Personalizing Treatment Selection in Platinum-Resistant Ovarian Cancer

In an interview with CancerNetwork®, Ursula A. Matulonis, MD, discussed the latest developments in gynecologic oncology, including the message she most wants oncologists to take away from the past year of ovarian cancer approvals. She also walked through how to consider 3 recently approved platinum-resistant regimens that have never been compared head-to-head: mirvetuximab soravtansine-gynx (Elahere), weekly paclitaxel plus pembrolizumab (Keytruda) with or without bevacizumab (Avastin), and relacorilant (Lifyorli) plus nab-paclitaxel.

She also discussed which biomarkers she believes should now be tested routinely in every patient with ovarian cancer and when they should be rechecked, what the landscape looks like for patients whose cancers lack those biomarkers, the upcoming trial she considers most consequential, as well as what she would encourage other centers to adopt.

Matulonis is chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School.

CancerNetwork: Given how much has changed in ovarian cancer in the past few years, what should clinicians not in gynecologic oncology know?

Matulonis: For oncologists who are not involved in solely taking care of patients with gynecologic cancers, I think it's important for them to partner with somebody who is. That can be a gynecologic oncologist surgeon, or it can be a medical oncologist, but really [someone] who focuses their time on caring for patients with gynecologic cancers.

As you know, a number of different treatments have come out within this past year. Some of them have been fully FDA-approved, and some of them have received accelerated approval. Some of them are on NCCN guidelines. Some of them are not. [It is about] really making sure that the treatment fits the patient. What's super important is to make sure that treatment is personalized to the patient and to her cancer, and that's true of all oncology as we get more targeted treatments. Some treatments are not necessarily targeted, or are targeted but can be given to a broader patient population, but [it’s important to focus] on efficacy and the avoidance of certain adverse effects. My messaging would be around personalization of treatment, both from an understanding of the biology of the cancer and from an understanding of the medical issues of the patient, as well as what the patient wants and doesn't want.

We've had several FDA approvals in platinum-resistant disease—mirvetuximab soravtansine, pembrolizumab plus paclitaxel, and relacorilant plus nab-paclitaxel—and none of them came with head-to-head comparisons. How do you integrate these into your practice and decide who gets what, and when?

You're absolutely correct. The more recent approvals have certainly been for mirvetuximab [soravtansine] for our patients with platinum-resistant ovarian cancer, up to 3 prior lines of treatment, and the cancer also has to be folate receptor α (FRα)–positive….

You're getting at the specifics of the approval. For example, the [KEYNOTE-B96 (NCT05116189)] trial led to the approval of weekly paclitaxel plus pembrolizumab with or without bevacizumab for patients with platinum-resistant, PD-L1-positive [disease], with a combined positive score [CPS] of 1 or higher, and up to 2 prior lines of treatment. In both of these approvals, we're seeing [eligibility] not necessarily restricted to the type of ovarian cancer. The histology is not in there, but there are biomarkers around that. Folate receptor alpha positivity is necessary for mirvetuximab soravtansine, and the presence of PD-L1 positivity by a CPS score of 1 or higher for the addition of pembrolizumab to weekly paclitaxel with or without the use of bevacizumab. Then the third is a little bit more biomarker agnostic, and that is nab-paclitaxel plus an oral drug called relacorilant, which disrupts the glucocorticoid receptor, for patients who have received up to 3 prior lines of treatment and have received prior bevacizumab, for—again—platinum-resistant ovarian cancer—the histology is not specified.

So how do we make these decisions? On a number of different planes. One would be the patient. Is the cancer FRα positive? Is it PD-L1 positive? Can the patient swallow an oral medication like relacorilant? Does she have an obstruction? If she can't swallow relacorilant, she can't receive that drug. Based on the FDA approvals, if the patient has not received bevacizumab, then she technically is not eligible by the FDA terminology for relacorilant and nab-paclitaxel. If FRα is positive, then certainly the patient can receive mirvetuximab [soravtansine].

The other aspects, besides the biomarker, [are] the clinical state of the patient, but also what the patient wants—and that's so important here. [With] weekly paclitaxel, nab-paclitaxel—that agent, paclitaxel, can cause hair loss and can cause neuropathy. Mirvetuximab soravtansine can also cause neuropathy, but it does not cause hair loss. Sometimes when patients are on the heels of carboplatin [and] paclitaxel, they develop platinum-resistant ovarian cancer, and they may say, “I'm okay about getting weekly paclitaxel, but I'm not.”

It's really important to bring the patient into this conversation about the next steps, and sometimes that takes more than one conversation. That's what I do: list the options, go over pros and cons, and let people think about what they want to do. Sometimes you don't have that luxury of time because the cancer is growing, but sometimes you do have that luxury of time, and somebody can take a few days to sit with that decision-making and really interact with you to make a truly shared decision.

Antibody-drug conjugates in ovarian cancer are now expanding to different targets like HER2, including trastuzumab deruxtecan (Enhertu) in first-line maintenance. What does that mean for molecular profiling at diagnosis, and does it open a path for HER2 testing to become routine?

Absolutely. The plethora of antibody-drug conjugates has just started. We've got 2 available for use for our patients with ovarian cancer. One we've talked about is mirvetuximab soravtansine. That has a payload called DM4, which is an antimitotic payload. Then trastuzumab deruxtecan, which has a topoisomerase 1 payload, targets HER2. It has accelerated FDA approval right now for immunohistochemistry (IHC) 3+ HER2 positivity, and on the NCCN guidelines, we can also use it for IHC 2+ or 3+ ovarian cancer. Those are the 2 medications that we have available currently.

I agree absolutely that those biomarkers—FRα, HER2, and now PD-L1—should all be standard immunohistochemistry biomarkers. All 3 should be routinely tested in our patients with ovarian cancer: FRα for mirvetuximab soravtansine, HER2 for trastuzumab deruxtecan, and then PD-L1 for paclitaxel plus pembrolizumab.

Every time a patient undergoes a biopsy or surgery, those markers should be rechecked. There certainly can be, especially with FRα, concordance with at least [the] initial operation or cytoreductive surgery, and then recurrence. But it's always good to check. The biomarkers can certainly change with time, but there's also tumor heterogeneity of the markers, and you obviously can't biopsy every site. But if there's a site that's particularly problematic that's causing the patient symptoms, and if that gets biopsied, it’s important to do all these tests again—however, I'm not a fan of rebiopsying patients just for the sake of rebiopsying, unless there's a really good indication to do that.

We've talked a lot about biomarker-based treatment. What does the landscape look like for your patients who don't have these biomarkers to guide treatment?

I do think that these other antibody-drug conjugates will be coming out that have topoisomerase 1 payloads and can be used irrespective of biomarkers. Rinatabart sesutecan targets FRα, and that agent has shown efficacy even with FRα levels of 0%. We mentioned sofetabart mipitecan, also FRα-targeting [with a] topoisomerase 1 payload. Data were presented at the 2026 Society of Gynecologic Oncology meeting, showing very nice response rates with varying levels of FRα-positivity.¹

There are others that are in clinical trial testing right now. One that targets CDH6 is called raludotatug deruxtecan—so targeting CDH6, topoisomerase 1 payload. It’s an active agent, with about a 50% response rate in ovarian cancer. Another one that we have in clinical trial testing right now is TUB-040, which targets NaPi2b but also has a topoisomerase payload.

All 4 [of these examples] are [in] clinical trial testing and [have] shown quite exciting response rates in platinum-resistant ovarian cancer, irrespective of the level of the biomarker that the drug is targeting. Those are going to be very exciting options for our patients, either [as] single agents or, depending on the drug, potentially in combination with other agents such as other chemotherapy drugs, bevacizumab, and immunotherapy.

As the chief of gynecologic oncology at Dana-Farber. Is there anything you encourage in your division might be beneficial for other centers to adopt?

It's really important that physicians and general medical oncologists who treat all types of patients with different types of cancers—they have an incredibly difficult job—partner with [gynecologic oncologists], and for even us to see patients earlier, because a lot of the clinical trials limit the number of lines of treatment that patients can have received. Giving our patients with recurrent ovarian cancer standard chemotherapy drugs like pegylated liposomal doxorubicin, topotecan, et cetera—sometimes that's a missed opportunity to allow that patient to enter a clinical trial of an antibody-drug conjugate or a different targeted therapy, where we really could make an impact early on.

Reference

1. Pothuri B, Ray-Coquard I, Kyi C, et al. Updated results from the first-in-human phase 1 study of LY4170156, an antibody drug conjugate (ADC) targeting folate receptor alpha (FRα) in recurrent platinum resistant high-grade serous ovarian cancer (HGSOC). Presented at: 2026 SGO Annual Meeting; April 10-13, 2026; San Juan, Puerto Rico.