PARP Inhibitors, ADCs, and Immunotherapy Approaches Advance the Treatment Paradigm in Gynecologic Oncology

Joshua G. Cohen, MD, FACOG, FACS

Practice-changing research on PARP inhibitors and antibody-drug conjugates (ADCs), as well as immunotherapy regimens across gynecologic cancers continues to maximize benefit and clarify the optimal role of these therapeutic approaches in a rapidly shifting treatment landscape, according to Joshua G. Cohen, MD, FACOG, FACS.

Several of these key data sets were presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, including the phase 3 RUBY (NCT03981796) and NY-GY018 (NCT03914612) trials of up-front dostarlimab-gxly (Jemperli) and pembrolizumab (Keytruda), respectively. The addition of these immunotherapies to standard-of-care (SOC) carboplatin/paclitaxel improved progression-free survival vs chemotherapy alone in patients with primary advanced or recurrent endometrial cancer, particularly those with mismatch repair–deficient (dMMR) and microsatellite instability–high disease ^1,2

“If you look back 10 years ago, [you can see] the progress that we’ve made with ADCs and the addition of immunotherapy, especially in endometrial cancer,” ​​Cohen said following an OncLive® Institutional Perspectives in Cancer webinar on gynecologic cancers, which he chaired. “[We’ve also gained a] better understanding of PARP inhibitors and where they’re going to [provide] the most benefit for patients [with ovarian cancer], ie. the up-front setting.”

In an interview with OncLive, Cohen expanded on key topics discussed by himself and his colleagues at the meeting, including the role of PARP inhibitors in the recurrent and up-front settings in ovarian cancer, and the clinical significance of the RUBY and NY-GY018 trials in endometrial cancer. Cohen also highlighted emerging ADCs and the evolving use of heated intraperitoneal chemotherapy (HIPEC) in ovarian cancer.

Cohen is the medical director of the Gynecologic Cancer Program, and an associate clinical professor in the Division of Gynecologic Oncology, Department of Surgery at City of Hope Orange County in Irvine, California.

OncLive: How have trials such as SOLO-1 (NCT01844986) and PAOLA-1 (NCT02477644) bolstered support for the use of PARP inhibitor maintenance therapy in ovarian cancer?

Cohen: PARP inhibitors remain an important mainstay in the treatment of patients with ovarian cancer. With some data that have come out in the past year, we’ve seen the shuffling around of indications. [This] can make it more complex for providers to understand when [it is] best to use PARP inhibitors. The most important thing that people will take away from our presentation is that PARP inhibitors really are best [utilized] in the up-front setting. The key is to identify those patients who are homologous recombination deficient [HRD] or have a germline or somatic BRCA mutation in that initial treatment course.

For instance, data from [the phase 3] SOLO-1 [trial] are impressive. Patients who receive PARP inhibitors in their initial management [approach] are [still] benefiting from that drug 7 years later. We’ve also identified synergy based on [the phase 3] PAOLA-1 [trial]. [In this trial], patients who were HRD-positive or had BRCA1/2mutations clearly benefited from the addition of bevacizumab [Avastin] to olaparib [Lynparza] maintenance in the [frontline maintenance] setting after their initial treatment course. These are examples of the importance of identifying patients who have deficiencies in homologous recombination repair, [and may] benefit from some type of PARP inhibitor.

How could future research help clarify the best use of PARP inhibitors in the recurrent and/or up-front settings?

We have exciting future endeavors [in the field of gynecologic cancers], whether that’s [research on the] combination of PARP inhibitors with immunotherapy, or potentially using PARP inhibitors in the neoadjuvant setting. Shannon N. Westin, MD, MPH, FACOG, of The University of Texas MD Anderson Cancer Center in Houston, just presented data [on] the [phase 1] NOW study [NCT03943173] at the 2023 SGO Annual Meeting. This may be a unique opportunity for us to move away from chemotherapy in certain settings. This still needs a lot of vetting and additional study, but [I give] credit to Dr Westin and her team for doing this initial feasibility study and showing that it may be possible to use PARP inhibitors as a neoadjuvant agent in the up-front setting.

Newer data in the recurrent setting have led clinicians to decrease their use of PARP inhibitors in certain scenarios. In what ways have these data affected current practice?

We need to be more cautious with the use of PARP inhibitors in the recurrent setting. It’s always hard to interpret overall survival [OS] data for patients with ovarian cancer because they get so many different medications and there is a lot of crossover with PARP inhibitors by the time they are no longer able to receive treatment. Some reasonable data indicate that treating patients in the recurrent setting with a single-agent PARP inhibitor does not make sense if they’ve had 3 or more prior lines of chemotherapy. That data are now pretty clear. [Accordingly], the FDA has withdrawn those indications. [It’s] really an exciting time for PARP inhibitors. The most important thing [for clinicians] is to identify patients who are going to benefit [from PARP inhibitors] in that initial setting, and [attempt to] move olaparib, niraparib [Zejula], and rucaparib [Rubraca] to the up-front setting. [This could] give [these patients] the best possible chance [at] responding to those drugs.

Shifting to the presentation on immunotherapy in endometrial cancer given by Mihae Song, MD, of City of Hope, how have data from the recently presented RUBY and NY-GY018 trials influenced the treatment paradigm in this disease setting?

Dr Song [discussed] 2 prospective trials from the 2023 SGO Annual Meeting: RUBY and NY-GY018. [These studies] showed that there is significant benefit [from] the use of immunotherapy in the up-front setting for patients who are receiving carboplatin and paclitaxel and have measurable stage III or IV advanced or recurrent endometrial cancer. This is a paradigm shift for patients and for providers [in] moving immunotherapy to the up-front setting for patients with metastatic or recurrent endometrial cancer. Dr Song did a nice job presenting and summarizing these data for our providers.

Moving forward, we are going to have some additional considerations. One [consideration will be] managing the toxicity of immunotherapy, given that more patients are going to be receiving it. As providers, we need to be adept at this. [Second], there will be an unmet need for patients who are both dMMR and mismatch repair proficient [pMMR], [who can] now receive immunotherapy in the up-front setting. Once they’ve received immunotherapy early [in the disease] course, what can we offer them in the second or third line? That’s going to be an area of active investigation. Certainly, RUBY and NY-GY018 [reported some] exciting, practice-changing data [on the] survival benefit for those patients, especially [those] with dMMR and pMMR.

Based on the presentation given by Barbara Buttin, MD, of City of Hope, what emerging ADCs are you excited to see coming down the pike for ovarian cancer? Additionally, what data are still needed to confirm the optimal application of these agents?

The [ADC] that continues to emerge, and is now FDA approved, is mirvetuximab soravtansine-gynx [Elahere]. We [saw] data presented at the 2023 SGO Annual Meeting by Robert Coleman, MD, FACOG, FACS of US Oncology Research, [which] looked at sequencing with bevacizumab and mirvetuximab soravtansine. There are now ongoing clinical trials [investigating the effect of] this ADC [on] different aspects of epithelial ovarian cancer. [Although] it’s here to stay, we’re still trying to figure out how best to use this ADC. [This includes] whether it’s going to be [used] in the recurrent setting as a single agent [or] in combination with bevacizumab, or in the up-front setting as a maintenance strategy. These considerations are going to be clarified [in] ongoing clinical trials.

There are other ADCs [that] we’re excited about. Upifitamab rilsodotin [(UpRi; XMT-1536)] is an active [agent] that we’re looking at, with NaPi2b as [its] target of choice. We’re excited to see where clinical trials with this ADC take us. There are several others that are still in clinical development. Dr Buttin did a nice job summarizing where we are [in the ADC landscape], with the understanding that we still have more work to do. [Another] example is fam-trastuzumab deruxtecan-nxki [Enhertu], which focuses on HER2. Again, these are all emerging strategies.

[Ultimately], the [ADC] that’s going to have [the most] clinical relevance for epithelial ovarian cancer is mirvetuximab soravtansine. More than one prospective trial [has] demonstrated [that it provides] benefit for patients that need [additional treatment] indications based on study criteria.

How has the use of HIPEC in ovarian cancer evolved over the past few years, as per the presentation given by Ernest Han, MD, PhD, of City of Hope?

HIPEC still tends to be a flashpoint for providers in the gynecologic oncology community, including medical oncologists. We [administered] intravenous intraperitoneal [IV-IP] chemotherapy for years, [but] moved away from that after [the phase 3] GOG-252 [study (NCT00951496), which] showed [that] the addition of bevacizumab likely [provided] less benefit. I still think [that this approach] would make sense for patients in certain settings. The addition of heated chemotherapy was first brought to the forefront in 2018 with a [phase 3] prospective trial [NCT00426257] published in the New England Journal of Medicine. Dr Han summarized the literature [on HIPEC] very well, and I think it is something that we should consider for our patients.

Interestingly, there are still centers that do not offer HIPEC. This is a shared decision-making approach. We [will] continue to gather more data about HIPEC, but it is something that we should offer here in the United States for the right patient. At City of Hope, we do routinely offer this treatment option to patients who meet criteria based on the available studies. We all feel that this is an important part of how we address epithelial ovarian cancer in the initial setting for patients who have undergone neoadjuvant chemotherapy.

What main message would you like to impart to colleagues regarding this session?

It’s an exciting time for gynecologic cancer. When I meet with patients, I tell them [that] this is a time where we’re seeing amazing, progressive discoveries year to year [or even] month to month. Gynecologic oncologists, medical oncologists, radiation oncologists, and allied health professionals [all need to] collaborate. As these treatments become more complex, synergy is needed, and we all want to work together. [We should also] continue to look for clinical trials to enroll patients to, [as] that’s the way these discoveries are made. A study presented at the 2023 SGO Annual Meeting showed patients with epithelial ovarian cancer live longer if they’re enrolled in clinical trials. [Practitioners should] seek out comprehensive cancer centers, such as City of Hope, and continue to work with [their] team to ensure patients have access to the latest and greatest clinical trials.

Would you like to highlight any trials in the field of gynecologic cancers that are being conducted at your institution?

At City of Hope, we’re constantly looking for the latest and greatest advances in ovarian cancer treatment. Lorna Rodriguez-Rodriguez, MD, PhD, of City of Hope, has an exciting trial evaluating the role of immunotherapy with intra-abdominal delivery. We are also trying to determine if CAR T-cell therapy is going to be a [option] for patients [with ovarian cancer]. City of Hope is actively engaged [in enrolling patients in] cooperative group trials looking at the management of ovarian cancer with CAR T-cell therapy.

Another trial coming down the pipeline is [the phase 3] GLORIOSA [trial (NCT05445778)], which looks at mirvetuximab soravtansine in the maintenance setting for patients with platinum-sensitive, recurrent [ovarian, fallopian tube, or peritoneal cancer]. That trial will be opened here at City of Hope Orange County, in addition to City of Hope Duarte. City of Hope is a special place. We now have sites in Phoenix, Chicago, and Atlanta, and we’re extremely excited to be able to collaborate across the different states. All [our centers are] now working together to provide the latest, most comprehensive gynecologic cancer care here in the United States.

References

1. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312