Chirag A. Shah, MD

 We have made a lot of progress, but there’s more work to be done in this space. The ongoing research that’s still taking place with drugs that are both approved with FDA fast-tracked designation, and hopefully at some point, we might have some accelerated approvals, are very interesting. The patients with platinum-resistant disease have always been a major difficulty. It’s difficult to go through aggressive surgery, chemotherapy, and then be faced with a short interval to recurrence; it’s crushing for us as providers. Just as the patients are starting to feel better off their treatment, they’re faced with learning that their cancer has recurred. I think immunotherapy has been very interesting because the initial trials for monotherapy for immunotherapy were fairly disappointing. The recent publication of the work at Roswell Park [Comprehensive Cancer Center] was a newer regimen that I’ve found very effective in these patients.

What we know is that ovarian cancers by default tend to be fairly cold. They don’t respond well to immunotherapy by themselves. But I’ve had tremendous success with adding metronomic cyclophosphamide along with Avastin [bevacizumab] combined with pembrolizumab, in the Roswell Park regimen, and the toxicities are actually quite tolerable. I’ve had patients who have had a significantly greater response to therapy and duration of response than they did their platinum-free interval. The recent fast-track designation of approval for nemvaleukin IL-2 [interleukin-2] therapy also in combination with pembrolizumab is very exciting. I think that there’s quite a bit of research also being done in terms of reintroducing sensitivity to PARP inhibitors for patients who progress, whether you reintroduce PARP inhibitor sensitivity by combining it with immunotherapy, or with the newer class of drugs, WEE1 inhibitors.

I think 2022 is going to be a very exciting year in this space; there are several promising research studies being done, some that already have results, and new additional ones. There’s expected to be 8 potential large clinical trials that will have results at various points this year. I think each meeting that we encounter this year is going to bring a plethora of valuable new information. To start with, looking at combinations of immunotherapy to try to make it more active in this space has been very promising. Nemvaleukin IL-2 therapy, looking at WEE1, where those fit, those are really the places where I have the most enthusiasm going forward.

When I look in the state of the science in early 2022, I’d always first suggest if you’re a medical oncologist or a gynecologic oncologist, to engage in discussion on how to treat patients with initial presentation ovarian cancer. I know that myself and my colleagues in our field are very much willing to be active participants in the care of these patients. We have taken a page out of the breast cancer literature in now discovering that in many solid tumors, maintenance therapy, which has really not been a very acceptable or safe way to approach ovarian cancer, should be the standard of care. From my perspective, it’s a paradigm shift. The way I look at it, the only patients who should not receive maintenance therapy are either those who are just not well enough to receive it; for example, you have a patient with a very poor performance status, who’s barely tolerated treatment. You’ve struggled to get her through her chemotherapy, and she’s just unable to do it, or those who just choose not to do it. In my practice, the proportion who choose after the counseling that we’ve had not to have maintenance therapy is very low. I think it’s really a matter of how you frame the discussion. I think back to my early residency days in fellowship, and the biggest problem with ovarian cancer was, it always comes back. You go through all this work, and you get someone in remission, and then lo and behold, it comes back in a time that’s way too short.

We know if we look at all these trials, that the time to recurrence, the median progression-free survival is in the 6- to 8-month range. There are thousands of women who have been studied in these first-line trials at this point, and what we have realized is that time interval that we get until they recur is much shorter than we really would’ve hoped for. Trying to extend that interval, give them more time where they get to be cancer-free, but understanding that some treatment is required to be there; that to me is how we get those prolonged benefits in overall survival. That doubling of the median overall survival in women with ovarian cancer, it’s occurred incrementally. It’s not just been one thing, but it’s getting that extra time in the first line, and then getting some additional time in the second line, and then down the road; that’s really helped us get to where we are. I’d strongly encourage everyone to at least have a discussion. It’s reached the point of being high-level evidence in the NCCN [National Comprehensive Cancer Network] guidelines to offer maintenance therapy to all our patients with first-line ovarian cancer.

Videos

Dr Chirag A. Shah highlights novel emerging treatments in ovarian cancer and provides advice for community oncologists.

Emerging Treatments in Ovarian Cancer and Advice for Community Oncologists

My personal clinical experience with niraparib has been extensive. I can tell you an anecdotal story of the first visit I had with a patient. I had seen the press release about the initial approval of niraparib in the platinum-sensitive recurrent setting. It was pretty amazing to think of an oral drug being given that could so greatly improve progression-free survival. I remember coming back to my office and having a patient bring the press release to discuss with me. She had a niece who was an oncology pharmacist, and she really wanted to dig into it. At that time, I had not had a great amount of experience with niraparib; that was probably a good 6 years ago. Since that point, I’ve both prescribed the medication to patients on a clinical trial, but also in my practice in several clinical settings. The drug is approved as we’ve discussed in the first-line setting for maintenance for patients who have had a response to platinum-based chemotherapy, but it’s also approved in later lines of therapy based off the NOVA trial. It’s approved for patients with platinum-sensitive recurrent ovarian cancer after platinum-based chemotherapy. But also after multiple lines of therapy, if they have a 

 mutation or have deficiency in homologous recombination, they can benefit from it as a monotherapy based off the NOVA trial.

I’ve learned a great bit about managing the toxicities. When we first started treating patients with the drug, we didn’t have the more contemporary information on adjusting the dosing to a patient’s underlying weight and what their platelet counts are. I think one component that is critically important that we’ve learned, and this case was a good illustration of this, is allowing patients to recover from their hematologic toxicity associated with their first-line treatment. You’ve put a patient through intraperitoneal chemotherapy, or even if you’ve just given them standard intravenous therapy; their bone marrow, in a lot of cases, takes some time to recover. Thankfully due to our experience and my personal experience with prescribing this medication, our clinical pharmacy is well adept at putting patients on PARP inhibitor maintenance. I’ll send the prescription to our oncology pharmacy, and we are able to have the drugs and dispense to our patients directly, and they’ll have the approval and be ready to go. I’ll have to remind my nurse and the pharmacy staff that we need my go-ahead before we can give it, because I really do think it’s important to make sure they’ve recovered from that toxicity.

Separately, it’s important to stay on top of the laboratory tests, at least initially, getting those weekly CBCs [complete blood counts] so that you can get ahead of any potential thrombocytopenia or other hematologic toxicities you might encounter. Starting the patient on the appropriate dose: if their weight is under 170 lb, or if their platelet count at the time you want to initiate or when they finish chemotherapy is below 150, starting them at that 200-mg dose or 2 capsules daily is FDA approved. I remember working on the clinical trial PRIMA when this amendment occurred, and we were able to treat people on trial. Now we are taking that from that clinical trial experience to the actual day-to-day treatment of our patients. I will use the appropriate dose for the patient. If they’re above that weight and have normal platelets and haven’t experienced hematologic toxicity, I’m very comfortable starting those patients at the FDA recommended dose of 300 mg. I tend to have fairly manageable toxicities that are consistent with what we see, but a big part of it is counseling.

I begin the discussion about maintenance therapy at the initial presentation when I meet the patient, when we talk about what their disease course is going to look like. I feel like it’s important to not just throw this on them at the end when they’ve gone through a large operation and had chemotherapy, to circle back and say, “By the way, you’re also going to have 3 years of an additional medication.” I think you really need to set the expectations; there’s a lot going on at that initial diagnosis. You’re talking about surgery and chemotherapy. I may not spend a tremendous amount of time getting into the exact intricacies, but I’ll frequently mention that there is an oral drug that’s approved that they can take that’s going to help keep this cancer from coming back. When we look at it historically, and it still continues to be the case, we’ve made a lot of progress in this area. The biggest issue isn’t always whether I can get a good response to chemotherapy and take the cancer away, it’s keeping it away, and that’s really where I feel like maintenance therapy is so valuable.

If a patient is responding to her niraparib maintenance, determining how long I’m going to keep her on that is really going to be more a question of progression. If a patient remains disease-free and hasn’t exhibited significant toxicities that I can’t manage with dose interruptions or reductions, that’s why starting on the right dose is so important. We can feel more comfortable keeping her on that dose for the full 3 years. We can do this confidently based upon the data that have been presented and available in the publications from NOVA and PRIMA, that modified dose doesn’t appear to affect efficacy. Then the hard question really becomes they don’t always want to stop, but staying consistent with the labeling for me is important. I usually paint the case to the patient that it’s an evolving area of research whether retreatment with a PARP is an option, but certainly if they don’t progress on their first-line PARP inhibitor, I would feel more comfortable retreating with PARP. So when you get to that 3-year mark, it’s easier to have that discussion, knowing that I might be able to reuse this medication.

One of the reasons that I feel strongly about potentially offering this to my patients in the front line is for those platinum-resistant patients off of a clinical trial, you may never get an option to give them a PARP inhibitor, unless they have a 

 mutation. For our HRP [homologous recombination proficient] patients or 

 wild-type HRD [homologous recombination deficiency] negative, you may never get the opportunity to give them a PARP inhibitor. That’s where I feel like starting the discussion about this early and considering it in a broad variety of patients is crucial.

Chirag A. Shah, MD, details his personal clinical experience with using niraparib for ovarian cancer maintenance therapies.

Niraparib for Ovarian Cancer

When we talk about the mechanism of action of PARP inhibitors, it is a molecule that’s primarily involved in DNA repair. In patients who have inherited a predisposition to inhibited DNA repair, our patients with 

 mutations or other mutations in the Fanconi anemia pathway that are considered 

-like, we notice that those patients already have inhibited DNA repair. When they’re treated with platinum-based chemotherapy and there’s DNA damage, and when you come through afterward and inhibit the PARP molecule, which is one of the primary ways to repair DNA, you really get a dual benefit; this is called synthetic lethality. In the patients who don’t have a knockout that’s related to an inhibited mutation, you still can inhibit the repair of that DNA through the poly (ADP-ribose) polymerase pathway. As a result, if there are residual tumor cells still present, even though there’s radiographic and laboratory biomarker, CA-125 [cancer antigen 125], evidence of complete response, we know that those patients probably benefit from maintenance therapy. Undoubtedly on a molecular level, there are potentially clinically active cells that are still present. As those cells potentially try to multiply, you’re inhibiting their ability to multiply by blocking that pathway and going down the much less efficient nonhomologous end junction repair pathway, which ultimately leads to cell death.

At this point, in the first line, we know that PARP inhibitors are efficacious in the treatment of women with ovarian cancers. The efficacy has been proven in 3 large-scale trials. We’ve mentioned 2 of them already, the PAOLA-1 trial, PRIMA, and SOLO-1. These trials all have some subtle differences. The niraparib trial included all comers, so it was any patient who had advanced ovarian cancer that had responded to platinum-based chemotherapy. The SOLO-1 trial was in 

-mutated ovarian cancers alone. The PAOLA-1 trial included patients who had 

 mutations, but also had HRD [homologous recombination deficiency] testing that was evaluated, and the end points were slightly different based upon the inclusion criteria of the patient population. What we know is that all 3 trials met their end points in their respective patient populations, but there’s a fairly large difference between all 3 studies in terms of the patients who were included and in terms of the maintenance treatment options.

In the PRIMA trial, it was 2:1 randomization of niraparib to placebo. There were similar randomizations, but SOLO-1 was olaparib alone; PAOLA-1 was olaparib plus bevacizumab. What we did find is in the PRIMA trial, niraparib was effective and improved the progression-free survival in all 3 arms, meeting its primary end points. In the overall patient population, there was a greater than 5-month improvement in progression-free survival between patients who were given niraparib compared to the patients who weren’t. However, when the subgroup analysis was done, it was effective in HRD patients, like our patient discussed in this case, but also in HRP [homologous recombination proficient] patients and in the 

-mutated patients as well. There’s broad evidence of impact.

When the olaparib trial was published, it was similarly a landmark paper, although it preceded the PRIMA trial. We saw some of the biggest improvements in overall progression-free survival in 

-mutated patients. When you look at the significant impact across the trials, what we clearly see is based upon the mechanism of action, I feel that there should not be any question about the standard of care being PARP inhibitor maintenance therapy in women with 

An expert shares data from several clinical trials on the use of PARP inhibitors for maintenance therapies in ovarian cancer.

PARP Inhibitor Maintenance Therapy for Ovarian Cancer

Of the FDA-approved treatments for first-line maintenance, we have PARP inhibitor therapy. PARP inhibitors can be given in monotherapy for all women who have responded to platinum-based treatment, such as this patient who reached a complete response to treatment; she would be an ideal candidate. Given the fact that she has a homologous recombination deficiency [HRD], she’s likely to have a robust response to a PARP inhibitor. The next class of drugs that’s approved in first line, whichpredated the PARP inhibitor approval, which I’m sure many of you who are watching this are familiar with, is bevacizumab. Antiangiogenic therapy has been proven to be effective in women with ovarian cancer in all lines of therapy. Recent research, including from the MITO series of trials, suggests that bevacizumab can be given in the first line, can be given later, and is still effective; that’s a very commonly used drug.

Where people use bevacizumab is really all over the map. In my experience, who decides to give bevacizumab to which patients is quite variable. I tend to use the approach of tailoring my highest-risk patients, those patients who are stage IV, who have suboptimally debulked disease, to think that those patients would benefit from bevacizumab. That is because that decision is often made very early in the time of treatment, sometimes before you even have any testing results back; it’s just based upon the clinical appearance of the patient. In addition, there’s approval for combination PARP and bevacizumab in patients who have HRD or a 

 mutation based upon the PAOLA series of trials. From the large-scale PRIMA trial, we have approval for niraparib, as was used in this case. Then from the series of GOG trials, and also the ICON trials in Europe, bevacizumab has been approved in the first line, and then the PAOLA trials, as I previously mentioned.

One of the questions that invariably comes up when you start a patient on maintenance therapy is what that duration of maintenance therapy should be. The initial bevacizumab trials that we alluded to primarily treated the patient for 1 additional clinical year. I’m a gynecologic oncologist by trade, I’ve been long comfortable with maintenance therapy, but this is newer to the gynecologic oncology realm in ovarian cancer. But bevacizumab was initially shown to be effective in the trials that it was administered in on a 12-month basis. The niraparib approval that was based off the large, randomized PRIMA trial treated patients for 3 years. Given the fact that that’s an oral therapy, I think that was more palatable. We enrolled and recruited patients and had patients on the PRIMA trial and found that that duration of therapy didn’t feel to be an obstacle to treatment. It still becomes difficult when you’ve had a patient on maintenance for an extended period to decide if it’s OK to take them off. I tend to follow what was done in the clinical trials. If I’m using Avastin [bevacizumab], I will typically stop that at a year afterward because these drugs can have toxicity. If I’m treating with a PARP, I’ll generally follow with 3 years, as long as the patient hasn’t progressed during that period.

Dr Chirag A. Shah explains the front-line treatment options for ovarian cancer and the factors considered in choosing maintenance therapies.

Ovarian Cancer: Systemic Front-Line Treatments

When we evaluate the role of molecular testing in patients with newly diagnosed ovarian cancer, I would certainly say that this has been an evolving area of research and guideline-based care. Approximately 5 years ago, the National Comprehensive Cancer Network [NCCN] recommended germline testing for all patients who were diagnosed with newly apparent ovarian cancer, fallopian tube cancer, primary peritoneal cancers; these cancers are all lumped together under the term ovarian cancer. More recently, the NCCN has also approved and recommended that these women undergo somatic testing. The reason behind this is that it has become apparent if you only obtain one test, whether it’s your germline or somatic test, you’re going to miss at least on the order of 5% of patients who have a mutation, whether it’s one that they inherited, a germline mutation, or somatic, which is tumor based.

The timing of testing has also been a rapidly evolving place. People have hypothesized about whether patients should undergo reflexive testing, for example, obtaining one test and if that’s negative, obtain the second test. Some people approach this in either fashion, obtaining the germline testing first or obtaining the somatic testing first. I think some of it becomes a question of what’s available at whatever institution you practice at. However, our approach has been to obtain both sets of testing; it provides the greatest amount of information. There’s information about the genomic signature that you can get from the somatic test that’s not provided by the germline test. As we’ve evolved to understand that genomic scar in the form of homologous recombination, it is a phenotypic biomarker for how these patients may do and how they may respond to future treatment. Essentially, molecular testing can be used to guide treatment; it can be used to provide prognostic information. It’s important to know both the germline portion so that the patient knows for herself and for her family what their inheritable risks are, but also knowing the genomic signature of the tumor to help explain what her response to therapies might look like. It could help explain what led to the development of this cancer for these patients, or to potentially identify, in the case of patients who are homologous recombination proficient, those who are at the highest risk of recurrence.

We have a protocol that’s taken about 2 years to come into existence through the various steps along the way. We’re evaluating this in the form of a clinical trial, where we’re obtaining germline testing using an online app to connect to patients through Ambry [Genetics] to get their germline results. At the same time, we’re using the molecular genomics laboratory at our facility and obtaining HRD [homologous recombination deficiency] testing in the approved process. Essentially for all intents and purposes, we’re collecting data while we obtain 3 sets of testing. The somatic testing is 2 parts, the true genomic testing, but also the formal HRD testing. Then the patient goes through the germline process and has an informational tool or an app that they can download. For patients who are unable to download the app, there is in-person and telephonic approaches to get counseling. That is our approach at our institution.

A gynecologic oncologist discusses the importance of molecular testing in ovarian cancer and how it influences treatment selection.

The Role of Molecular Testing in Ovarian Cancer

I’d like to review a case of a 59-year-old female, postmenopausal, who initially presented with abdominal discomfort, some abdominal bloating, but was also noted to have modest weight loss. In terms of her past medical history, she was noted to have hypercholesterolemia that was well managed with medications. She had no known family history of malignancy. On physical examination, she was noted to be 150 lb, and appeared to be a generally healthy female, but had diffused tenderness to abdominal palpation. On her exam, she was also noted to have a firm fixed left ovarian adnexal mass. Her overall performance status was good, ECOG performance status 1. Subsequent clinical work-up involved pelvic ultrasound, which revealed a 5-cm left ovarian mass. She was noted to have a cancer antigen, CA-125, of 460 U/mL. This was followed by a chest, abdomen, and pelvis CT. This noted that same adnexal mass but also noted pelvic lymph nodes. There was no evidence of pleural effusions, but there was significant ascites. After the CT, the patient underwent a paracentesis, which revealed 2300 mL of fluid and on histopathologic evaluation was found to be a high-grade, serous epithelial ovarian cancer.

Following this discovery, she was referred to genetic counseling and underwent germline molecular testing. This revealed 

 wild type. She also underwent somatic testing of her tumor cells, and these were found to be HRD [homologous recombination deficiency] positive. Her ultimate diagnosis was stage III, high-grade serous epithelial ovarian cancer. After her diagnosis, she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, lymph node dissection with optimal tumor debulking to no gross residual disease, or R0 resection. At the time of her surgery, she had an intraperitoneal port placed and underwent postoperatively intraperitoneal and intravenous paclitaxel and cisplatin therapy. After 6 cycles, she achieved a complete response. During her therapy, she did experience mild cytopenia during rounds 4 and 5 of her chemotherapy, and had her counts subsequently followed for the initial interim after completion of chemotherapy. Her platelet counts recovered to the normal range within 4 weeks of finishing chemotherapy. After finishing chemotherapy, the patient was started on maintenance therapy with 200 mg oral niraparib given daily. This was initiated 12 weeks after the completion of her last cycle of chemotherapy. She initially had weekly blood count monitoring and then monthly as recommended in the niraparib maintenance protocols.

In describing this case in terms of my initial impressions, I would characterize this as the classic presentation for most women with ovarian cancer. They usually present with abdominal or GI [gastrointestinal] symptoms, the most common being abdominal bloating, early satiety, increased abdominal girth and urinary frequency. Seventy five percent of women who are diagnosed with ovarian cancer present at an advanced stage, similar to our patient in this case. Thankfully, the prognosis for these patients has improved dramatically over the last 20 years. We’ve seen a near doubling in the survival of a patient with newly diagnosed ovarian cancer. The average patient with ovarian cancer can now live for up to 8 years, and a large part of that is due to advances in newer treatment options that have become available in the last 5 to 7 years.

Chirag A. Shah, MD, presents and reviews the case of a 59-year-old woman with ovarian cancer.

Chirag A. Shah, MD | Authors

Articles

Emerging Treatments in Ovarian Cancer and Advice for Community Oncologists

Niraparib for Ovarian Cancer

PARP Inhibitor Maintenance Therapy for Ovarian Cancer

Ovarian Cancer: Systemic Front-Line Treatments

The Role of Molecular Testing in Ovarian Cancer

Case Presentation: A 59-Year-Old Woman with Ovarian Cancer