Lyndsay Willmott, MD

 The ARIEL4 trial was a clinical trial designed to look at randomization of patients who have a 

 mutation, either germline or somatic, in the setting of a recurrence to receive either cytotoxic chemotherapy or rucaparib. The comparison is between chemotherapy and oral PARP inhibition. The chemotherapies that the patients received in this clinical trial were based on their platinum sensitivity. If these patients were platinum-resistant, then they went on to paclitaxel. If they were platinum sensitive, then they went on to a platinum-based regimen. They were randomized to receive either of those chemotherapeutic agents or rucaparib.

When we look at the outcomes, the patients who were randomized to rucaparib had improvements in their progression-free survival vs patients who were randomized to the cytotoxic chemotherapy. That makes sense mechanistically. We were looking specifically at a patient population of those women who had a 

 mutation. Based on the mechanism of action of rucaparib, the fact that these patients responded perhaps a little more robustly to the PARP inhibition vs the cytotoxic chemotherapy makes sense from a mechanistic standpoint.

The clinical trial did include a small subgroup of patients who had evidence of 

-reversion mutations. Those were patients who had a 

 mutation and then subsequently had a reversion mutation. In other words, they’re acting like patients with 

 wild-type disease. Those patients showed they had the reverse. It‘s a small group of patients, but in that patient population, they performed worse if they were randomized to rucaparib. It makes sense mechanistically. If they‘re very effectively able to repair their DNA double-stranded breaks because their 

 is functioning more appropriately, then perhaps they’re less likely to respond to rucaparib monotherapy in this setting.

This allows us to consider whether you want to place a patient onto chemotherapy at time of recurrence. The truth is the majority of our patients are likely going to be exposed to PARP inhibition in earlier lines of therapy given the fact that PARP inhibitors are approved for use in the up-front setting and have been widely available for use in the platinum-sensitive recurrent setting for maintenance. The patient pool we’re talking about in this setting, who likely have never seen PARP inhibitors previously and who may be candidates for PARP inhibition at time of recurrence, is small. But there are certainly some patients who have a 

-associated ovarian cancer who haven’t received PARP inhibitors, and you should keep this in the back of your mind as an opportunity to consider monotherapy with PARP inhibitor as opposed to cytotoxic chemotherapy.

When we’re talking about ovarian cancer, we’re always trying to push the bar forward with our goal to cure more patients. That’s obviously the goal for all of us. We recognize that the opportunity for cure is likely most profound at the time of diagnosis. When you‘re looking at clinical trials, we’re starting to utilize a number of therapeutic modalities in the upfront setting in combination. There are number of clinical trials undergoing evaluation or that have completed accrual and are awaiting completion of their events, including the use of checkpoint inhibitors along with PARP inhibition. Unfortunately, thus far in ovarian cancer trials, checkpoint inhibitors haven’t been successful. We haven’t seen significant improvement in progression-free survival in prior clinical trials that have used checkpoint inhibition.

There have been some subset analyses from these trials trying to better understand, of the patients who are enrolled, are there a group of patients—perhaps biomarker driven with PD-L1 testing, for example—who may be more likely to respond to checkpoint inhibition? Or perhaps we need to utilize multiple drugs together to make these drugs more likely to be successful, combining drugs and hoping to see more robust response. There are a number of clinical trials that are pending their outcome evaluations that include checkpoint inhibition. I’m curious to see if some of those combination strategies may allow checkpoint inhibitors to be utilized in ovarian cancer.

We all understand that the viewpoint of ovarian cancers is drastically different from how it was 5 years ago. Five years from now, the landscape will have continued to shift and grow. We recognize that surgery and chemotherapy remain mainstays of treatment of patients with ovarian cancer in the up-front setting. But we also recognize that maintenance therapies can hopefully help us improve progression-free survival. In patients who have 

 mutations, it’s truly standard of care to utilize PARP inhibition as part of their maintenance strategy. We certainly recognize that the presence of homologous recombination deficiency is also very prevalent, and these patients are also likely to benefit.

There’s the availability for patients, even those who are homologous recombination proficient, to go onto PARP inhibitor maintenance or course bevacizumab maintenance. But it’s that homologous recombination proficient group that remains our most challenging treatment population and the group of patients for whom we need to continue to try to push the bar forward. Because when we look at the outcomes from studies evaluating PARP inhibition in patients who are homologous recombination proficient, unfortunately that improvement in progression-free survival isn’t as profound as in patients who have a 

 mutation or a homologous recombination deficiency. Those patients represent a more challenging group, and I’m very interested to see if we can make some progress in that group, especially to help them have improvements in their platinum-free intervals. Hopefully 1 day we can see improvements in overall survival in all our patients with ovarian cancer and improve our chances of curing patients.

Case Overview: A 57-Year-Old Woman With Ovarian Cancer

A 57-year-old woman presented with progressive abdominal discomfort and bloating, early satiety, new-onset constipation, and unintentional weight loss

PMH: postmenopausal; hypertension—medially controlled; osteoarthritis

PE: right lower quadrant tenderness on palpation

Pelvic exam with ultrasound showed a ~4.5-cm right ovarian mass

Chest/abdomen/pelvis CT with contrast revealed a right adnexal mass with lymph node involvement and ascites

Paracentesis (1200cc) cytology confirmed high-grade serous epithelial ovarian cancer

Diagnosis: Stage III, high-grade serous epithelial ovarian cancer

Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0

Carboplatin/docetaxel q3 weeks for 6 cycles; CA-125 normalized; CR

At 2 years post chemotherapy, patient experienced abdominal bloating and pain, nausea and vomiting and progressive fatigue; CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery

Rechallenged with carboplatin/docetaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes

Rucaparib single-agent maintenance 600 mg bid

Patient developed clinically significant thrombocytopenia; dose reduced to 500 mg and patient remained on treatment until disease progression

Videos

An expert reviews the ongoing ARIEL4 phase III trial and explains what the future of ovarian cancer treatment looks like.

Future Treatments in Ovarian Cancer

 PARP inhibitors as a class share a number of toxicities. The most common of which are typically fatigue, GI [gastrointestinal] toxicities with nausea and vomiting, and then impact on bone marrow function, including anemia and thrombocytopenia. Though these toxicities are common and the majority of patients who are put on PARP inhibitor maintenance will experience toxicity, the good news is that we have ways to mitigate these toxicities to allow patients to stay on the therapy. When you look at the trials, most patients were able to stay on the PARP inhibitor. Not many patients had to come off because of toxicity. But many patients required a dose interruption or reduction.

When I talk to my patients about these toxicities, I describe that there are some things we can do to try to prevent them. Starting first with nausea and vomiting, it’s very important for patients to stay very well hydrated. That can certainly contribute to nausea and vomiting. I also make sure my patients have an antiemetic that’s filled and ready to go. Most of them are going to have those medications because they were just on chemotherapy. If they’re experiencing any nausea with their PARP inhibitor, then I recommend they prophylactically take an antiemetic before their PARP inhibitor. I also recommend trying to eat or having small frequent meals, which can also help a lot with nausea.

Certainly, some patients, despite these mitigation strategies, may experience very severe nausea and vomiting, in which case you can pause the PARP inhibitor, give them a dose break, and then if their symptoms have improved, you can subsequently perform a dose reduction. Typically with these preventive strategies, dose interruptions, and dose reductions, most patients can stay on rucaparib despite experiencing nausea.

In terms of fatigue, this also is a challenging adverse effect to manage because fatigue can impact a patient’s desire to stay on a maintenance strategy. They’ve just come off their chemotherapy, they’re looking forward to getting back into the swing of their life, and if they’re feeling fatigue, that could be a very frustrating symptom. Similarly, we can utilize the same type of strategy with encouraging patients to make sure they’re being active. Sometimes during chemotherapy, patients may not be able to get out and exercise as much, or they may learn dysfunctional sleeping patterns where they’re not using good sleep hygiene. I typically recommend to my patients that they assign themselves a bedtime, and that if they nap during the day, they’re limiting the length of their naps. Also, [I recommend] getting up and being physically active, like trying to go for a walk or do some sort of other physical activity. This usually helps them sleep better at night, which may significantly improve fatigue.

It’s also important to evaluate for other potential causes of fatigue. For example, thyroid dysfunction, and certainly likely underdiagnosed depression. In a patient who’s been diagnosed with a recurrent ovarian cancer, depression is something we need to consider and can also contribute to fatigue. We can utilize a similar strategy for what we use for nausea management, which is a dose interruption and a dose reduction if patients are experiencing severe fatigue. With these types of strategies, though fatigue can be an issue, in general, patients can still get out, enjoy their lives, and have degrees of fatigue that are acceptable to them.

When we think about bone marrow toxicity, for example cytopenias, this is an important thing to consider with rucaparib maintenance. The recommendation is to check monthly CBC [complete blood count] to monitor for any impact to bone marrow function and cytopenias, and also to allow our patients to recover from the cytopenias related to their cytotoxic chemotherapy before we initiate their PARP inhibitor maintenance. If patients are still showing evidence of anemia or thrombocytopenia after we’ve completed their cytotoxic chemotherapy, you need to give them some time to recover before you start the PARP inhibitor. Then you should monitor their CBC monthly. In general, we could use the same type of dose-interruption and dose-reduction strategy. But in a patient who has a significant anemia or thrombocytopenia and you’ve interrupted their dose, you must monitor their CBC weekly. If their CBC hasn’t improved by a month after this interruption has started, then you need to consider whether additional evaluation needs to be performed. Typically, that would be a bone marrow assessment with a bone marrow biopsy to rule out any evidence of MDS [myelodysplastic syndrome] or AML [acute myeloid leukemia].

The good news is that, even though we’re concerned about how frequent we would evaluate or identify patients who have AML or MDS who are on PARP inhibitors—there was some concern that those numbers would be significantly increased—when we look across trials, thankfully, the numbers of patients who have AML or MDS is quite low. But it’s very important that you evaluate for those conditions in patients who have persisting cytopenias because, No. 1, you wouldn’t want to miss that condition, and No. 2, MDS and AML are both absolute contraindications to resumption of PARP inhibition therapy.

When you talk to patients about reducing dose, they become reluctant or anxious because they’re worried that a reduction in dose may mean a reduction in efficacy or effectiveness. But the truth is, when you look across the clinical trials, there were significant numbers of patients who required dose reductions. The trial outcome data include those patients. We’re seeing that despite a dose reduction, we still have a maintenance of effective therapy. The way I explain this to my patients is that we’re trying to find the dose of the medication that works best for her and that she can tolerate. Because our goal is to keep patients on this therapy for hopefully a very long time. We don’t want to push them through toxicities that are unmanageable and require them to come off the treatment. Appropriate modifications or interruptions allow patients to stay on these drugs with appropriate adverse effects.

The clinical trials also assessed quality-of-life data, because they’re also important. Patients don’t want to exchange their cytotoxic chemotherapy for a maintenance drug that causes them to have a significant reduction in their quality of life. We look at quality-of-life data from these PARP inhibitor maintenance trials, including ARIEL3. We see that there isn’t a significant reduction in quality of life between those patients who are randomized to the active treatment arm vs placebo. That’s also reassuring to patients, understanding that though they may have adverse effects, we can manage them, they can live their life, they’re on a pill, they’re not tied to a new infusion center, and their quality of life can be maintained.

Lyndsay Willmott, MD, explains the tolerability of PARP inhibitors for ovarian cancer and how to discuss dose reductions with patients.

Toxicities With PARP Inhibitors for Ovarian Cancer

 The ARIEL3 trial was a large clinical trial looking at patients with platinum-sensitive recurrent ovarian fallopian tube or primary peritoneal carcinoma. These patients received platinum-based cytotoxic chemotherapy and then were candidates for enrollment on the trial if they had at least partial response to their platinum-based chemotherapy. The patients who enrolled on this trial could enroll regardless of 

 mutational status. In other words, all comers were eligible for enrollment. That would include patients with a 

 mutation, patients who had homologous recombination deficiency by virtue of loss of heterozygosity, and patients who were without evidence of homologous recombination deficiency—in other words, patients who were homologous recombination proficient.

All patients were able to enroll and were randomized to receive either rucaparib at the standard starting dose of 600 mg by mouth twice daily or placebo. These patients were subsequently followed until evidence of disease progression or course-prohibitive toxicity. The primary outcome from this clinical trial is progression-free survival. It was done in an interesting trial design of a nested cohort. The initial cohort that was assessed were patients who had a 

 mutation. If there was a signal in that population, which there was, it then opened up to include patients with a 

 mutation and presence of loss of heterozygosity. The third cohort included those 2 first cohorts as well as those patients who were homologous recombination proficient. Then the outcomes assessed all the patients: the large intent to treat group along with these subgroup analyses of these various cohorts.

The outcome from the trial showed that there was very profoundly statistically significant improvement in progression-free survival among all the groups. The most profound was seen in patients with a 

 mutation, which could include either germline or somatic. The second cohort—those patients with a 

 mutation and presence of homologous recombination deficiency—had slight diminishment because of high loss of heterozygosity but still very profound improvement in their progression-free survival.

And then that final cohort, which included patients who are homologous recombination proficient, also had slight diminishment but still profound improvement in progression-free survival that favored randomization to the rucaparib arm. What this is saying and what subsequently occurred is that all patients, regardless of 

 status, are candidates for consideration for rucaparib monotherapy after you finished your platinum-based cytotoxic chemotherapy, along with patients with a platinum-sensitive recurrence, as long as they’ve had at least a partial response to their platinum-based chemotherapy.

We recognize that homologous recombination deficiency is a very important characteristic in the development of ovarian cancer. This leads to problems with the repair of double-stranded DNA breaks. And when you have an accumulation of double-stranded DNA breaks, this leads to genomic instability and the subsequent development of malignancy. When we recognize their inherent problems with the way that ovarian cancer cells can fix their DNA, perhaps we can take advantage of that. That’s this concept of synthetic lethality.

PARP inhibitors work by impairing PARP enzymes, poly [ADP-ribose] polymerase. PARP enzymes are responsible for repairing single-stranded DNA breaks. If we can impair the functionality of that enzyme, or we can perhaps bind that enzyme to the DNA, then that leads to an accumulation of single-stranded DNA breaks. Over time, if those aren’t being repaired, then they can turn into double-stranded DNA breaks. In patients who lack the ability to appropriately repair their double-stranded DNA breaks, they subsequently have overwhelming accumulation of errors and the cells die. This is taking advantage of an underlying impairment in the cancer cell that has led to development of cancer but using it to our advantage.

The ARIEL3 trial confirmed our understanding of PARP inhibition in ovarian cancer. It’s an important trial that demonstrates that patients may be candidates for PARP inhibition regardless of certain types of testing in the recurrent setting. In other words, because of this nested trial design, we’d be able to see if there are only particular patient populations that benefit, and we saw that it appears that all comers benefit. What’s the shared thing that these patients had? This was platinum sensitivity. Platinum sensitivity, in and of itself, is absolutely a biomarker for how patients may respond to PARP inhibition and maintenance.

Obviously, the goal is to push out our platinum-free interval. When we look at the control population from the ARIEL3 trial—those patients who are randomized to placebo—among all these nested cohorts, the median progression-free survival in the patients who are randomized to receive placebo was less than 6 months. When patients are having a recurrence less than 6 months from the completion of their platinum, they are deemed platinum resistant. A platinum-resistant phenotype is a much more complicated phenotype to treat. Unfortunately, there are fewer agents available, and the likelihood of response is poor. Our goal is to try our hardest to maintain platinum sensitivity. If we understand that patients who have a platinum-sensitive recurrence and have responded to their platinum may subsequently be placed onto a PARP inhibitor—in this circumstance, rucaparib based on the ARIEL3 trial—then hopefully they’ll have significant lengthening of their progression-free survival, enabling them to remain in this platinum-sensitive category. Perhaps at the time of recurrence, it will allow us to subsequently re-expose them to platinum.

There are several options for PARP inhibitor maintenance in the recurrent setting. With rucaparib, the ARIEL3 trial has a unique design. There are a large number of patients who were randomized in this trial. Rucaparib itself is a twice-a-day medication. The dosing strategy for rucaparib is different from other PARP inhibitors. There’s a lot more room for a dose modification as necessary. In general, when we start patients on PARP inhibitor maintenance following a platinum sensitive recurrence, that PARP inhibitor is continued until disease progression or prohibitive toxicity. We want to make sure we’re managing toxicities quickly so patients can hopefully stay on these medications for a very long time.

With rucaparib, there’s significant room for dose-reduction strategies. With these dose reductions, we’re not causing huge reductions in the actual amount of dose delivered. The standard starting dose for rucaparib is 600 mg by mouth twice daily. The first dose reduction is to 500, then 400, then 300 mg twice daily. There are multiple levels of dose reductions available, which allows for some degree of flexibility with patient care and is perhaps different from other PARP inhibitors that are available.

A key opinion leader shares data from a phase III, ARIEL3, clinical trial on rucaparib maintenance treatment for ovarian cancer.

Rucaparib Maintenance Therapy in Ovarian Cancer: The ARIEL3 Trial

 This patient was treated by her provider with carboplatin and paclitaxel, which has been established as the standard of care for frontline therapy of ovarian cancer. This is a very reasonable choice. When providers are deciding what they may choose to do in the adjuvant setting, part of what impacts that choice is based on the patient’s surgical outcome. If this patient undergoes up-front surgery and has resected to no gross residual disease, then we may consider them to be in lower-risk group. Though the truth is there are probably no real cases of lower-risk advanced-stage ovarian cancer. But lower-risk groups may include those women who were deemed candidates for surgical excision and then undergo surgery and have resection of all their visible or gross disease, and then subsequently placing them onto carboplatin and paclitaxel.

Interestingly, this patient was then placed onto bevacizumab in maintenance, having not been on bevacizumab as a component of her up-front adjuvant therapy. Personally, I don’t typically start bevacizumab in maintenance setting if I haven’t used it along with cytotoxic chemotherapy, because that isn’t how the initial trials were designed. The initial trials utilized bevacizumab along with the cytotoxic chemotherapy, and then after completion of the cytotoxic chemotherapy, transition to bevacizumab. I’m a rule follower in general, so I typically would utilize the bevacizumab along with the cytotoxic and then start the bevacizumab maintenance.

There have been a number of trials that have had secondary analyses to see who may benefit from the addition of bevacizumab. There’s some suggestion that perhaps these higher-risk patients—patients who required neoadjuvant chemotherapy because their disease burden was too much to undergo an up-front surgery, or patients who had evidence of residual disease at the completion of their surgery—they may benefit from the addition of bevacizumab to the cytotoxic backbone. There may be some consideration for utilizing that triplet therapy in those higher-risk patients.

As far as whether I may have made this with modifications, this patient had a lot of testing in the up-front setting, including HRD [homologous recombination deficiency] testing. Obviously, that’s a different group of patients, so there could be a consideration that if you wanted to use bevacizumab in that patient population, if you’ve used the bevacizumab along with the cytotoxic and the patient subsequently has a diagnosis of HRD, then they would be a candidate to have olaparib added in for maintenance along with their bevacizumab, based on the PAOLA-1 trial. Or if this patient hasn’t had bevacizumab along with her cytotoxic, you could consider adding niraparib after completion of her carboplatin and paclitaxel as maintenance. That’s single-agent niraparib maintenance. That’s based on the PRIMA trial. In that trial, the biomarker specificity wasn’t required to allow those patients to receive niraparib monotherapy based on their trial and break down of the subgroups that were evaluated, which included all comers regardless of 

 status or homologous recombination deficiency. Those are some options for treatment for this particular patient that were a little different from what was discussed within the case.

Many providers have questioned whether all patients with ovarian cancer are candidates for some form of up-front maintenance therapy. Certainly, based on indications, all patients could be candidates for maintenance therapy. Does that mean all patients should get maintenance? These are 2 different questions and answers. The most important thing when we’re talking with our patients with cancer is to understand their goals of therapy and for them to understand the pros and cons of maintenance. Obviously, we have multiple maintenance opportunities, including bevacizumab maintenance, and combination maintenance strategies for patients who have 

 mutations or homologous recombination deficiency with bevacizumab plus olaparib. Patients who have a 

 mutation, either germline or somatic, could be candidates for olaparib monotherapy. For all comers, regardless of 

 mutational status or homologous recombination deficiency status, they could be candidates for niraparib therapy as far as maintenance strategies are concerned.

As it turns out, it appears that all patients with ovarian cancer may be candidates for maintenance. But obviously, these medications have toxicities and pros and cons for use, so it’s very important to talk with your patient about their opportunities for maintenance. Discuss why they meet benefits based on their own particular tumor profiling or genetic status and talk to them about their feelings regarding these toxicities. That can help decide whether patients should go onto maintenance therapy.

The factors that help determine whether you’re going to use maintenance therapy, or which maintenance therapy you use, are determined by which cytotoxic combination you choose. If a patient is going to be going on to neoadjuvant chemotherapy, or someone with significant disease burden was unable to be successfully cyto-reduced to no growth residual disease, and you decide that patient is someone who you want to place onto cytotoxic [chemotherapy] plus bevacizumab, then that may help to direct what you’ll use for maintenance. For example, the majority of providers who start a patient on bevacizumab during their cytotoxic chemotherapy would then subsequently continue that bevacizumab in maintenance. And if you have done molecular testing during treatment, including assessment for presence of homologous recombination deficiency or 

 mutation, then that patient, based on the PAOLA-1 trial, could subsequently start olaparib in maintenance along with their bevacizumab.

Another example of this would be a patient in whom you test during their treatments and you determine that they have evidence of a 

 mutation. That certainly might allow you to decide that you want to transition them from their cytotoxic [chemotherapy] onto PARP inhibitor maintenance. One of the most important things when we look at these clinical trials is that patients have to have at least responded to their platinum-based cytotoxic chemotherapy with partial response at the completion of their up-front chemotherapy. Patients who aren’t responding to their platinum are thankfully very uncommon, but platinum-refractory primary patients probably wouldn’t be the best candidates to go on to a PARP inhibitor, based on their own response. These patient characteristics can help decide what you’re going to use for your initial treatment strategy. And then your initial treatment strategy can certainly influence if you choose to use maintenance, and if so, if you’re going to use some single-agent maintenance or if you’re going to use a combined modality maintenance therapy.

Dr. Lyndsay Willmott discusses the front-line therapy options for ovarian cancer and the factors considered in choosing maintenance therapies.

First-Line Therapies in Ovarian Cancer

 Molecular testing in ovarian cancer is very important—genetic testing, namely. For many years, we used an algorithm to help determine who should be tested, but now we recognize that every woman should be tested for genetic abnormalities regardless of any other prognostic or historical factor, such as age or family history. These types of things no longer matter. Anyone diagnosed with an ovarian fallopian tube or primary peritoneal cancer should have genetic testing. Certainly, there are a number of strategies that can be utilized to determine how you perform this testing. This could mean that you start with germline testing to assess for germline mutation. The majority of providers now recognize that doing 

-specific germline testing is probably not the best way to do this. We should be utilizing panel testing, which can capture a number of the other homologous recombination proteins that can be abnormal in the setting of ovarian cancers. Other providers will start with somatic testing, which can test the tumor to evaluate for the presence or absence of these mutations.

The important thing to remember is that if the testing is negative, that’s not where you should stop. If you have a negative germline test, then perhaps you should subsequently reflex to a somatic test. Similarly, if your somatic testing is negative, then you should consider reflexing to germline testing. Somatic testing can also be a good way to capture patients who have a germline abnormality. If you detect a 

 mutation on a somatic test but the patient hasn’t undergone germline testing, then you should certainly do germline testing to see if that mutation is originating from a germline source. The important difference is that germline testing obviously has implications for this patient. It could mean that she has higher risk of other kinds of malignancies. Also, very importantly, it would trigger us to recommend testing for her family. You’d want to make sure we’re capturing any family members who have these mutations so that we could then intervene to prevent them from developing a malignancy.

Last but not least, it’s important to consider doing homologous recombination deficiency testing. There are a number of tests available, including panels that can assess and assign a homologous recombination deficiency score, or presence or absence of homologous recombination deficiency. Some providers are starting with that testing first because it captures the greatest pool of patients. We estimate that at least 50% of our patients with ovarian cancer have homologous recombination deficiency. If we start with assessment for homologous recombination deficiency, we can subsequently reflex back to the other types of testing, including germline mutational testing. The truth is that we have a number of ways of testing for these abnormalities, and all patients should be getting this testing. The algorithm that you use can be determined by your preferences or your practice’s. It’s important that you’re applying that to all patients so we’re not missing mutations or deficiencies when they occur.

Another important question is whether this testing should be repeated after a patient has been diagnosed with a recurrence. There’s importance to consider that. Certainly, you could consider repeating this testing to see if the patient has developed a 

 mutation. Occasionally, we see the patients in the setting of recurrence actually have subsequently developed a somatic mutation. That may have implications for how you counsel a patient, for how she may respond to certain kinds of therapy, and it may certainly have implications for choices of therapy. It’s important to consider retesting the tumor after the time of diagnosis.

An oncologist explains the importance of molecular testing in ovarian cancer and the implications of testing on treatment selection.

Molecular Testing: Ovarian Cancer

 We’d like to discuss a patient who’s presenting with classic symptoms of ovarian cancer. This is a 57-year-old woman who presented with progressive abdominal discomfort and bloating, as well as early satiety, new onset constipation, and unintentional weight loss. Her past medical history is significant for hypertension, but this has been controlled with medications. She also has a history of osteoarthritis. She comes in for her visit and physical exam reveals some right lower-quadrant tenderness. She is healthy with a performance status of 1.

To work up her symptoms, she undergoes imaging, including an ultrasound, which reveals a 4.5-cm ovarian mass. A CT scan reveals this mass, along with what appears to be lymphadenopathy and ascites. She undergoes a paracentesis for further evaluation, with cytology from that study revealing high-grade serous ovarian cancer. She then also has additional testing following this diagnosis, including germline testing, which reveals no evidence of a 

 mutation, and somatic testing, which is also negative for 

. She has subsequent testing to look for homologous recombination deficiency, and this confirms that she is showing evidence of homologous recombination deficiency.

The patient underwent up-front surgery, which included a debulking with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and resection of those involved lymph nodes. She was able to be resected to no gross residual disease. She was subsequently placed on adjuvant therapy with carboplatin and paclitaxel, which she had every 3 weeks for 6 cycles. She had normalization of her CA [cancer antigen]–125 and no evidence of disease at the completion of her treatment. Following this course of therapy, the patient and her physician had a conversation, and she was subsequently placed on bevacizumab maintenance. Following this, she was monitored. She experienced recurrence of symptoms 2 years later, which included, similar to her initial presentation, abdominal bloating and pain. She underwent imaging as well as continued CA-125 monitoring. CA-125 started to increase, and her imaging revealed recurrent retroperitoneal adenopathy. Because of her disease distribution, she was counseled about returning to chemotherapy. She was placed back onto carboplatin and paclitaxel and experienced a partial response. Following this, she was subsequently placed onto PARP inhibitor maintenance with rucaparib 600 mg twice daily. She experienced toxicity with some thrombocytopenia requiring interruption of her dose and subsequent dose reduction to 500 mg twice daily. The patient is doing well and is being monitored with a plan to continue this therapy until she experiences either additional toxicity or evidence of disease progression.

This young woman is a very classic presentation of ovarian cancer. Unfortunately, ovarian cancer has no screening modality; therefore, the majority of women who present with ovarian cancer present with these relatively innocuous symptoms and unfortunately are diagnosed in stage III or IV disease. The good news is that the majority of women are also platinum sensitive, so most women can get into remission despite presenting with advanced stage. We obviously understand that there are some prognostic factors that can help predict patients who may perform better, including certainly performance status. Other important things include 

 mutation or homologous recombination deficiency, this often means that they’re more likely to be platinum sensitive. The reason for that is related to the mechanism of action of a platinum drug. This causes DNA adducts and subsequently DNA double-stranded breaks. In women who have a 

 mutation, they lack the ability to appropriately repair those breaks and are more likely to be more profoundly platinum sensitive. This patient did not have a 

 mutation, but she was homologous recombination deficient, and that may also allow us to expect that she’d be more likely to have a more profound platinum-sensitive interval. And this person certainly did. This patient had 2 years from completion of her platinum-based chemotherapy before she had evidence of recurrence. These bigger platinum-free intervals are also associated with better likelihood to respond to a platinum rechallenge.

Lyndsay Willmott, MD, presents the case of a 57-year-old woman with ovarian cancer.

Lyndsay Willmott, MD | Authors

Articles

Future Treatments in Ovarian Cancer

Toxicities With PARP Inhibitors for Ovarian Cancer

Rucaparib Maintenance Therapy in Ovarian Cancer: The ARIEL3 Trial

First-Line Therapies in Ovarian Cancer

Molecular Testing: Ovarian Cancer

Case Presentation: A 57-Year-Old Woman With Ovarian Cancer