Moore Details Ongoing Research Aiming to Fill Unmet Needs in Ovarian Cancer

Kathleen N. Moore, MD, MS

Several questions regarding the use of biomarkers in gynecologic malignancies are under investigation and as investigators continue to explore promising developments with antibody-drug conjugates (ADCs) and novel drugs for ovarian cancer, the evolving landscape of PARP inhibitors and the exploration of alternative options for patients not cured by PARP inhibitors remains a focus, according to Kathleen N. Moore, MD, MS.

“As researchers, we have to pivot and understand the data as it comes out and change our behavior. I still look at PARP [inhibitors] for everybody, but I don’t use them on everybody based on other clinical features and how patients are responding to platinum and other clinical trials in a biomarker-negative setting,” Moore said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on gynecologic cancer, which she chaired. Moore is an associate director of Clinical Research at the Stephenson Cancer Center, in Oklahoma City, Oklahoma.

In the interview, Moore, who is also the director of the Oklahoma TSET Phase I Program, as well as a professor in the Section of Gynecologic Oncology at the University of Oklahoma College of Medicine, discussed key aspects of her colleagues’ presentations from the SOSS, expanded on the importance of continuing to investigate PARP inhibitors in ovarian cancer, and highlighted key updates to have come out of the 2023 ESMO Congress.

OncLive: Christina Washington, MD, of the University of Oklahoma Health Stephenson Cancer Center, presented on PARP inhibitors in advanced ovarian cancer. Are these agents still being investigated in the all-comers population?

Moore: PARP inhibitors have been transformative in ovarian cancer and other than platinum-based [chemotherapy], the biggest achievement has been [the efficacy of] PARP inhibitors in biomarker-selected populations. They do have a role in all comers, and we’ve seen that in several trials. There is a gradation of benefit from biomarker-positive BRCA-[mutated disease] to biomarker-positive homologous recombination deficient [HRD] BRCA wild-type [disease], and then to biomarker either undetermined for those that don’t have a biomarker or have HRD-negative [disease].

We have all comer indications, and at this point it’s still appropriate to use PARP inhibitors in the front line setting with shared decision making with the understanding that we are curing approximately 20% of patients [per] the BRCA literature—now we have follow-up data from the phase 3 SOLO-1 trial [NCT01844986] out to 7 years, so that’s what we can comment on it. Approximately 20% of patients are cured without PARP inhibitors, and that looks true in the PAOLA-1 study [NCT02477644] in patients with HRD-positive disease [who had] mostly BRCA-[positive disease]; we are sitting at approximately 19% at 5 years, so it looks similar to the SOLO-1 7-year [data] and it will probably hold.

There is a group of patients who don’t need anything—they don’t need a PARP [inhibitor]—so it would be nice to definitively know who they are and not expose them to [treatments]. That would be outstanding, but we cannot [as of right now], and we rescue about 25% of [patients]. Therefore, approximately 45% of patients [were] without recurrence at 7 years in SOLO-1; that’s a rescue and those patients would have recurred and many of those patients are likely cured. We will have some late recurrences that we will try to salvage but most of those women will be cured, and that’s transformative.

How many patients with BRCA wild-type HRD [disease] will be cured? I don’t think we’re going to know [because] in PAOLA-1, that was a very small number of patients. In the phase 3 PRIMA clinical trial [NCT02655016] with niraparib [Zejula], there was a very clinically high-risk group, so we did not see cures there. That’s a little harder to call. I don’t think we’re curing anyone with PARP [inhibitors] in the HRD-negative group and we can probably do better there.

We’re evolving and with everything you do a trial, adopt the medicines, and then keep learning to figure out whether what you were doing was right and how you can do better. PARP inhibitors are here and they’re here to stay, though they’re going to get appropriately more targeted to the right populations as we develop new therapies for those who get marginal benefit from them.

Joyce F. Liu, MD, MPH, of Dana-Farber Cancer Institute, in Boston, Massachusetts, presented on beyond PARP inhibitors in ovarian cancer. For those patients who may not be cured from a PARP inhibitor, what are some other options that could potentially be used to help in these settings?

It’s very multifactorial and the importance of the time from last platinum [therapy received] remains very prognostic. The time from last PARP inhibitor is likely prognostic, so in the front line we use PARP [inhibitors] for a limited period. If a patient progresses on PARP inhibitor, that is 1 group, and for those that progress after the PARP inhibitor is discontinued that is starting to look like a different group. There is early data that comes mainly from PAOLA-1 and a couple other studies [that] is exploratory, but it is looking like a [there is a] different group in terms of resistance mechanisms. We may be even in a ‘platinum-sensitive’ population, which is 6 months from last platinum, and we may be doing different things.

For a group that progresses on a PARP inhibitor, we may get innovative enough to say we’re convinced that the efficacy and the duration of efficacy from platinum is poor enough that we’re okay using something else. We’re thinking about that. Whereas patients who have tumors that progress after PARP inhibitor treatment seem to do just fine on subsequent platinum [therapy]. Furthermore, there’s some exploratory data that even they benefit from PARP inhibitors again, which we’ve waffled on that issue.

Overall, we have a lot to learn here in that space. Even in the ‘platinum-sensitive’ space, we have a lot to learn. We’re going to see new criteria for how and what you might consider in that space. But, platinum remains the standard of care. Maintenance is challenging [because] we don’t have anything other than bevacizumab [Avastin] and PARP inhibitors, and sometimes you’re repeating something that someone got in the front line which is okay, but what are the downstream effects of repeat use of PARP inhibitors? Of course, there are the concerns of survival detriment with PARP inhibitors in the recurrent setting, which is why those indications outside of BRCA have been restricted. There are a lot of questions in this space that we need to work together to answer.

Once tumors are considered inappropriate for platinum-[based therapy] for a variety of reasons. There are many [agents] in trials that are promising and probably the leading category [includes] ADCs. In our phase 1 unit, [ADCs] are our favorite things to use because we expect them to work and help patients. Mirvetuximab soravtansine-gynx [Elahere] is the first approved [agent] in this space and that approval hopefully will be confirmed soon with the phase 3 MIRASOL study [NCT04209855] and will be available globally. Right now, it’s just available in the United States which is frustrating to our European partners who participated in the clinical trials and can’t access the drug right now. I’m hopeful this will be available soon to them.

Next up, is raludotatug deruxtecan [DS-6000] which targets CDH6 and we presented updated data on [the agent] at the 2023 ESMO Congress.1 That’s looking very promising and is moving into late phase studies soon.

Those are your 2 leading new agents. There’s other things in the folate [receptor] space that are coming, [FRα] and CDH6. The ADCs targeting [voltage-] gated sodium phosphate channels, though upifitamab rilsodotin [XMT-1536] was discontinued because of toxicity and poor efficacy which was quite a surprise. There’s still unpacking to do with what happened with that program. We had that drug open in a phase 1 [trial at my institution], and we saw very nice responses. However, there are other ADCs in development with that target, [NaPi2b], and alternative platforms that will likely zoom into the space now and enter clinical trials. We’re excited about those. ADCs are the belle of the ball right now in terms of ovarian cancer development.

Novel drugs targeting replication stress or restoration of HRD where it has been lost are another strategy. ATR inhibitors are next up, though a little bit behind ADCs in development, but kind of coming up fast. We’ve known about these for a long time and they work well in biomarker-selected groups; second- and now third-generations are coming around that are probably better. We’ll see these come into play as well.

Floortje J. Backes, MD, of the Ohio State University Comprehensive Cancer Center – James Cancer Hospital, and Shannon N. Westin, MD, MPH, FACOG, of the University of Texas MD Anderson Cancer Center, in Houston, discussed endometrial cancer. What are some of the factors that drive treatments decisions in each respective treatment setting for patients with dMMR/MSI-H disease?

Patients with front line metastatic mismatch repair–deficient[dMMR]/microsatellite instability–high [MSI-H] [disease] should be getting dostarlimab [Jemperli], because this is FDA approved and has a positive European Medicines Agency letter as well. Therefore, [treatment should consist of] paclitaxel, carboplatin, and dostarlimab, and dostarlimab maintenance. All patients should be tested and should get this medicine.

There was updated data at ESMO from both the phase 3 RUBY study [NCT03981796] of dostarlimab, as well as the phase 3 NRG-GY018 [NCT03914612] study of pembrolizumab [Keytruda]. They’re different studies but they are similar in their results in the subgroup as they’re transformational. It’s like PARP inhibitors and BRCA. You have patients who may be cured, who would never have been cured in the past, and there was no 20% cure rate in this population. It has to be the standard of care that patients be tested and you should be using this—that goes without saying.

The next phase of studies mirror PARP development, although there are different drugs, as there’s patients who are cured and then there are those who progress on dostarlimab, like there are those who progress on PARP inhibitors who have BRCA-[mutated disease]. Why did that happen? Do they need a combination for maintenance? Is there something we can do to rescue them? Even in that subgroup, dMMR/MSI-H, we should celebrate what’s been accomplished and then figure out why it didn’t work in patients that have the biomarker. We’re not done with BRCA [mutation] and PARP inhibitor [exploration], and we’re not done with the MSI-H checkpoint inhibitors either. However, we have done phenomenal things and those data were updated and reconfirmed at ESMO.

MMR-proficient/MSI-stable [populations are] another story. Both studies did show benefit in that subgroup, although different magnitudes of benefit. There are differences between those 2 studies that we’re still trying to tease out.

There was another study presented at ESMO, the phase 3 AtTEnd trial (NCT03603184), which used atezolizumab and did not show a benefit in that group. It did not harm [patients] but it is a different population. This is like BRCA wild-type [with] PARP [inhibitors]: you show a benefit, but it’s not that great and you aren’t curing more patients. We’re starting to look at the subgroups now in these populations to try to figure out who should get immuno-oncology [therapies], and in whom we need to keep working and keep doing clinical trials.

As an example, there’s MMR-proficient serous [ovarian cancer], which we’re looking now at [with] TP53mutations. Do these [patients] need something different? Within that group are HER2-expressing tumors and they need something different likely in the form of either BNT323 [DB-1303] which is an ADC targeting HER2, or fam-trastuzumab deruxtecan-nxki [Enhertu]; both [agents had] updated data presented at ESMO in the recurrent second-line setting with phenomenal response rates and duration [of responses] in a patient population where we previously had nothing active. Those need to move up, and we’re developing the trials right now.

That group certainly benefits from IO—I am using it even though it is not FDA approved, it’s NCCN listed, so in the US we can use it. I’m using it because it helps a little and that’s good, but I’m not opposed to clinical trials coming into that space and trying to do better because that is the majority of our patients, and we are not curing the majority of our patients. We need to keep working. We have lots of options, certainly ADCs in that space such as HER2 and Trop-2 in the endometrial space. Should they be in the front line or not? We have to figure that out. Endocrine therapies for certain patients mirror breast cancer with certain molecular subtypes. Should we be using endocrine interventions there as opposed to ADCs? There’s a lot of moving parts right now as this data starts to come out.

Reference

Moore K, Philipovskiy A, Harano K, et al. Raludotatug deruxtecan (R-DXd; DS-6000) monotherapy in patients with previously treated ovarian cancer (OVC): subgroup analysis of a first-in-human phase I study. Ann Oncol. 2023;34(suppl 2):S510. doi:10.1016/j.annonc.2023.09.1924