The treatment paradigm for platinum-resistant ovarian cancer has advanced with the integration of therapies like mirvetuximab soravtansine-gynx (Elahere); however, improved definitions for platinum resistance and the development of other antibody-drug conjugates (ADCs) could also create more shifts in this treatment paradigm in the future, according to Kathleen N. Moore, MD, MS.

“With additional data, we're about to change a lot of these paradigms for the betterment of patients [by providing a] better selection of drugs,” Moore said in an interview with 

In the interview, Moore discussed how mirvetuximab soravtansine has altered the ovarian cancer treatment paradigm, expanded on the evolving definition of platinum resistance, and highlighted other ADCs currently under development.

Moore is a professor in the Section of Gynecologic Oncology, associate director of Clinical Research at Stephenson Cancer Center, and director of the Oklahoma TSET Phase I Program at the University of Oklahoma College of Medicine in Oklahoma City.

: How has the treatment landscape evolved for patients with platinum-resistant ovarian cancer?

Moore: The treatment paradigm for patients whose tumors are no longer expected to respond to platinum has changed somewhat. However, it is about to change much more with [various] trials that are expected to read out.

[First], the definition for [which] patients are [considered platinum-resistant] is under some evolution. [The definition] used to be very strict, and it still is from a regulatory standpoint, referring to patients whose tumors progress within 6 months of their last platinum[-based treatment]. That's still a regulatory requirement, but I do think that there's an increasing understanding; that is not the absolute definition of tumors that are probably inappropriate for platinum. It also includes patients who received platinum, and the tumor didn't shrink at all. Maybe they were on some kind of maintenance therapy, [such as] bevacizumab [Avastin], and [the tumor] didn't grow for eight months. That tumor is not platinum-sensitive, as it did never respond to platinum.

There's an increasing understanding of these nuances, [and ineligibility also includes] patients who have allergies to platinum and can't receive platinum anymore. There is also a group of tumors that have progressed during PARP inhibitor maintenance and are still considered platinum-sensitive because of the length of time from their prior platinum, but we are starting to understand that some of these tumors respond less robustly to platinum. They're not entirely resistant, but they're not as sensitive as we might otherwise think, and we may be looking at differently at those tumors, as well. The definitions are shifting as we get more definitive data in those spaces.

What have been some of the other key updates in the advanced ovarian cancer space?

We have had 2 important [developments] in the past year to 2 years. The first is mirvetuximab soravtansine, which is 

 and is pending global approvals for patients whose tumors are platinum-resistant and are folate receptor–alpha [FRα] high.

In the United States, the National Comprehensive Cancer Network [NCCN] Guidelines allow for the use of mirvetuximab soravtansine plus bevacizumab in FRα-expressing tumors. That's based on the data from [the phase 1b] FORWARD II trial [NCT02606305]. [Mirvetuximab soravtansine] is the first [ADC] to gain approval and a compendium listing in the NCCN Guidelines for ovarian cancer, and it has been a great addition to the armamentarium, at least in the FRα-high population as a monotherapy, [where we have seen] improvements in progression-free survival, overall survival [OS], and overall response rate [ORR]. We've never seen improvements in OS in this setting, so that's a big accomplishment.

The second is a little less [eye-catching] but it is also important, and that is the fact that we have pulled out weekly paclitaxel with or without bevacizumab as a very different agent for the platinum-resistant setting. It used to be lumped into these investigator choice arms, and you'd have this historical benchmark of expectations of response of about 15%. However, weekly paclitaxel has been looked at alone in 3 big phase 3 studies that have read out.

One trial [NCT03398655] was the VBL gene therapy. Another study [INNOVATE-3 (NCT03940196)] investigated tumor-treating fields, and [the other] one was [the phase 3 AXLerate-OC trial (NCT04729608)] of batiraxcept (AVB-S6-500)]. All of these [studies] added a new drug to weekly paclitaxel vs weekly paclitaxel alone, and all 3 of those studies were negative. All 3 of those studies showed the impressive performance of weekly paclitaxel, with ORRs [ranging from] 30% to 50%.

Mirvetuximab soravtansine and weekly paclitaxel [represent] new drugs into the armamentarium. [Regarding the latter], weekly paclitaxel [may be a preferred regimen] in the eyes of treating physicians as the preferred regimen. I would call it the preferred regimen for anyone who's FRα low or medium. I would use that potentially first, and it would be my go-to after I use mirvetuximab soravtansine. That’s how I would sequence those medications.

That's important for patients and for providers to understand. Weekly paclitaxel and docetaxel are entirely different agents from an efficacy standpoint. There are differences in adverse effects, scheduling, and things that go into shared decision-making, and those are important for patient-centered care. However, purely from an efficacy standpoint, [paclitaxel and docetaxel] are very different agents.

What other ADCs are under development for patients with ovarian cancer?

We're [also] going to see several ADCs with different targets, different payloads, and different linker technology [move into] late-phase clinical trials in ovarian cancer. One is raludotatug deruxtecan [DS-6000], which targets CDH6, and it has a deruxtecan payload. That drug is in phase 2/3 testing right now. The other is rinatabart sesutecan [PRO1184], which is another FRα[-targeted] ADC with an exatecan payload.

These are camptothecin payloads, which are different than microtubule toxin payloads like mirvetuximab soravtansine. These are distinctly different agents, and you could see a patient potentially getting [these agents] in sequence. There are a number of other [ADCs] that are a little bit farther behind [in development]. We just saw readouts in the phase 1 expansion cohorts for several of the TROP2-directed ADCs, and we saw [promising data for] TORL-1-23, which [targets] Claudin-6 with another microtubule toxin [payload]. 

There are a number of [ADCs] that are vying for a spot in the [ovarian cancer treatment] paradigm. We're going to see some big shifts in the sequencing of these medicines in the platinum-resistant space, and we will also see the incorporation of some of these medications into earlier lines of therapy. [The] platinum-sensitive setting is a space I'm interested in putting something head-to-head with platinum to see if platinum really is the best agent in that particular setting. We don't know yet, and that requires a trial. However, that’s a space I'm interested to look at, and many are interested in studying these [ADCs] as maintenance [therapy], which is an exciting opportunity, but it comes with some questions about tolerability of long-term use, potential resistance mechanisms, and how the sequencing of drugs will look [in later lines]. There's a lot of excitement about ADCs moving forward across the treatment paradigm, not just in the resistance setting.

Articles

Kathleen N. Moore, MD, MS, discusses the evolving treatment landscape of platinum-resistant ovarian cancer.

Refined Definition of Platinum Resistance, Novel ADCs Could Bring More Changes to Ovarian Cancer Treatment

Treatment individualization is at the core of adjuvant therapy optimization for patients with breast cancer across the spectrum of hormone receptor (HR) positivity and HER2 expression, according to Kari Wisinski, MD.

®, Wisinski highlighted treatment options for patients with node-positive and -negative HR-positive, HER2-negative breast cancer, where chemotherapy fits into the triple-negative breast cancer (TNBC) treatment paradigm, and the evolving role of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for patients with HER2-positive breast cancer with brain metastases.

She shared her insights on the use of CDK4/6 inhibitors in patients with HR-positive metastatic breast cancer 

Wisinski is the Endowed Professor of Hematology and Oncology and chief of the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine at the University of Wisconsin (UW) School of Medicine and Public Health in Madison. She is also the associate director of Clinical Research and co-lead of the Breast Cancer Disease Oriented Team at the UW Carbone Cancer Center.

: What is the current treatment strategy regarding the use of adjuvant regimens in patients with premenopausal HR-positive, HER2-negative breast cancer?

: For premenopausal women, the decision about when to add chemotherapy is still an evolving area. For lymph node–negative breast cancer, use of a genomic predictor, such as Oncotype DX or the 21-gene recurrence score, can be a useful tool in making these decisions. There are clear-cut points for where we should recommend chemotherapy and where [a patient] likely does not need it.

However, then there’s this middle range, between [the Oncotype DX scores of] 16 and 25, where [this decision] becomes more nuanced and difficult. There needs to be a discussion with the patient regarding the other tumor features, the tumor size, the grade, what might be the absolute benefit of chemotherapy for that patient, and whether we know if that’s a chemotherapy benefit vs an ovarian suppression benefit from the chemotherapy. I have those conversations in the clinic and then try to make an individualized decision with each patient about whether to layer in the chemotherapy to their adjuvant endocrine therapy. The National Comprehensive Cancer Network guidelines support that; they [recommend] both options, which gives us the discretion to have these types of conversations and individualize patient decisions.

The second question is: What do we do for premenopausal women who have HR-positive, HER2-negative, node-positive disease, especially if it’s in the range of 1 to 3 positive nodes? At this point, that is also a difficult group to make decisions for. The phase 3 RxPONDER trial [NCT01272037] findings indicate that there’s potentially some chemotherapy benefit in those patients, but there remain questions about whether that is truly chemotherapy benefit vs suppression of the ovaries and effect on endocrine efficacy. The current standard is to consider chemotherapy for premenopausal patients who have node-positive disease. The phase 3 OFSET study [NCT05879926] is an important study that we are doing nationally to address this question, and I’m hopeful that the outcomes of that study comparing chemotherapy plus ovarian function suppression [OFS] and endocrine therapy vs OFS plus endocrine therapy alone will help address this question in the future.

What is the significance of the final overall survival (OS) data from the phase 3 KEYNOTE-522 trial (NCT03036488)?

The KEYNOTE-522 data, when they first came out, demonstrated improvement in pathologic complete response and then event-free survival. This was exciting information for the management of advanced TNBC, and the recent OS data have helped us clearly understand that this treatment is having the effect we had hoped for: that it is preventing recurrences and improving survival for a disease that affects many people, especially at young ages, and can have devastating outcomes. Our next question, because there’s always a next question, is: Do we need all the chemotherapy that is part of the KEYNOTE-522 regimen: anthracyclines, cyclophosphamide, carboplatin, and taxanes? It’s a lot of chemotherapy. There’s good work going on nationally, including the scarlet study, that is trying to evaluate whether [treatment] de-escalation with an anthracycline-free regimen can have the same efficacy as the KEYNOTE-522 regimen.

Lastly, one of the key challenges we face still with immunotherapy is lifelong adverse effects that can happen in the setting of these agents. Developing better predictors for which patients are going to benefit from these agents again, or who might develop toxicities and in whom we might want to avoid [these agents], continues to be a high priority.

How might the data from the phase 3 DESTINY-Breast12 trial (NCT04739761) influence clinical practice for patients with HER2-positive brain metastases?

In HER2-positive breast cancer, brain metastases remain one of our biggest challenges. Although we can often control the systemic disease well elsewhere in the body, brain metastases often develop and become a life-limiting consequence of the disease. At the same time, we’ve also had difficulty identifying newer systemic therapies that can effectively control or shrink brain tumors. Therefore, we’ve relied for many years on radiation and surgery as primary treatments [for these patients].

However, we’ve seen advances in the past few years, with agents like tucatinib [Tukysa], with some central nervous system [CNS] activity. As T-DXd has come into the realm of treatment for [patients with] HER2-positive breast cancer, there have been interesting observations that [this agent could] have activity also in patients who are affected by brain metastases. The results of the DESTINY-Breast12 study are further evidence that T-DXd seems to have CNS activity, and that this agent can be considered as one of our approaches for patients who have HER2-positive breast cancer with brain metastasis.

What is your main message for colleagues about individualized breast cancer management?

Treatment for breast cancer needs to be individualized based on discussions with the patient about their preferences and understanding their underlying other medical issues. The other consideration that is important in this individualization is considering how we use our tools, [such as] molecular testing like Oncotype DX or next-generation sequencing [NGS], to look for tumor mutations to help identify a treatment strategy that makes sense for what’s going on in that patient’s tumor. [We are making] important advances with both circulating tumor DNA and NGS but we also need to understand some of the limitations of those tests when we’re interpreting them and discussing treatment options for patients, making sure we’re putting that all into context.

Kari Wisinski, MD, highlights treatments for HER2– breast cancer, the role of chemotherapy in TNBC, and the benefits of T-DXd for brain metastases.

Genomic Predictors Inform the Evolving Role of Chemotherapy in Breast Cancer Management

Ribociclib (Kisqali) and abemaciclib (Verzenio) are top frontline and adjuvant treatment choices for patients with hormone receptor–positive metastatic breast cancer, although, in the absence of predictive biomarkers, decisions between CDK4/6 inhibitors in these settings often ultimately hinge on patient characteristics and ability to tolerate each agent, according to Kari Wisinski, MD.

“There’s high-level evidence that ribociclib and likely abemaciclib improve overall survival [OS] for first-line metastatic hormone receptor–positive breast cancer,” Wisinski said in an interview with 

 following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Wisinski discussed factors that influence her decision between available CDK4/6 inhibitors for patients with previously untreated, hormone receptor–positive metastatic breast cancer, questions regarding the potential role of these agents in the adjuvant setting, and what the future may look like regarding the sequential use of these agents.

Wisinski noted that data from trials such as the phase 3 NATALEE trial (NCT03701334) are helping to inform the adjuvant use of CDK4/6 inhibitors, although questions about optimal patient selection remain. In NATALEE, at a median follow-up of 44.2 months, ribociclib plus a nonsteroidal aromatase inhibitor (AI) generated an invasive disease-free survival (IDFS) benefit vs a nonsteroidal AI alone in patients with hormone receptor–positive, HER2-negative early breast cancer (HR, 0.715; 95% CI, 0.609-0.840; nominal 1-sided 

 Furthermore, at a median follow-up of 44.3 months, investigators observed a positive trend for overall survival (OS) favoring the ribociclib arm (HR, 0.827; 95% CI, 0.636-1.074; nominal 

She also pointed out that gaps in currently available trial data indicate the need for improved patient selection tools when considering using one CDK4/6 inhibitor after another. For instance, although the phase 3 postMONARCH trial (NCT05169567) showed that treatment with abemaciclib plus fulvestrant (Faslodex) following disease recurrence on a prior CDK4/6 inhibitor in the advanced setting led to a 27% reduction in the risk of developing a progression-free survival (PFS) event vs fulvestrant alone (HR, 0.73; 95% CI, 0.57-0.95; nominal 

= .02), it is not yet known which subgroups of patients may benefit the most from this treatment approach.

: How is your selection between the currently available CDK4/6 inhibitors for patients with previously untreated HR-positive metastatic breast cancer influenced by the safety profiles of these agents and patient characteristics?

: I tend to pick [either ribociclib or abemaciclib] to start, often ribociclib because it is the only agent that has shown a clear survival [benefit compared with chemotherapy]. There are times, though, that either the [ribociclib dosing] schedule of 3 weeks on and 1 week off vs the daily [abemaciclib dosing schedule] or safety can encourage you to pick a different medication, and that’s often [decided] in discussion with the patient. 

For example, if a patient is a little more frail and I’m a bit more worried about the adverse effects [AEs] of diarrhea or neutropenia or just general tolerance, I have picked palbociclib [Ibrance] at times. Although the neutropenia rates can be similar [between all these agents], I find [palbociclib] to be a bit more tolerable from an AE standpoint than both the other agents. Sometimes, because of cardiac risk factors, I’ll pick palbociclib as well. Occasionally, there’s [a patient for whom the] 3 weeks on 1 week off schedule [of ribociclib] will be harder for them to follow, so abemaciclib is a good choice too. I continue to keep all 3 [agents] on my radar and use all 3. The PFS outcomes were similar between all the first-line studies [of these agents], but the OS data have sent me to use ribociclib or abemaciclib more often.

What new information do we still need to learn about CDK4/6 inhibitors to optimize their use in the adjuvant setting?

In the adjuvant setting with the CDK4/6 inhibitors, there remain some key questions. First and foremost: Does an improvement in IDFS lead to an OS benefit? That may be difficult for us to ever prove, as patients go on to receive subsequent lines of therapy, but it remains a big question.

The second big question is the selection of patients. The [phase 3] adjuvant CDK4/6 inhibitor studies that demonstrated [IDFS] benefit [vs standard of care], monarchE [NCT03155997] and NATALEE, showed that the absolute number of [patients who] benefit is still relatively small, and therefore the number [of patients] needed to treat [to see that benefit] is relatively high. That just means it would be ideal if we could develop an improved biomarker to help select which patients get the benefit from this therapy, or maybe flip it the other way [to determine] which patients don’t need that therapy because they’re going to continue to do well because that is what we see in most of these patients.

The third big question I have is: How long is the optimal duration [of treatment]? Is it 2 years, which [is the length of] abemaciclib [treatment]? Is it 3 years [like the length of treatment with] ribociclib? Could it be shorter? It is a big commitment for patients to continue that therapy, [including] additional visits for them in the clinic. Even if we can think about creative strategies like telemedicine, [treatment with these agents] still ends up [taking] more time and more potential AEs for a long duration of time.

Is the sequential use of CDK4/6 inhibitors feasible and effective?

In the metastatic setting, switching from a first-line CDK4/6 inhibitor to a subsequent-line CDK4/6 inhibitor plus endocrine therapy is reasonable and feasible. Overall, it’s a well-tolerated approach and can be a way to delay the onset of systemic therapies, either antibody-drug conjugates or chemotherapy, for at least a period. The challenges we have now are identifying whether we should use a sequential CDK4/6 inhibitor vs a different genomically targeted agent, such as an AKT inhibitor, in this setting if a patient has a known PI3K pathway alteration. We don’t know the answer to that, and that remains one of our challenges.

In addition, the PFS benefits seen [with CDK4/6 inhibitor switch] in both the [phase 3] MAINTAIN [NCT02632045] and postMONARCH studies were relatively modest. I think that tells us we still need to have better tools to select which patients are going to benefit the most from this type of approach and [which patients] should maybe move on to a different therapy.

Fasching PA, StroyakovskiyD, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. 

. 2024;35(suppl_2):1-72. doi:10.1016/annonc/annonc1623

Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. 

. 2024;42(suppl 17):abstr LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001

Kari Wisinski, MD, discusses factors that influence her decision between CDK4/6 inhibitors for patients with treatment-naive, HR+ metastatic breast cancer.

State of the Science Summit Recaps | Supplements and Featured Publications

Refined Definition of Platinum Resistance, Novel ADCs Could Bring More Changes to Ovarian Cancer Treatment

Genomic Predictors Inform the Evolving Role of Chemotherapy in Breast Cancer Management

AE Profiles and Dosing Schedules Define the Role of CDK4/6 Inhibitors in HR+ Metastatic Breast Cancer