Chirag Shah, MD, MPH

We have made a tremendous amount of progress, but we have a long way to go if we are going to able to use the word 

 in the management of women with advanced ovarian cancer, which has proven to be a deadly, fatal disease to date. We need to build on the backbone of chemotherapy, and PARP inhibitors have been a tremendous step forward. The use of drugs such as niraparib and olaparib in first-line maintenance setting have extended progression-free survival. Incorporating bevacizumab has also given us 1 more option to consider in these patients, but there is more work to be done.

There are unanswered questions in terms of where immunotherapy, immune checkpoint inhibitors will fit. Ongoing clinical trials will address this question. To-date, the data in immunotherapy have been less than encouraging because of the cold nature in the tumor microenvironment, but we can potentially mediate this with the addition of chemotherapy, biologic agents, and PARP inhibitors. Additionally, looking at TP53 inhibition is a promising area with WEE1 inhibitors. There are data that these may be beneficial in the recurrent setting and where those might fit. There are always emerging data on novel therapeutics, so this is an incredibly exciting time in the management of women with ovarian, fallopian tube, and primary peritoneal cancer. I am thrilled to have the opportunity to offer more than just surgery, carboplatin, and paclitaxel, which have been around forever.

Thank you so much for taking the opportunity to listen to these exciting new data about options that we have or additional treatments in our armamentarium for managing women with epithelial ovarian, primary peritoneal, and fallopian tube cancer. You, our community partners, are such an integral part and are on the forefront of treating these women. We have come a long way from watchful waiting in women with ovarian cancer, when we gave them chemotherapy and knew that they were going to recur at a high rate. We now have not only single-agent PARP inhibitors and single-agent bevacizumab to combination therapy, but there is also a tremendous amount of work being done in clinical trials that we will soon have available. For that, stay tuned to see what we have. It is critical that you take the opportunity to be cognizant of the maintenance options available for these women and have a discussion with them about what the risk-benefit profile looks like and what maintenance therapy provides for them in terms of prolonging their interval to resuming systemic chemotherapy.

Case: A 67-Year-Old Woman With Ovarian Cancer

A 67-year-old female presented with abdominal discomfort and modest weight loss

PMH: unremarkable, postmenopausal; no known family history of cancer

PE: diffuse tenderness to abdominal palpation, abdominal bloating

Pelvic exam with transvaginal ultrasound showed a left ovarian mass

Chest/abdomen/pelvis CT with contrast revealed a left adnexal 5-cm mass, pelvic and inguinal lymph node involvement, no pleural effusion

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

Diagnosis: Stage 4, high-grade epithelial ovarian cancer

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

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A leader in gynecologic oncology, Chirag Shah, MD, MPH, provides insight into the future of ovarian cancer by discussing the potential for immunotherapy, TP53 inhibition, and novel therapeutics on the horizon.

Future Directions in Ovarian Cancer

As we circle back to our patient in this case presentation, this question of platinum sensitivity is going to define what happens next. If she is platinum resistant, the treatment options are different from platinum sensitive. In the setting of platinum-sensitive recurrence, the standard of care would be re-treatment with platinum-based doublets. There are a range of options that could be considered: carboplatin; liposomal doxorubicin, which is consistent with the CALYPSO trial; re-treatment with carboplatin-paclitaxel, which has been evaluated in a number of trials; or carboplatin-gemcitabine with the use of bevacizumab, which was evaluated in the OCEANS trial.

Subsequently from the data that were presented from the NOVA trial, if a patient has a platinum-sensitive recurrence, you could re-treat with the PARP inhibitor theoretically as long as the patient had not had progression while she was on her frontline PARP inhibitor. The benefit of PARP inhibitor therapy in patients who have progressed is unknown and likely not effective.

Chirag Shah, MD, MPH, discusses platinum sensitivity vs resistance impact treatment selection in subsequent lines of therapy.

Platinum Sensitivity vs Resistance and Treatment Selection in Ovarian Cancer

The landmark PRIMA trial was published in late 2019. This trial evaluated over 700 patients in a randomized, double-blinded, placebo-controlled fashion with a 2:1 randomization of niraparib vs placebo. The primary end point in this trial was progression free survival [PFS] in the group of women with homologous or a combination deficiency. There was a coprimary end point of looking at the progression-free survival in the overall patient population. The response rates were derived in terms of resist and response rates. It was an international trial with a robust scientific design as well as large volume of patients.

In addition, in terms of the study trial design, after the completion of chemotherapy, the patients received 3 years of niraparib vs placebo in that 2:1 randomization. In terms of results, 50% of the patients did have HRD [homologous recombination deficiency]. In that patient population, there was a highly statistically significant benefit to the use of niraparib as compared with placebo, with nearly a doubling of the progression-free survival of 22 months vs 10 months. In the overall study population, which was a predefined coprimary end point, there was also a statistically significant benefit with a PFS advantage of over 5 months: 13.8 months vs 8.2 months.

The most common adverse events of grade 3 or higher in the trial were anemia, thrombocytopenia, and neutropenia, ranging in rates from 12% to 30%. These were consistent with what were seen in previous trials and were well managed with dose reductions and modifications. The overall discontinuation rate due to toxicities in the trial was relatively low at 12%. Additional adverse effects that were seen included, nausea, abdominal pain, and fatigue, and these were also seen at fairly common rates in the patients who were in the placebo group.

In terms of my clinical experience, I have both enrolled patients on the PRIMA trial, because we [at Swedish Cancer Institute] were a study site for this trial. In addition, off-trial, we have used niraparib in frontline maintenance, and I have found that the benefit is consistent with what has been seen in this clinical trial. The toxicities often become something that we have to manage. There are the toxicities we see, then there are the toxicities patients feel. Those in the labs in terms of the hematologic toxicities are often things that we have to follow pretty closely. In terms of monitoring, 1 of the additional pieces that has to be monitored to address toxicities is the CBC [complete blood count], but also consistent with the new labeling is watching blood pressure. CBCs and blood pressure should be monitored weekly in the initial period.

Oftentimes, the dose may need to be adjusted within the first month of therapy. Based on this trial, there is new dosing dictated by the patient’s weight and by what their most recent platelet level is. If their platelet level is below 150,000 per mm3 or if their weight is below 70 kg, then the starting dose that is recommended is 200 mg daily, which is 2 capsules daily. For patients who are above that weight or platelet level, the standard dosing is 300 mg. Monitoring these labs and frequent communication with the patients will allow you to be more thoughtful in terms of avoiding significant grade 3 toxicities. Once you get to a stable dose, in my experience, most of the time, patients are able to stay on that dose for an extended period of time. The clinical trial was designed to have maintenance therapy continue for 36 months or 3 years, which is what I recommend to patients. The discontinuation would primarily be because of toxicities or at progression.

When we look at agents in addition to chemotherapy in the treatment of women with ovarian cancer, there has certainly been a push to try to get agents to the earlier lines of therapy, primarily because we know that there is such a high recurrence rate. Additionally, this defined concept of platinum resistance ends up potentially limiting our options. As we look at the PRIMA trial and others like it, such as the SOLO-1 trial, which evaluated the use of olaparib in patients with germline 

 mutations as maintenance, the primary rationale was to try to get synergy with the PARP inhibitor after platinum-based chemotherapy. This was building on data that we have seen in the preclinical setting that suggest that PARP inhibition after platinum-based chemotherapy is beneficial and prolongs or maintains remission.

In 2019, the international NOVA trial was also published. This trial had 550 patients who were broken into 2 primary cohorts. The first was patients that were germline 

 mutated, and then the second cohort of patients was those who were nongermline 

 mutated. These patients were then randomized after platinum-based chemotherapy when they were found to have a response in the platinum-sensitive setting, which means they had a greater than 6-month treatment-free interval to their platinum-based chemotherapy. After re-treatment with platinum chemotherapy, they were started on niraparib vs placebo at a 2:1 randomization. The primary end point in the NOVA trial was progression-free survival. In the trial, progression-free survival was significantly improved in both cohorts: both the germline 

-mutated cohort as well as the nongermline 

-mutated cohort, there was a highly statistically significant benefit in terms of progression-free survival with the patients receiving niraparib having a median progression-free survival of 21 months vs 5.5 months in the placebo group. In the nongermline 

-mutated cohort, there was also a statistically significant benefit to niraparib. The niraparib cohort had a 9.3-month progression-free survival vs 3.9 months for the placebo group.

An expert in gynecologic oncology reviews the PRIMA and NOVA clinical trials and discusses their implications for the management of ovarian cancer. 

Clinical Trials in Ovarian Cancer Maintenance: PRIMA and NOVA

In my practice [Swedish Cancer Institute], I consider and discuss maintenance therapy with all my patients. That discussion usually happens prior to when they begin systemic therapy. It is best to define what their treatment course is going to look like prior to when they are having oncologic therapy. The discussion also helps frame the fact that surgery, chemotherapy, and maintenance are all designed to derive the best long-term patient benefit.

The question of which maintenance therapy to employ will boil down to the individual patient. For any patient who has been diagnosed with a germline 

 mutation, it would absolutely be in that patient’s best interest to be on a PARP inhibitor. The question of whether to add something in addition to that PARP inhibitor boils down to what that individual patient’s situation is. A patient with significant ascites, stage IV disease, similar to our case here, might benefit from the addition of Avastin [bevacizumab]. The question of whether to combine agents is evolving, and we have a number of clinical trials, that are either accruing or have accrued, that will help us define this emerging area. But for the time being, the option of maintenance is something important to discuss with every one of my patients.

In practice, for the patients who do not receive maintenance of some type, it is almost exclusively because they are either not healthy enough or they have had too much toxicity from their earlier lines of therapy, which is primarily the chemotherapy. It could also be the case that their performance status is poor, or they are the rare person who decides after counseling that they just do not want to proceed with any form of maintenance therapy.

Chirag Shah, MD, MPH, provides key insights into factors to consider when counseling patients with ovarian cancer on the available treatment options for maintenance therapy.

Options for Maintenance Therapy in Ovarian Cancer

This question of tumor testing and germline testing is about what type of testing we use and for whom do you get what test. It has been a moving target over the past few years. We have certainly come a long way in our understanding of the genetics and the Fanconi anemia pathway through the hard work of investigators and discovering that, in addition to BRCA, there are other mutations that can occur, both germline inherited or within the tumor that predispose a patient to the development of these cancers.

Our current pathway is to obtain germline testing for all women who are diagnosed with epithelial, ovarian, primary peritoneal, or fallopian tube cancers. This is consistent with NCCN [National Comprehensive Cancer Network] Guidelines, which suggest that all patients should obtain germline tumor testing. The subsequent pathway is then dependent on your germline testing results. If the patient is known to have a germline tumor test that is positive, then the need for molecular testing somewhat obviated, at least in the initial setting. Based on the results of the germline tumor test, we then reflexively decide to do molecular testing. If a patient is germline 

 negative, tumor testing can then be obtained. There are a number of tumor tests that are commercially available, and there are institutional tumor tests. We are predominantly speaking about HRD [homologous recombination deficiency], which has been demonstrated to be present in about 50% of somatic samples or tumors that are found of this type, and it also includes the tumor 

 mutations. In addition, it is present in tumors that have large-scale translocations, telomeric allelic imbalance, and then loss of heterozygosity [LOH], which are the scars that result in tumors that have deficient DNA repair. This can be quantified by these assays and then used as an actionable target for determining if patients might derive additional benefit from a molecule such as a PARP inhibitor.

The primary benefit is that it can help you be consistent with FDA approvals and decide what medication or combination of medications you might consider for maintenance therapy. It is also incredibly useful for counseling our patients in terms of what the prognostic implications of the addition of maintenance therapy might mean for them. Essentially, the pathway that we employ is to begin with germline tumor testing, and the patient usually goes through the process of referral to genetic counselors. Once we obtain those results, we will move forward with tumor testing. There are additional benefits to tumor testing outside the LOH or HRD status; the discovery of mutations that might be actionable targets for therapy in the recurrent setting is also useful. For patients who do not receive PARP inhibition up front or who are not started on that medication initially, it may help us to define their benefit in subsequent lines of therapy.

Key opinion leader in obstetrics and gynecology Chirag Shah, MD, MPH, discusses best practices for molecular testing and genetic counseling for patients with newly diagnosed or relapsed ovarian cancer.

Molecular Testing in Ovarian Cancer

This is a fairly characteristic patient that we might see in my practice [Swedish Cancer Institute]. The average age of incidence of most nongermline 

-mutated ovarian cancers is 61 years of age, so patients often present in the postmenopausal setting with fairly nonspecific symptoms. Thankfully, because of a number of advances that we are going to have the opportunity to discuss today, the survival for ovarian cancer has improved over the last 2 decades, although historically, if we go back to the mid-2000s, we had about a 10-year gap where there was no novel therapeutic agent for women with ovarian cancer.

The biggest issue with women with ovarian cancer is that, although they respond well to frontline chemotherapy as our patient in this hypothetical example did by ending up with a complete remission, there is high relapse rate: 70% to 80% of patients that reach a remission will still have recurrent disease. Unfortunately, a significant proportion will have disease recurrence in less than 6 months, which we use to define what is called the platinum-free interval. If a patient has recurrence in less than 6 months, they are defined as platinum resistant. If their recurrence happens at greater than 6 months, they are defined as platinum sensitive.

The overall prognosis for this patient is improved by the fact that she had a complete surgical cytoreduction. Certainly the longest overall survival we have seen is in patients who were able to be cytoreduced to no gross residual disease, so this is a paradigm shift from a decade ago or longer when an optimal surgical cytoreduction was the goal, where we were just trying to get to less than 1 cm of disease. Suboptimal patients, which are those who have the poorest prognosis, are patients who have greater than 1 cm of disease. First of all, our patient here fell into the best prognostic category in terms of her surgery, ending up with a complete cytoreduction.

We know a priori that patients with stage IV disease tend to do more poorly, and that is where the question of maintenance therapy is in forefront of the management of women with epithelial, ovarian, fallopian tube, and primary peritoneal cancer. Those 3 disease sites, for all intents and purposes, get managed under the same umbrella of ovarian cancer. They are felt to be the same biologically, they are felt to be the same molecularly, and they behave the same clinically.

As I mentioned, the recurrence risk is quite significant, so through rigorous clinical trials and now clinical experience, we have grasped what is occurring in a number of other solid tumors, which is a maintenance therapy. This patient was started on niraparib maintenance, but there are other maintenance options available. The FDA has approved frontline bevacizumab maintenance for patients with epithelial, ovarian, primary peritoneal, and fallopian tube cancers. In addition, with the combination of bevacizumab and olaparib, another PARP inhibitor, or olaparib frontline maintenance, there are various differences to the indications of those particular medications. The FDA approvals for any patient regardless of their status are for niraparib alone as monotherapy in maintenance and bevacizumab as frontline maintenance.

Chirag Shah, MD, MPH shares insight into factors influencing the prognosis of patients with ovarian cancer.

Chirag Shah, MD, MPH | Authors

Articles

Future Directions in Ovarian Cancer

Platinum Sensitivity vs Resistance and Treatment Selection in Ovarian Cancer

Clinical Trials in Ovarian Cancer Maintenance: PRIMA and NOVA

Options for Maintenance Therapy in Ovarian Cancer

Molecular Testing in Ovarian Cancer

Predictors of Recurrence in Ovarian Cancer