Multifaceted Future of Ovarian Cancer Treatment to Reduce Recurrence or Relapse

Sanaz Memarzadeh, MD, PhD

Although platinum-based chemotherapies are remarkably effective in treating patients with ovarian cancer, the rate of relapse remains high, explained Sanaz Memarzadeh, MD, PhD. Therefore, ongoing multidisciplinary research with PARP inhibitors, antibody-drug conjugates, and even surgery in the recurrent setting, may provide answers in targeting pre-existing tumor-resistant cells.

Memarzadeh, is a professor and gynecologic cancer surgeon in the Department of Obstetrics and Gynecology at UCLA Ronald Reagan Hospital, director of the G.O. Discovery Laboratory at the UCLA Broad Stem Cell Research Center. She recently spoke to OncLive®, a sister publication of Oncology Nursing News®, about exciting updates in multidisciplinary approaches to ovarian cancer treatment and where she expects treatment directions to evolve in coming years.

Addressing Unmet Needs in Recurrent Ovarian Cancer

Despite the efficacy of platinum-based drugs in ovarian cancer treatment, relapse is still a common challenge. One contributing factor is the presence of tumor cells that are resistant to therapy, explained Memarzadeh. These tumor cells may lay dormant and become active to repopulate the cancer. For this reason, first-line combination therapies to target these cell populations represent a potentially effective strategy to prevent relapse.

“Trials testing these combinations are ideal because patients with ovarian cancer often present with advanced-stage disease and receive neoadjuvant chemotherapy,” she shared. “This gives us an opportunity to not only treat the patient with standard-of-care chemotherapy, as well as the biologic agents of interest in the trial, but also look at the tumor pre-treatment and after administration of 3 or 4 cycles of this combination therapy see what happens to the tumor cell populations. Are we targeting the resistant population of tumor cells?”

The success of these trials will be related to their design, she continued. A smart trial design will encompass extensive translational end points and be focused on understanding the tumor cell populations. Furthermore, there remains to be the sufficient level of interested and funding necessary to bring these trials into existence. Achieving the appropriate level of funding to conduct this research will be the first step to eradicating ovarian cancer early on and proactively preventing relapse.

Image Guided Ablation

According to Memarzadeh, image guided ablation is an exciting approach that must be individualized to the patient. The efficacy of the procedure is dependent on the location of the tumor. Patients who have oligometastatic metastatic disease report better responses to this treatment. In addition, the number of tumor sites should be considered when deciding whether image-guided ablation is appropriate for a patient.

Ongoing research seeks to combine this strategy with other treatments, such as immunotherapy, to achieve a more lasting response in targeting the cancer.

PARP Inhibitors

“Currently, [utilizing PARP inhibitors] early on is the best approach,” shared Memarzadeh. “The rationale for this is that a surrogate biomarker of PARP sensitivity is platinum sensitivity, and it is known that over time, tumors become more platinum-resistant.” She acknowledged that this standard may change in the future once the mechanisms of PARP resistance are better understood.

Furthermore, emerging data indicate that PARP inhibitors may become an alternative to chemotherapy in treating patients who carry germline BRCA mutations or tumors with somatic BRCA-like mutations.

The phase 3 PRIMA trial (NCT02655016) assessed the efficacy of niraparib (Zejula) in a first-line setting for this patient population. Researchers consequently determined that this FDA-approved PARP inhibitor has clinical benefit in this setting, across all patients, in its ability to effectively improve progression-free survival (PFS).

Nevertheless, researchers noted that PFS was most evident in patients with a homologous recombination deficiency in their tumors. “This speaks to [the importance of] having effective biomarkers of response to these PARP inhibitors,” Memarzadeh said.

Another trial that she discussed was the phase 2/3 ROCSAN trial (NCT03651206), in which niraparib as a monotherapy agent is being evaluated against chemotherapy in recurrent ovarian and uterine carcinosarcoma. The trial seeks to determine whether a PARP inhibitor can be an alternative to chemotherapy, either as a monotherapy or in a combination regimen.

“In this patient population, the patients have recurrence of disease,” she explained. “The rationale for picking carcinosarcomas is because these tumors likely have high DNA damage response activity, and high mutational burden.”

Antibody-Drug Conjugates vs Immunotherapy

Mirvetuximab soravtansine (IMGN853) will most likely be incorporated into the treatment paradigm in the recurrent setting, said Memarzadeh. Findings presented at the 2021 ASCO Annual Meeting from the phase 1/2 FORWARD II trial [NCT02606305] indicate that the drug, in conjunction with bevacizumab [Avastin] is well tolerated. Notably, the response is more pronounced in tumors with high levels of folate receptor α expression and so patients with this specific characteristic would be the most appropriate candidates for this treatment type. Ongoing trials are continuing to further explore that relationship.

Immunotherapy should be assessed through the lens of checkpoint inhibitors. “Unfortunately, results with checkpoint inhibitors have not been promising so far in ovarian cancer,” she said. “Part of the challenge is that ovarian cancers are not “hot” tumors, and do not have a lot of tumor mutational burden or neoantigen presentation. Biomarkers of response to these checkpoint inhibitors are also not very clear.”

T cells present an interesting direction in ovarian cancer immune treatment. There is “evidence that tumors that have a higher number of tumors-infiltrating lymphocytes have a better prognosis. As such, if there was a way to energize the T cells and activate them to help fight the cancer, that would be an ideal model” she said, though she acknowledged that more research needs to be conducted on this pathway.

In addition, adoptive T cell transfers, or CAR T-cell therapies and other cellular therapies, might help address the need to prime and activate the exhausted T- cell populations, according to Memarzadeh, particularly in “cold” tumor cell populations. Although CAR T-cell therapy has not yet proven effective in solid tumors, researchers are optimistic about its results in the future.

Surgery

Two recently published randomized trials, DESKTOP 3 [NCT01166737] and phase 3 SOC1 [NCT01611766], showed that surgery improves patient outcomes in the recurrent ovarian setting. Furthermore, the data indicate that a longer period length of platinum-free treatment is associated with improved outcomes for the patients. “Additionally, [patients with] isolated tumors that can be cytoreduced entirely, and removed during surgery, [have improved outcomes] in the recurrent setting,” she added.