Investigative Directions in Ovarian Cancer Continue to Comprise Multidisciplinary Approaches

Though platinum-based chemotherapies have been a mainstay in the treatment of patients with ovarian cancer, the persistent challenge of recurrence and resistance to therapy has emphasized the importance of multidisciplinary approaches to treatment, according to Sanaz Memarzadeh, MD, PhD, who added that ongoing research with PARP inhibitors, antibody-drug conjugates, and even surgery in the recurrent setting could hold promise.

“For research purposes, it is important to utilize a multidisciplinary, collaborative approach, and to bring different minds, with different areas of expertise, to work together so we can improve outcomes for patients [with ovarian cancer] together,” Memarzadeh said.

Memarzadeh was the chair of the Institutional Perspectives in Cancer webinar on ovarian cancer, which focused on recurrent platinum-sensitive and platinum-resistant disease, the role of surgery, ablative techniques for oligometastatic ovarian cancer, and laboratory and collaborative efforts for disease management at University of California Los Angeles (UCLA).

In an interview with OncLive^® during the meeting, Memarzadeh, professor and gynecologic cancer surgeon in the Department of Obstetrics and Gynecology at UCLA Ronald Reagan Hospital, and director of the G.O. Discovery Laboratory at the UCLA Broad Stem Cell Research Center, focused on these ongoing multidisciplinary research directions aimed at improving outcomes for patients with ovarian cancer.

OncLive^®: How are areas of unmet need being addressed in recurrent ovarian cancer?

Memarzadeh: I have always been struck by how well platinum-based drugs work in treating patients with ovarian cancer. However, regardless of how well they work, the cancer often relapses, which has been a challenge. One of the reasons for this is because there may be a pre-existing population of tumor cells that is resistant to therapy, and although those tumor cells may become dormant, later they can potentially repopulate the cancer. Using combination therapies upfront that can potentially target this tumor cell population is going to be very important.

Trials testing these combinations are ideal because patients with ovarian cancer often present with advanced-stage disease and receive neoadjuvant chemotherapy. 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?

These trials are feasible and can be designed, but the design should be smart. There should be extensive translational end points, with a focus on understanding the tumor cell populations. [Moreover], these trials can be designed if there is interest and funding for them, which is where there is somewhat of an unmet need. This is where potentially we can intervene with designing treatment strategies that can eradicate the cancer early on, and prevent a recurrence altogether.

What questions remain with image guided ablation? Are there any instances in which you would steer away from using this approach?

This is an exciting approach that is available at UCLA, but it must be individualized to the patient. Instead of deciding whether this is a feasible approach or not, we must look at the location of the tumor, which is more efficacious in patients who have oligometastatic metastatic disease. Location is important, as well as the number of tumor sites, in making this determination.

Ongoing research will address whether using combinations of these ablation technologies with other treatments, such as immunotherapy, can result in a more lasting response in terms of targeting the cancer.

What are some factors to consider in terms of sequencing available PARP inhibitors for patients with platinum-sensitive disease?

Currently, [utilizing PARP inhibitors] early on is the best approach. 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. This may change in the future as we learn more about the mechanisms of PARP resistance, and consider combination therapies that can overcome this challenge.

Additionally, there are emerging data suggesting that PARP inhibitors may be able to potentially substitute for chemotherapy, in patients who are germline BRCA carriers, or harbor tumors with somatic BRCA-like mutations.

During the webinar, there were discussions on approaches being studied in the recurrent ovarian cancer setting. Regarding ADCs, where do you see an agent like mirvetuximab soravtansine (IMGN853) fitting into the treatment paradigm? What about immunotherapy?

Mirvetuximab soravtansine will likely be used in the recurrent setting. Results from the phase 1/2 FORWARD II trial [NCT02606305] that were reported at the 2021 ASCO Annual Meeting looking at the agent in combination with bevacizumab [Avastin] showed promising data. The combination is well tolerated, and most importantly, the activity is more pronounced in tumors where there are high levels of folate receptor α expression. Mirvetuximab soravtansine is going to have a role for patients with tumors with this specific characteristic, and there are ongoing trials that will address this further.

[In terms of immunotherapy], we should break it down by looking at the role of checkpoint inhibitors first. Unfortunately, results with checkpoint inhibitors have not been promising so far in ovarian cancer. 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. Additionally, to achieve success using these checkpoint inhibitors in ovarian cancer, there is a need for priming and activating these exhausted T-cell populations. Clearly, the T cells are in the tumor, and 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, but more work needs to be done on this front.

Another approach in immunotherapy, particularly in “cold” tumors, that is now being investigated is using adoptive T-cell transfers, CAR T-cell therapies and other cellular therapies. [These approaches can] potentially be promising, but the results thus far have not been successful in solid tumors. The most important thing is to target an antigen that is highly expressed in the tumor, and low in the other normal tissues of the body, which can be challenging. This work is ongoing, and hopefully, we will see more exciting results in the future.

Surgery has an evolving role in ovarian cancer treatment, which was highlighted during the webinar. What data have we seen with this approach in the recurrent setting?

There were 2 recently published randomized trials, DESKTOP 3 [NCT01166737] and phase 3 SOC1 [NCT01611766], that have looked at [surgery in recurrent ovarian cancer]. Both trials demonstrated that in patients where the cancer is completely resectable, the outcomes of these patients are improved with surgery in the recurrent setting. Selection of patients for the surgery is critically important, as these trials have demonstrated. The longer the platinum-free interval, the better the outcomes are. Additionally, [patients with] isolated tumors that can be cytoreduced entirely, and removed during surgery, [have improved outcomes] in the recurrent setting.

Niraparib (Zejula) is one of 3 FDA-approved PARP inhibitors in ovarian cancer. Could you discuss the data from the phase 3 PRIMA (NCT02655016) and phase 2/3 ROCSAN (NCT03651206) trials? How have they contributed to our understand of utilizing niraparib as both a single-agent and in combination?

The PRIMA trial looked at niraparib as maintenance therapy in the frontline setting for patients with ovarian cancer. What this trial taught us is that this drug has benefits in this setting. The benefit was seen in all patients, in terms of improving progression-free survival, but it was most pronounced in patients who had an homologous recombination deficiency in their tumors. This speaks to [the importance of] having effective biomarkers of response to these PARP inhibitors.

The ROCSAN trial is interesting because it is examining patients with recurrent ovarian and uterine carcinosarcoma. In this trial chemotherapy is being compared with niraparib alone, as well as niraparib in combination with a PD-1 inhibitor. The idea is to see whether a PARP inhibitor alone, or in combination, can substitute for chemotherapy. In this patient population, the patients have recurrence of disease. The rationale for picking carcinosarcomas is because these tumors likely have high DNA damage response activity, and high mutational burden.