?

There has been some concern around platelet counts, especially with niraparib, but as we have adjusted the dosing based on weight and platelet counts at baseline for a given patient, that perhaps has been a bit better now.

If somebody has really struggled with blood counts during their treatment, we would perhaps use a PARP inhibitor rather than niraparib. But apart from that, no [particularly] great baseline markers [influence our selection].

Do you still use a PARP inhibitor if a patient doesn’t have germline or somatic abnormalities? It’s FDA approved in that setting. However, in my view, the absolute magnitude of benefit in that setting tends to be smaller, and that’s why we don’t routinely use a PARP inhibitor in HRP settings.

You said that for a patient whose tumor is HRP, you would be less likely to prescribe a PARP inhibitor. Is that because you would be concerned about exposure downstream?

In an HRP setting, typically, we wouldn’t really use a PARP inhibitor much at all unless somebody has a very long progression-free interval before they have relapsed disease. In that setting, for someone who has platinum-sensitive relapsed disease, following platinum-based therapy, a PARP inhibitor certainly can be used. Still, if such a long interval has occurred, even if a PARP inhibitor was given up front, not a lot of data are [there]. However, some emerging data [suggest that] repeat exposure to a PARP inhibitor could be considered in patients who have particularly long intervals.

What questions will be important to explore in this setting moving forward?

Patients who have HRD tumors, overall, seem to derive benefit from PARP inhibitors. But, even in that setting, not every patient with a 

 mutation or HRD derives benefit. Trying to understand what’s different in those patients—at a biomarker level and mechanistically—and why they don’t get as much benefit [is important]. Could other drug combinations be considered in that setting?

Another very important space is patients who have HRP disease. We’re trying to see if rational drug combinations with PARP inhibitors could be used where the PARP inhibitor, or at least the combination, could work well for disease control for extended periods of time. There is also some thought that these drugs may combine well, for example, with certain immune drugs. But the data are very early, and those kinds of combinations are being tested and developed further. We still need to understand and develop [a great deal] in all these areas.

There had been a lot of interest in considering maintenance strategies, but only over the past 7 years or so have the maintenance strategies really shown promise and begun to be increasingly used. It’s certainly an exciting time given all the new drug development that’s occurring. Although the PARP inhibitors and bevacizumab have been important developments, we certainly hope for a lot more opportunities.

[To that end], we’re working on a large-scale clinical trial that would be under an adaptive trial mechanism. It would offer opportunities for drug development in the maintenance space, and there would also be opportunities for patients with relapsed disease. In my view, this up-front maintenance environment is so important, and that’s why we are really excited about this adaptive clinical trial design and [are] looking forward to launching this kind of clinical trial within the next year.

Monk BJ, Gonzalez-Martin A. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 study. Presented at: SGO 2020 Annual Meeting; March 28-31, 2020; virtual. Abstract 31.

Anil K. Sood, MD, provides insight into his approach toward the frontline maintenance treatment of women with advanced ovarian cancer.

HRD Status Drives Decisions With Frontline PARP Inhibition in Advanced Ovarian Cancer

Anil K. Sood, MD, professor, director, Ovarian Cancer Research, co-director, Center for RNA Interference and Non-Coding RNA, vice chairman, Division of Translational Research, director, Blanton-Davis Ovarian Cancer Research Program, co-director, Ovarian Cancer Moonshot Program, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, discusses navigating frontline maintenance therapy in ovarian cancer.

All patients with high-grade serous or endometrioid ovarian cancer should undergo up-front germline genetic testing to determine whether they harbor 

 mutations, Sood says. Data suggest that approximately 15% to 20% of patients will have a germline mutation present; however, the remaining patients should undergo tumor testing to identify somatic 

 mutations or homologous recombination deficiency (HRD), Sood explains. 

-mutated or HRD-positive ovarian cancer can be considered for frontline maintenance therapy with a PARP inhibitor, Sood says. In patients without such defects, up-front maintenance therapy with bevacizumab (Avastin) may be considered, or the patient may not receive frontline maintenance at all, Sood concludes.

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Anil K. Sood, MD, discusses navigating frontline maintenance therapy in ovarian cancer.  



Dr. Sood on Navigating Frontline Maintenance Therapy in Ovarian Cancer 

Richard T. Penson, MD, MRCP, clinical director, Medical Gynecologic Oncology, Medicine, Massachusetts General Hospital, associate professor of medicine, Harvard Medical School, discusses selecting between PARP inhibitors for switch maintenance therapy in recurrent ovarian cancer.

Currently, 3 PARP inhibitors are FDA approved as switch maintenance therapy options for patients with platinum-sensitive recurrent ovarian cancer who had a complete or partial response to platinum-based therapy, Penson says. These agents include olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) and all have demonstrated similar efficacy in this patient population.

Regarding safety, the 3 agents also have similar safety profiles, assuming the 200-mg dose of niraparib is utilized, Penson explains. Common adverse effects include nausea and fatigue. Additionally, patients must be informed about the small risk for myelodysplastic syndrome and acute myeloid leukemia with PARP inhibitors.

Ultimately, switch maintenance therapy with PARP inhibitors improves outcomes for patients with recurrent ovarian cancer and is a standard treatment option, Penson concludes.

Richard T. Penson, MD, MRCP, discusses selecting between PARP inhibitors for switch maintenance therapy in recurrent ovarian cancer.  



Dr. Penson on PARP Inhibitors as Switch Maintenance Therapy in Recurrent Ovarian Cancer 