Progress Moves Full Steam Ahead in Gynecologic Malignancies

On the heels of strides made with checkpoint inhibitors, PARP inhibitors, and antibody-drug conjugates (ADCs) in gynecologic malignancies, ongoing research is seeking to push the bar further with biomarker-driven trials like BOUQUET (NCT04931342) and extend advances to patients with rare and aggressive tumors like carcinosarcomas in trials such as ROCSAN (NCT03651206), explained Jubilee Brown, MD.

“What really strikes me is how far the field has come and the exciting things on the horizon. The clinical trials that are ongoing now are changing the landscape of how we treat patients with gynecologic cancers. For every single disease site, whether it’s uterine cancer, cervical cancer, or ovarian cancer, we’re seeing majoropportunities in taking care of our patients up front and with recurrent disease,” said Brown, director of Gynecologic Oncology at the Atrium Health Levine Cancer Institute, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on gynecologic malignancies.

The virtual meeting covered updates in endometrial cancer and cervical cancer, frontline and second-line maintenance, and novel immune-oncology combination strategies in ovarian cancer. In the interview, Brown, who co-chaired the event, contextualized these updates in each field.

OncLive®: You were a study author on the phase 1 GARNET trial (NCT02715284), which evaluated the anti­–PD-1 antibody dostarlimab (Jemperli) in patients with advanced solid tumors. What was the rationale for this trial?

Brown: Patients with endometrial cancer or uterine cancer historically have very limited treatment options, so this is really an area of unmet need. That’s really the rationale behind this study. Patients who have mismatch repair deficient [dMMR] endometrial cancer have a different response rate [with immunotherapy than those with mismatch repair-proficient disease], and the [former group] has a target that we can exploit. That’s why we opted to perform the GARNET study in this group of patients with dMMR endometrial cancer.

Where could these data direct future research with the agent?

The preliminary results showed a 42% overall response rate [ORR]. A total of 12% of those patients were in complete response [CR], so it’s going to be exciting to see how those data mature. Of course, these data led to an FDA approval already, but as we get more follow-up on those patients, it will be exciting to see how we can use dostarlimab in combination with other agents moving forward.

Speaking of targets, what is your hope for the upcoming, biomarker-driven BOUQUET trial?

The BOUQUET trialisone that I’m heavily involved in that is exciting. It’s a platform trial for rare tumors that just opened in the European Union and will open in the United States very shortly. This is a biomarker-driven platform trial that currently has 4 arms, and patients undergo molecular profiling, and then independent of the type of their rare tumor, they’re slotted based on those biomarkers. For example, patients with PTEN, PIK3CA, or AKT mutations will get ipatasertib and paclitaxel. Patients who don’t have any specific mutations will be eligible for atezolizumab [Tecentriq] and bevacizumab [Avastin]. This trial can home in on how we treat patients with rare tumors in a biomarker-driven fashion.

R. Wendel Naumann, MD, of Atrium Health, discussed the ROCSAN trial in his presentation. What do you find appealing about that trial?

The ROSCAN trial is a phase 2/3 trial that has 3 arms: dostarlimab/niraparib [Zejula] vs niraparib vs physician’s choice of chemotherapy in a 2:2:1 randomized fashion. This trial is for patients who have uterine carcinosarcoma after at least 1 line of chemotherapy. This is a trial in progress. We don’t yet have data [on it], but it’s a very exciting trial because we really hope this combination is going to be effective. Rather than just answering 1 question at a time, we’re going to be able to answer multiple questions at 1 time.

Robert Coleman, MD, FACOG, FACS, of The US Oncology Network, highlighted tisotumab vedotin-tftv (Tivdak) in his presentation. What is the significance of the data with this agent, and why is it important in the paradigm?

This is very timely, because tisotumab vedotin was just FDA approved for cervical cancer treatment after chemotherapy in patients with recurrent or metastatic cervical cancer who show progression after chemotherapy. This is very exciting. These data were published in Lancet Oncology and showed a 24% ORR in this group, with a 7% CR rate. This is really interesting because it’s really a novel compound. It targets tissue factor through an [ADC], so this is great news in an area of unmet need for patients with recurrent cervical cancer.

Thomas Herzog, MD, of NewYork-Presbyterian, discussed the PRIMA study (NCT02655016)in his presentation, which evaluated niraparib vs placebo in patients with advanced ovarian cancer. Which patients should be offered the possibility of receiving niraparib based on the data from that trial?

The PRIMA study was very interesting because it allowed us to look at niraparib in the frontline setting. It was segmented out based on based on mutation and homologous recombination deficiency [HRD], and included homologous recombination proficient patients. There is really a benefit in all-comers there. When we look at all patients after frontline therapy, we see a benefit in the niraparib arm.

The details of that trial really inform us for how we treat our patients after they finish their up-front taxane chemotherapy. I think it makes us, based on that improvement in progression-free survival [PFS], more likely to put patients on a PARP inhibitor like niraparib after their initial therapy, independent of germline or somatic BRCA mutation. Patients who have HRD, we’re going to want to treat with a PARP inhibitor, and it allows us to introduce into the conversation, even patients who don’t have an identified germline or somatic mutation––even patients who don’t have HRD, we may want to consider niraparib in those patients.

Angeles Secord, MD, of Duke University presented on second-line maintenance in advanced ovarian cancer. How have studies like ARIEL3 (NCT01968213) shed light on the role of PARP inhibitors in this setting?

As we use PARP inhibitors more, we see that PARP inhibitor sensitivity is almost equated with platinum sensitivity. It’s common now, based on studies like ARIEL3, to put patients on PARP inhibitors, even in the recurrent setting, who are platinum sensitive, because it works. Because we see, based on ARIEL3 and other studies, an improvement in PFS, no longer are we limited to using PARP inhibitors up front in the maintenance setting. We know now that we can use this in patients who have platinum-sensitive disease.

Ritu Salani, MD, of UCLA, presented on immunotherapy and novel strategies in ovarian cancer. Could you speak to the current role of checkpoint inhibitors in ovarian cancer and some of the novel strategies that are under investigation?

This is really an interesting area of development. It wasn’t long ago when we really didn’t have anything on the table for patients with ovarian cancer, and now we have so many new compounds and novel therapies coming out. Certainly, patients with clear cell carcinoma of the ovary, for example, may benefit from checkpoint inhibitors. As we move forward and get more results from studies that use checkpoint inhibitors in combination with other agents, we’re going to see a change in the field. Some of the other novel compounds and therapeutics that are going to be important to watch for are vaccine therapies, and, certainly, folate receptor antagonists.

How would you define all the progress that has been made in gynecologic malignancies in recent years?

It was great to hear all these experts come together. We’re curing patients that couldn’t be cured before. Clinical trials are certainly the way to go because there are so many different options to choose from.