Targeted Therapies, ADCs, and Oral SERD Combos Expand Treatment Possibilities Across Breast Cancer Settings

Recent clinical progress in breast cancer treatment highlights a shift toward highly individualized care, where the selection of therapies like CDK4/6 inhibitors and oral selective estrogen receptor degraders (SERDs) depends on a balance of survival data, mutation status, and patient quality-of-life (QOL) goals, according to Megan Kruse, MD.

“Earlier-line antibody-drug conjugate [ADC] use is becoming a theme across metastatic breast cancer management,” Kruse said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Kruse discussed CDK4/6 inhibitor decision-making for patients with hormone receptor–positive breast cancer, potential future directions for oral SERD use in this disease subtype, and the evolving role of ADCs for patients with triple-negative breast cancer (TNBC), regardless of PD-L1 status.

Kruse is an associate staff member in Hematology and Medical Oncology at Cleveland Clinic and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center in Ohio.

OncLive: In hormone receptor–positive breast cancer management, what patient factors influence your decision between the available CDK4/6 inhibitors?

Kruse: When we're selecting a first-line CDK4/6 inhibitor for a patient, a lot of that decision-making comes down to what's important for a patient regarding their QOL. That could factor in with the anticipated adverse effects associated with the drugs, the schedule of the medications, the accessibility of the medications, and what is most cost-effective for a patient. It comes down to all those practical factors, because we feel confident that all 3 CDK4/6 inhibitors currently available have excellent activity in terms of improving cancer control and progression-free survival [PFS] for patients with hormone receptor–positive metastatic breast cancer.

There are some individual nuances there, and we have, for the past few years, felt confident with first-line use, particularly of ribociclib (Kisqali), given that it has shown both PFS and overall survival [OS] advantages in all its published phase 3 studies. Abemaciclib [Verzenio] has first-line OS results that weren't statistically significant, but the magnitude of benefit is clinically meaningful. [Regarding] first-line palbociclib [Ibrance], it is still a bit of a mystery why the large phase 3 study did not show us an OS benefit, when in real-life practice and real-world studies, we see pretty much equivalent effects on PFS and OS for patients with all 3 available CDK4/6 inhibitors. You're considering the strength of the data as a provider, but you're also thinking about your patient's everyday life, and, in reality, whichever of these medications a patient has access to and can tolerate for the long haul is the medication I want them to receive.

Now that the pace of oral SERD development is accelerating in the hormone receptor–positive disease setting, what might be the potential for using this class of agents in broader patient populations than they're currently approved for?

Oral SERDs are available for patients with hormone receptor–positive metastatic breast cancer with an ESR1 mutation; that is the FDA label for both elacestrant [Orserdu] and imlunestrant [Inluriyo]. These drugs can have meaningful activity for patients, and they are generally well tolerated, so we hope more patients will be able to receive oral SERDs over time. What we have seen with combinations of oral SERDs plus other targeted therapies so far has been that these combinations are again tolerable and effective.

One of the more exciting themes we're seeing is that some of the oral SERD combination regimens can be effective not just in that ESR1-mutant patient population, but also in ESR1 wild-type patients. We've seen this with the combination of imlunestrant and abemaciclib, as well as elacestrant and abemaciclib or everolimus [Afinitor]. That is exciting because we've gotten used to combination therapies in the hormone receptor–positive metastatic breast cancer setting with our first-line CDK4/6 inhibitor and endocrine therapy combinations, and there's an appetite to continue combination therapy use in the second-line setting, particularly because it looks like those responses and the duration of cancer control we see with those combinations are longer than with single-agent endocrine-based therapy.

Over time, we're likely to see more combination options with an oral SERD backbone become available for patients with ESR1 mutations, as well as those with ESR1 wild-type disease. It's especially that wild-type population where this is needed, given that these patients can have poor outcomes with single-agent endocrine therapy in those second- or third-line settings and have to move on to cytotoxic therapy faster. There's also the combination of giredestrant [GDC-9545] and everolimus that's going to be reviewed by the FDA in 2026. That may bring another option into the fold that looks more active for the ESR1 wild-type population.

On the heels of all of this enthusiasm in the metastatic setting, we'll likely see the expansion of the oral SERDs into the early-stage setting as well. We're excited based on the results of the phase 3 lidERA study [NCT04961996] that we saw at the 2025 San Antonio Breast Cancer Symposium, again with giredestrant. These oral SERDs look more active than our standard endocrine therapy options, and they may be better tolerated in some ways. That's a story that's still playing out, and the tolerability piece may not be reflected in our currently available studies…but it seems like patients who are receiving oral SERDs are tolerating them well.

How is sacituzumab govitecan-hziy (Trodelvy) making its way into the TNBC treatment paradigm, and in what context would it be appropriate to weigh the use of this agent against datopotamab deruxtecan-dlnk (Dato-DXd; Datroway)?

Sacituzumab govitecan has become a familiar option for us as medical oncologists in the management of later-line hormone receptor–positive [disease] and TNBC. The results of the phase 3 ASCENT-03 [NCT05382299] and ASCENT-04 [NCT05382286] studies show clear signals of efficacy, at least regarding PFS, with sacituzumab govitecan[-based therapy] over standard cytotoxic chemotherapy in the first-line setting for patients with metastatic TNBC, regardless of their PD-L1 status. We have been looking for PD-L1 in the first-line metastatic TNBC setting to help determine which patients would be candidates for immunotherapy in combination with chemotherapy.

The ASCENT-03 and ASCENT-04 studies are comprehensive in that way, because ASCENT-03 included patients with PD-L1–negative disease or who were immune checkpoint inhibitor ineligible, whereas ASCENT-04 investigated the combination of sacituzumab govitecan and pembrolizumab [Keytruda] vs standard chemotherapy plus pembrolizumab in patients with PD-L1–positive disease. With both trials being positive for their primary end points of PFS, we can feel confident in moving sacituzumab govitecan into that first-line treatment setting for metastatic TNBC. That's reassuring, because when you meet a patient, you may not know their PD-L1 status up front, and you may be waiting for that testing to come back. This allows you to start talking about a treatment plan with the idea that you could add in the immunotherapy to the sacituzumab govitecan backbone if you need to later on.

These trials are also important as you think about what they mean for OS trends. In the later-line setting, sacituzumab govitecan can show PFS trends before OS trends, and [in the ASCENT trials], the OS results were a bit bigger than what we expected based on the PFS results. I'm excited to see what OS looks like in the long run for both of these trials. It will be a bit of a challenge for the results of ASCENT-03 to make that determination, because in that study, crossover was allowed, where patients in the standard-of-care arm were allowed to receive sacituzumab govitecan as part of their protocol therapy in the second-line setting. That may mute some of the OS advantage that we would typically see, but I think it's a reasonable way, and the right way, to run a study, in the sense that we want to give patients access to our most effective therapies. In some areas of the world, they would not have had access to the sacituzumab govitecan otherwise.

Then, this conversation gets a bit more complicated as we consider other options in this first-line metastatic triple-negative setting with the results from the phase 3 TROPION-Breast02 study [NCT05374512] using Dato-DXd. In TROPION-Breast02, we saw positive results in favor of Dato-DXd over standard chemotherapy for patients with metastatic TNBC. We saw both a PFS and OS result that was positive.

When deciding between sacituzumab govitecan and Dato-DXd in the first-line metastatic TNBC setting, it's going to come down to a lot more practical decision-making. These drugs are active, so patients should be receiving an ADC, not standard cytotoxic chemotherapy. The choice of ADC may come down to the individual drug toxicities and the [administration] schedule of the drugs. These drugs have different infusion schedules, and they have different toxicity profiles.

It may also come down to what therapies a patient received in prior lines, if they have recurrent metastatic breast cancer after early-stage treatment, as well as what lingering toxicities they may or may not have from that prior therapy. It's great to have options. It allows us to individualize the treatment plan for our patients.

References

1. Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Ann Oncol. 2025;36(suppl 2):S1680-S1681. doi:10.1016/j.annonc.2025.09.030
2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959
3. Datroway approved in the U.S. as first TROP2 directed antibody drug conjugate for first-line treatment of patients with metastatic triple negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. News release. Daiichi Sankyo. May 22, 2026. Accessed June 10, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/datroway-approved-in-the-us-as-first-trop2-directed-antibody-drug-conjugate-for-first-line-treatment-of-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-pd-1pd-l1-inhibitor-candidates