Experts in Ovarian Cancer Discuss Targeted Agent Combinations and Disparities in Care

The ovarian cancer treatment landscape, including the use of cytotoxic and targeted therapies, is continuously evolving for patients. Although the standard of care in the front-line treatment of advanced ovarian cancer is a combination of chemotherapy and surgery, recent trials have evaluated PARP inhibitors, antiangiogenic agents, and other targeted therapies. Investigators are looking at strategies to individualize care, not only to find the best treatment practices but also to ensure all patients receive the care they need regardless of where they live or their financial status.

The ongoing research in this setting is encouraging because ovarian cancer is the fifth-ranking cancer for number of deaths among women, with an estimated 13,770 who will die from the disease in 2021 in the United States.¹ Approximately 21,410 women will receive an ovarian cancer diagnosis in 2021. Although the disease mainly develops in women over the age of 50 years, it can affect women of any age.

“The most common type of ovarian cancer, serious carcinoma, more commonly affects women in their 50s and 60s, but that is not to say that does not affect young women who are in their reproductive years or women who are already mothers into their older years,” Erin E. Medlin, MD, a clinical physician at Penn Medicine Lancaster General Health in Lancaster, Pennsylvania, said in an interview with Targeted Oncology.

A Genetic Disease

“About 25% of all ovarian cancers are going to be caused by an inherited genetic mutation, meaning patients inherit something in their DNA from 1 or both parents that puts them at an increased risk for developing ovarian cancer, in addition to other cancers,” Joshua P. Kesterson, MD, a gynecologic oncologist and chief of the Division of Gynecologic Oncology at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, told Targeted Oncology.

BRCA mutations are one of the most common genetic aberrations that can be passed down to daughters or sons of BRCA-mutation carriers.² The standard in this setting is to test all women with newly diagnosed ovarian cancer for BRCA or other inherited mutations, “with genetic counseling and genetic testing, blood or saliva is used to [discover] what’s going on at a DNA level,” according to Kesterson.

Olaparib (Lynparza) plus bevacizumab (Avastin), olaparib plus rucaparib (Rubraca), or olaparib as monotherapy can be used for patients with BRCA mutations after chemotherapy.³ Niraparib (Zejula) can be used as maintenance after platinum chemotherapy or after several lines of chemotherapy.

While ovarian cancer most often affects post-menopausal women, young women interested in preserving their fertility options may also be affected.

“In terms of how we see therapies related to fertility, carboplatin-based therapies for women who are able to preserve fertility have little effect on the long-term reproductive outcomes,” Medlin said.

Several trials have examined the preservation of fertility. One of those was ended early because the treatment of oocyte vitrification, or freezing the patients’ retrieved oocytes through vitrification, was deemed a standard of care before the trial finished (NCT01268592).

“Some women who have an early-stage ovarian cancer will be candidates for fertility- preserving surgery, meaning that they’re able to keep their uterus and ovary. If that is something that could be considered, they should talk to their provider,” Medlin said.

Potential Treatments and Strategies in Ovarian Cancer

Investigators are looking into how to individualize care for these patients. At present, the surrogate biomarker used most often is platinum sensitivity; however, identifying more biomarkers, and targeted agents for those biomarkers, will be beneficial to this setting.

“Something that I think will probably come first and what has been the trend within trials is [that investigators will] look first in the recurrent setting,” Medlin said. “[In other words, they will be] looking at women who have platinum-sensitive recurrence and instead of getting a platinum- or carboplatin-based therapy, swapping that out for a PARP inhibitor or another targeted agent and comparing that with chemotherapy. [Investigators are] trying to understand if we could give a PARP inhibitor or a more targeted therapy in this setting as opposed to chemotherapy, which has less toxicity or [fewer] adverse effects.”

Immunotherapy is also undergoing evaluation. Although it hasn’t shown much efficacy as a single-line treatment, immunotherapy is now being investigated in combination with chemotherapy. One such trial is looking at pembrolizumab (Keytruda) plus cisplatin and rintatolimod in patients with recurrent ovarian cancer (NCT03734692). This regimen is a combination of systemic immune checkpoint blockade and intraperitoneal chemoimmunotherapy.

“The peritoneal cavity is where these tumors often present and recur. So we need to treat locally but do so with the benefit of not just traditional cytotoxic agents, but also inducing an immune response or immune-modulating agent locally. I think that’s incredibly exciting,” Kesterson said. He believes this strategy of treating patients could lead to a potential paradigm shift.

Investigators are also studying chimeric antigen receptor (CAR) T cells to see how well they will work in ovarian cancer. “Those trials are undergoing intense scrutiny as well,” Medlin said. Investigators in 1 trial, which is based in China, are studying mesothelin (MESO)-CAR T-cell therapy in patients with relapsed or refractory disease (NCT03799913). This early phase 1 trial is still actively recruiting patients to receive anti–MESO-CAR T cells, fludarabine, and cyclophosphamide.

Antifolate antibody therapy, antibody-drug conjugates, and hormonal therapy are other possibilities in different types of ovarian cancer and are undergoing research in this setting. Beyond the newer therapies being investigated, another important aspect is determining the optimal sequence of therapies to provide the best quality of life, as well as the longest survival rate possible.

“Speaking to quality of life, I think we have an increased appreciation of the need to truly monitor the patient-reported outcomes beyond that metric of just progression-free survival and overall survival. Although [those are] incredibly impactful and appreciated from a clinical trial and efficacy standpoint, what we need to do is individualize that care so we can align patient expectations with physician expectations to choose the ideal regimen for these women,” Kesterson explained.

Finding the best sequence of treatment will be beneficial, especially for patients who have progressed on platinum chemotherapy, who Medlin believes have an unmet need in this space. “Once patients progress, they tend to cycle through treatment options and continue to fail next-line therapies,” she said. To find an appropriate treatment beyond chemotherapy, she suggests exploring possibilities such as precision medicine, using molecular testing to find biomarkers, getting more up-to-date biopsy samples, or using artificial intelligence technology.

“Potentially, artificial intelligence [could] take all that information from patients and help the clinician find the drug that’s going to be most helpful to them. I think we’ll continue to build it in that space as these more targeted therapeutics come out, [and figure out] how we can get all these patient data and funnel them into the correct choice as the next line for the patient, Medlin said.

Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer

At the annual SGO meeting in March, results were presented from multiple studies on different therapies that may be used to treat patients with ovarian cancer and potentially change the standard of care in this setting.

“I think there’s some incredibly clinically relevant data…coming out regarding the use of PARP inhibition in the recurrent setting. [It’s] showing some impressive efficacy, even in those who had platinum-sensitive recurrent ovarian cancer, who are BRCA mutated, or who were treated with either a PARP inhibitor or with a platinum-based regimen,” Kesterson said. “Those treated with PARP inhibitors did exceedingly well; that rivaled, if not surpassed, the benefit from an outcomes perspective as well as from an adverse effect perspective, when compared with our standard of treating this platinum-sensitive patient with a platinum-based doublet in a recurrent setting.”

One trial whose results showed significant improvement among patients in progression-free survival and duration of response was the multicenter, randomized, phase 3 ARIEL4 study (NCT02855944).⁴ When compared with standard-of-care chemotherapy, rucaparib demonstrated better efficacy for patients with BRCA-mutated advanced, relapsed ovarian cancer (HR, 0.64; 95% CI, 0.49-0.84; P= .001). “Instead of getting the third platinum therapy, they received a PARP inhibitor…. Those patients did as well or better than the chemotherapy arm. [These agents] were directly compared so it does appear they are able to be swapped out. I anticipate they’ll gain approval for that in this setting, and we’ll continue to see that shift [going] forward,” Medlin said.

Other findings presented at SGO, from the phase 2 OPAL study (NCT03574779), showed that adding dostarlimab, an investigational anti–PD-1 agent, to niraparib and bevacizumab for patients with platinum-resistant ovarian cancer produced positive antitumor activity.⁵ In this trial, investigators looked at the combination in 39 evaluable patients, 17.9% of whom had an objective response (90% CI, 8.7%-31.1%); 7 patients had partial responses. Twenty-three patients had stable disease and there was an overall disease control rate of 76.9% (90% CI, 63.2%-87.4%).

“I think there are some interesting data out there looking at the targeted therapies, as well as exploring the role of the immune system, which we know to be incredibly impactful on patient outcomes and disease markers and prognosis,” Kesterson noted. “Finding ways to augment the immune system to make the tumors more recognizable, …whether it be in a systemic fashion or a localized fashion, has been incredibly interesting. The data are quite riveting and warrant further study in larger patient populations.”

Addressing the Disparities in Care

In Kesterson’s view, the SGO has made an active effort to address differences in care and how the oncology community can do better at offering the standard of care to a larger range of patients. This includes those “from diverse backgrounds, ethnicities, and locations, so that we can standardize care for all and try to elevate not just the care for an individual woman but for women in general.”

“There’s incredibly meaningful and impactful progress…being made,” Kesterson continued. “I think SGO, and we as members of SGO, appreciate that there’s a need to make sure that care is delivered to all, regardless of background, location, or other factors that may previously have resulted in them receiving what we call substandard care.”

This year’s SGO meeting featured an education forum titled “Eradicating Racism and Discrimination in Medicine.” The presentations covered the historical effects of racism on the current practices used in oncology and cancer-specific statistics; how unconscious bias affects patient care and how care providers can combat their biases; and racism in academia and diversifying workforces.⁶

Keely Ulmer, MD, retrospectively looked at disparities in ovarian cancer survival rates for patients in urban settings versus patients in rural settings.⁷ In their poster, Ulmer and colleagues showed that women in rural areas are at significantly greater risk of poorer overall outcomes. In Kesterson’s words: “We need to do a good job of taking care of not just women…living in a bigger city who may have access to a tertiary or a large medical center, but…of all women, regardless of location, …socioeconomic status, or demographic background.”

According to Medlin, giving all women access to cutting-edge treatment, ensuring that treatment is cost effective, and finding a way to make care cheaper without sacrificing its quality are currently the most important unmet needs in this space.

Enrolling a more diverse range of patients in clinical trials is also a prevalent topic. Medlin believes investigators and physicians should be “making sure that not just the wealthy and well connected have access to trials but that all women have access to clinical trials, so they have access to these up-and-coming treatments and know about them and are able to get [transportation] there.”

Despite the unmet needs that remain, care providers are working on ways to ensure better, more encompassing care for patients with ovarian cancer.

“In terms of looking at women across the globe and across the age spectrum, ovarian cancer has a lot of adverse effects. [There’s] a lot of hardship in terms of getting through treatment, and [the cancer] often will recur,” Medlin said. “[It] may be a lifelong journey that women are on in terms of therapy, [which] can impact their ability to see their loved ones or participate in activities that they love.

“We are constantly looking at how we can make women’s lives better, how they can continue to do the activities they love and be with the people they love, and ultimately get them more quality time with their families and their loved ones,” Medlin concluded.

_References:

_{1. Key statistics for ovarian cancer. American Cancer Society. Updated January 12, 2021. Accessed April 19, 2021. https://bit.ly/3gjxW9L}

_{2. Gene mutations. Target Ovarian Cancer. Updated February 2020. Accessed April 20, 2021. https://bit.ly/3egjqwS}

_{3. Targeted therapy for ovarian cancer. American Cancer Society. Updated June 10, 2020. Accessed April 19, 2021. https://bit.ly/2REbayS}

_{4. Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib vs chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase 3 study. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021. Abstract 11479.}

_{5. Liu JF, Gaillard S, Wahner Hendrickson AE, et al. An open-label phase II study of dostarlimab (TSR-042), bevacizumab (bev), and niraparib combination in patients (pts) with platinum-resistant ovarian cancer (PROC): cohort A of the OPAL trial. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021. Abstract 23.}

_{6. Education forum V: eradicating racism and discrimination in medicine. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021. Accessed April 19, 2021. https://bit.ly/3dxOau1}

_{7. Ulmer K, Cardillo N, Bender D, McDonald M, Goodheart M, Gonzalez-Bosquet J. Disparity of ovarian cancer survival between urban and rural settings. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021. Accessed April 19, 2021. https://bit.ly/32t0MMH}