Hello. My name is Shannon Westin, and I am a Professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at the University of Texas MD Anderson Cancer Center in Houston, Texas. 

In this module, I will be talking about “Improving Provider Awareness About Healthcare Equity: Improving all Patients’ Access to Care in Ovarian Cancer.”

The charts on the right show more detail about the racial and ethnic differences that may have a role in ovarian cancer risk and survival outcomes. Sometimes healthcare professionals assume that racial and ethnic women present with worse histologic subtypes, which contributes to their worse outcomes. However—and in fact—Black women have a lower overall incidence of ovarian cancer, yet across different histologic subtypes and different stages of disease they experience the worst 5-year survival outcomes.⁹

How might we make things better? Data show that treatment at high-volume centers does improve outcomes, and that has been demonstrated specifically in Black patients with ovarian cancer. 

More than one half of all patients with ovarian cancer receive treatment in a low-volume hospital by a low-volume physician, and that is tied to worse overall outcomes for those patients.^10,11 Specific sociodemographic factors are independently associated with receipt of care at a low-volume hospital by a low-volume physician, including Hispanic ethnicity, Asian/Pacific Islander race, Medicaid insurance coverage, and low socioeconomic status (odds ratio: 0.9-2.84). Thus, factors beyond a patient’s control, such as socioeconomic status and race and ethnicity, can affect their overall survival.

The slide on the right emphasizes the importance of guideline-recommended care. Many healthcare professionals rely on the National Comprehensive Cancer Network guidelines to inform how to best care for patients on a day-to-day basis, and data show that patients with ovarian cancer who do not receive guideline-based care experience worse outcomes. One study by Chatterjee and colleagues¹² found that 56% of patients with ovarian cancer do not receive guideline-based care. Specifically, 25% of these patients received care at low-volume centers, and this was an independent predictor of worse overall survival. In another study by Bandera and colleagues,¹³ the inadequacies in care delivered to Black patients included lower doses of chemotherapy, delays in treatment, and early discontinuation of therapy.

Strategies for counteracting disparities in patients with ovarian cancer include following clinical guidelines and directing patients to high-volume hospitals. Participation in clinical trials also may help overcome disparities. Data from a retrospective study presented in 2018 found that White race was associated with significantly better overall survival in ovarian cancer (P = .0591).¹⁴ Of interest, underrepresented patients of color who participated in clinical trials had survival that approached that of White patients (median overall survival: 53.5 vs 50.9 months; P = .6269). This was very exciting because it suggested that receiving care within a clinical trial could improve overall survival for underrepresented patients of color. 

I would like to move on to discuss risk factors, as well as the testing that can be done to help guide care in ovarian cancer.

Based on current guidelines, genetic/molecular testing is indicated for all patients with ovarian cancer.^15-18 At a minimum, germline testing should be performed for BRCA1, BRCA2, and other ovarian cancer susceptibility genes, such as Lynch syndrome genes and others.19 Genetic testing should be performed for any patient with epithelial ovarian cancer regardless of family history or age at diagnosis. In addition, somatic tumor testing is essential for BRCA1, BRCA2, and other likely pathogenic variants. Although somatic testing is recommended for patients without germline mutations, it can be done for all patients with epithelial ovarian cancer. It is important to remember that patients with nonserous subtypes such as clear cell, mucinous, and endometrioid ovarian cancer should undergo testing, as well.

Key genetic findings of interest involve alterations in homologous recombination repair genes. Presence of these alterations informs the need for screening to reduce the chance of other cancers in these patients and the ability to implement certain treatment options. Aberrations in BRCA1, BRCA2, RAD51C promoter methylation, and other genes in the Fanconi anemia pathway, all of which contribute to homologous recombination deficiency (HRD), are found in approximately 50% of high-grade serous ovarian cancers, which could make these tumors sensitive to PARP inhibition.²⁰

When looking at guideline-recommended genetic testing in women according to race, fewer Black patients with ovarian cancer receive testing compared with other races.²¹ Testing of Hispanic women also is quite low. That said, only 24.9% of non-Hispanic White women undergo such testing, so clearly we have a long way to go for all races. 

Regarding treatment of advanced ovarian cancer, the combination of surgery and adjuvant chemotherapy has been the standard of care for some time, although some patients may receive neoadjuvant chemotherapy.¹⁵ In general, a platinum doublet that includes paclitaxel is the standard of care, although other combinations might be used, as well. The addition of bevacizumab has been used both in the adjuvant setting in combination with chemotherapy and in the maintenance setting. For patients with BRCA1/2 mutations or HRD status, PARP inhibitors can be used in the maintenance setting. 

When patients develop disease recurrence, a wider array of options is available—typically single-agent chemotherapy or combination chemotherapy in tandem with bevacizumab. Molecular testing also can be used to guide therapy in the recurrent setting. For example, patients with high microsatellite instability or the presence of high tumor mutational burden potentially can receive immunotherapy. Patients with NTRK fusions can receive entrectinib or larotrectinib. Although not very common in ovarian cancer, RET fusion‒positive tumors can be treated with selpercatinib.

As previously mentioned, single-agent PARP inhibitors are indicated for frontline maintenance. Niraparib is indicated across all-comers who responded to first-line platinum-based chemotherapy,²² whereas olaparib is indicated for patients with germline or somatic BRCA-mutated ovarian cancer who responded to first-line platinum-based chemotherapy.²³ If you have a patient with HRD-positive disease whom you already started on bevacizumab, you can continue bevacizumab in combination with olaparib.

In the recurrent setting, maintenance options include all 3 PARP inhibitors: olaparib, rucaparib, and niraparib. 

Olaparib can be used for patients with a germline/somatic BRCA mutation or HRD status and fewer than 3 previous chemotherapy regimens.²³ Rucaparib can be used for patients with a germline/somatic BRCA mutation or HRD status and fewer than 2 previous chemotherapy regimens.²⁴ Niraparib can be used only in the setting of deleterious (or suspected) germline BRCA mutation and fewer than 3 previous chemotherapy regimens.²² In the recurrent setting, all patients must have platinum-sensitive disease, regardless of the biomarker.

Now I would like to switch focus to the PARP inhibitor data that led to the current indications in ovarian cancer. The table on the right shows a compilation of clinical trials for the various PARP inhibitors currently used in the frontline setting. They include:

• PRIMA: a phase III trial that assessed niraparib in patients with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer and response to first-line platinum-based chemotherapy regardless of BRCA status²⁵
• PRIME: a phase III trial performed only in China that used an individualized dosing strategy for niraparib of 200 mg for patients weighing <77 kg or with a platelet count <150,000/µL, or the standard dosing in all other patients²⁶
• SOLO-1: a phase III trial that evaluated olaparib in stage III/IV high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with BRCA mutation²⁷ 
• ATHENA-MONO: a phase III trial that assessed rucaparib in patients with stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer regardless of BRCA status²⁸ 
• PAOLA-1: a phase III trial that evaluated the combination of olaparib and bevacizumab in patients who already had received bevacizumab with adjuvant chemotherapy and HRD testing²⁹ 

Although there are some minor differences in all of these trials, the bottom line is that the PARP inhibitors were given to patients who benefitted from frontline platinum-based therapy. These trials consistently demonstrated benefit across all-comers. However, the largest reductions in the risk of progression were observed among patients with a BRCA mutation and/or HRD status. There does seem to be a modest benefit for patients with homologous recombination proficient disease, but it is not as dramatic as the outcomes for the other 2 biomarker-driven groups.

When administering maintenance therapy, especially in the frontline setting, it is important to consider the potential adverse events (AEs) that patients might experience. As a class, PARP inhibitors are associated with various gastrointestinal toxicities, such as nausea (53%-77%), diarrhea (18%-34%), constipation (27%-39%), and dysgeusia (26%).^25,29,30 In addition, fatigue often is an issue and should be monitored closely. Bone marrow toxicity, including anemia, thrombocytopenia, and lymphopenia, also is commonly observed across all the PARP inhibitors. Anemia was a key AE of interest with olaparib in SOLO-1³⁰ and niraparib in PRIMA.²⁵ In PAOLA-1, hypertension emerged as a key AE of interest when olaparib was combined with bevacizumab.²⁹ In addition, the incidence of thrombocytopenia was a bit higher for patients who received niraparib in PRIMA (46%).²⁵

Overall, the majority of patients receiving PARP inhibitor maintenance will have AEs.^22,23,25,31 Grade >3 AEs were numerically higher in the PRIMA study vs the SOLO-1 study (71% vs 40%). Moreover, 80% of patients in PRIMA required a dose interruption vs 52% in SOLO-1.^25,31 However, we need to remember that the PRIMA results were reported before implementation of the individualized dosing strategy, which would prescribe for a dose reduction automatically based on patients’ weight or platelet count, as stated before.²² Of importance, the rates of myelodysplastic syndromes and acute myeloid leukemia (0.8%-1%) in these frontline studies are quite low, as are the rates of new primary malignancies (3%). 

There are strategies for preventing and managing the hematologic AEs associated with PARP inhibitors to help patients stay on treatment and live longer.^22-24,32 The strategy for patients with grade 1 hematologic AEs is to watch them closely and perhaps investigate other causes of cytopenia. Grade ≥2 anemia or neutropenia is the time to hold therapy and monitor blood counts until they return to grade 1 or better. Unfortunately, if things do not get better after 28 days, the patient should stop therapy. At that point, in the context of anemia or even neutropenia, one may want to consider a bone marrow biopsy to ensure the patient has not developed myelodysplastic syndromes or acute myeloid leukemia. 

For thrombocytopenia, the management approach is a bit different.^22-24,32 For grade 1 thrombocytopenia, one should hold treatment because the platelet count can fall quite quickly. To that end, it is important to monitor the complete blood count for patients at least weekly, especially those receiving niraparib. Treatment can be resumed at the same dose or at a reduced dose depending on how well the platelet count returns to normal. A patient with ≥2 instances of grade 1 thrombocytopenia needs a reduced dose. For grade 2 or 3 thrombocytopenia, treatment should be held for a maximum of 28 days and then resumed at a reduced dose, or discontinued if the patient is already at the lowest dose.

To see recommendations from 5 experts for maintenance therapy for advanced ovarian cancer based on specific patient and disease characteristics visit: clinicaloptions.com/GYNCI2022tool

Now I will move on from frontline maintenance to a novel treatment called mirvetuximab soravtansine, an antibody‒drug conjugate targeting folate receptor α (FRα) in patients with platinum refractory/resistant ovarian cancer. Mirvetuximab soravtansine was approved by the FDA in November 2022 for adult patients with FRα-positive ovarian, fallopian tube, or primary peritoneal cancer refractory or resistant to platinum-based chemotherapy and 1-3 previous chemotherapies. The approval of mirvetuximab soravtansine was based on positive results from the single-arm phase III SORAYA study.^33,34 For enrollment on SORAYA, patients had to have high-grade serous disease, prior bevacizumab, and high expression of FRα, defined as positive staining of ≥75% of cells. Patients were treated every 3 weeks with IV mirvetuximab soravtansine until disease progression or unacceptable toxicity. The primary endpoint was overall response rate by the investigator. The results for the primary endpoint showed that mirvetuximab soravtansine yielded a 32% response rate, with a median duration of response of 6.9 months. The FDA approval has the requirement of a companion diagnostic for the FRα expression.

Some of the most common AEs with mirvetuximab soravtansine are related to eye toxicity, including corneal inflammation (29%), dry eye (25%), and blurry vision (41%). Patients should be advised to promptly tell their provider about any new or worsening vision changes or eye pain. Moreover, gastrointestinal symptoms of diarrhea (22%), nausea (29%), and vomiting (11%) also were observed. Most ocular and gastrointestinal AEs were low grade and reversible. 

Grade ≥3 treatment-related AEs led to dose delays in 33% of patients, dose reduction in 20%, and treatment discontinuation in 9%.

It also is important to consider that patients receiving mirvetuximab soravtansine may need to undergo frequent eye exams during treatment and use prophylactic steroid eye drops: 1 drop per eye 6 times per day before infusion and on infusion Day 1 to 4 days after infusion, 1 drop per eye 4 times per day 5-8 days after infusion, and preservative-free lubricating eye drops 4 times per day or as needed. 

The confirmatory trial of SORAYA, called MIRASOL, has begun enrollment, and we are awaiting the results. In this phase III trial, patients with platinum-resistant ovarian cancer are randomized to receive either mirvetuximab soravtansine or the investigator’s choice of chemotherapy, which could be weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan (NCT04209855).

As previously mentioned, we want to encourage enrollment of underrepresented patients of color on clinical trials. To do this, we need to meet patients’ needs and values by understanding what their preferences and goals are if participating in these trials.

Over the years, we have seen significantly lower participation of Black patients in clinical trials, particularly compared with White patients. An analysis that assessed studies performed by the Gynecologic Oncology Group in patients with ovarian cancer, endometrial cancer, cervical cancer, and sarcoma very conclusively showed low participation rates among Black patients compared with White patients.³⁵ Despite outcomes often being worse in Black patients and their higher incidence of advanced disease, they still were not included on these clinical trials.

The same study also explored enrollment on clinical trials based on the age-adjusted incidence of the gynecologic malignancies to determine whether the frequency of these cancers had a role in the disparities.³⁵ When comparing the expected clinical trial participation rates of Black patients with the observed rates, there was approximately a 15-fold underrepresentation of Black patients with ovarian cancer, a 10-fold underrepresentation of Black patients with endometrial cancer, a 4-fold underrepresentation of Black patients with cervical cancer, and a 5-fold underrepresentation of Black patients with sarcoma. These very clear differences underscore the unmet needs regarding enrollment of Black patients on these clinical trials.

If we look at the preferences of patients with ovarian cancer, they want to understand the trade-offs between quantity of life and quality of life.^39,40 Is the treatment worse than the disease? How will this affect their family? Those issues need to be included in the educational process so patients can choose the right option for themselves. 

Regarding the goals of treatment, it is important for patients to understand whether we are hoping to achieve complete tumor resection or extend disease remission and improve quality of life. That type of targeted education and understanding will help overcome misconceptions and help patients feel more comfortable enrolling on clinical trials.

As healthcare professionals, we need to ensure that we are effectively communicating with patients and understand their satisfaction with their treatment.^36,37,40,42 How well are they tolerating therapy? What are their symptoms, and how severe are they? Do they feel supported? Are they able to get to and from their treatment appointments and clinical visits? Are they experiencing financial toxicity? Understanding all of these issues is necessary for fine-tuning treatment, helping patients navigate insurance claims or financial assistance programs, and trying to develop a unique care plan for each patient.  

A useful patients resource with links to financial assistance programs can be downloaded here. 

Several ongoing trials in ovarian cancer are evaluating promising therapies such as mirvetuximab soravtansine (GLORIOSA; NCT05445778); tumor-treating fields in combination with targeted therapy, immunotherapy, or platinum-based chemotherapy (2021-0299; NCT05092373); relacorilant, a glucocorticoid inhibitor, with nab-paclitaxel vs nab-paclitaxel (ROSELLA; NCT05257408); and niraparib plus bevacizumab with or without dostarlimab immunotherapy, or platinum-based chemotherapy with or without bevacizumab (OPAL; NCT03574779). Visit clinicaltrials.gov for enrolling clinical trials near you.

Regarding communication, we need to improve communication between patients and healthcare professionals, acknowledge patients’ beliefs and values, minimize healthcare professional bias, ensure that we are offering clinical trials to all patients, and work on having the medical care team be representative of the patients they are treating.^12,38,43 Regarding costs, we have to work on reducing treatment costs and provide support for costs unrelated to medications, such as transportation and missed wages. Regarding gaps in outcomes research, we need to increase the representation of underrepresented groups in clinical trials and understand not only the social differences, but also the genetic and potential molecular differences in tumor biology based on race. 

Oncology pharmacists, nurses, patient navigators, and other members of the healthcare team can help empower patients and ensure that they have adequate resources and education so they can make the right treatment choices for themselves. 

A useful handout to help inform patients about improving patient-HCP communication and treatment choices for the management of cervical cancer can be downloaded here.