Breast Cancer Experts: Key ADC Developments and CDK 4/6 Inhibitor Updates Set to Dominate ESMO 2025

As anticipation builds for the 2025 ESMO Congress, readouts across two primary fields of investigation are already generating significant buzz in the breast cancer space.

“A lot of incredible abstracts and late-breakers will be [presented during] ESMO 2025, [but] there are 2 main categories [of research driving the conversation],” Paolo Tarantino, MD, a research fellow in the Department of Medicine at the Dana-Farber Cancer Institute in Boston, Massachusetts, shared with OncLive®. “One, as it often happens, is antibody-drug conjugates [ADCs]. The other hot [topic] is new drugs for hormone receptor [HR]–positive breast cancer…[including] CDK 4/6 inhibitors combined with PI3K/mTOR inhibitors.”

In the preview article below, Tarantino’s insights are accompanied by exclusive perspectives from the following KOLs:

• Kelly McCann, MD, PhD, an associate clinical professor of medicine in the Division of Hematology/Oncology at the University of California Los Angeles Health.
• Jason A. Mouabbi, MD, an assistant professor in the Department of Medical Breast Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
• Erika P. Hamilton, MD, the director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee.

Read on to learn which presentations are drawing the most attention and how such research could have meaningful implications for clinical practice going forward.

​​Editor’s note: This preview will continue to be updated with additional abstracts to watch in Breast Cancer leading up to the 2025 ESMO Congress.

What ADC Data in Breast Cancer Are on the Docket for ESMO 2025?

291O - DESTINY-Breast11: Neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC)

Session time: Saturday, 10/18, 16:30 - 16:42 CEST

Tarantino: All eyes are on the [phase 3] DESTINY-Breast11 trial [NCT05113251] in the plenary session. This trial is evaluating fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] either alone or sequenced with trastuzumab [Herceptin], pertuzumab [Perjeta], and paclitaxel [THP] compared with an anthracycline-taxane-based regimen for HER2-positive breast cancer in the neoadjuvant setting. We already know that the trial is positive; there was a positive press release. What we know is that replacing the anthracyclines with T-DXd, and also giving THP afterward, can improve the rate of pathological complete response without an increase in the risk of pneumonitis or interstitial lung disease, which was one of the concerns.

There are high hopes that this trial may replace anthracyclines, which are effective but burdened by severe toxicities. This would be a very important step forward, but it comes with a lot of questions as well, because there are other regimens in this field.

LBA20 - Primary results from ASCENT-03: A randomized phase 3 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)

Session time: Sunday 10/19, 09:15 - 09:25 AM CEST

McCann: [Data from the phase 3] ASCENT-04/KEYNOTE-D19 study [NCT05382286], which is studying sacituzumab govitecan-hziy [Trodelvy] plus pembrolizumab [Keytruda] vs chemotherapy of physician’s choice [gemcitabine plus carboplatin, nab-paclitaxel, or paclitaxel] plus pembrolizumab in the first line for metastatic PDL1-positive TNBC was presented at the 2025 ASCO Annual Meeting, showing a median PFS of 11.2 months with sacituzumab govitecan vs 7.8 months with chemotherapy.2

ASCENT-03 is the sister trial with sacituzumab govitecan vs chemotherapy of physician’s choice in the first line for metastatic PDL1-negative TNBC. ADCs seem to have several advantages over traditional cytotoxic chemotherapies, including a longer half-life and more payload delivered directly to the cancer cell. Sacituzumab govitecan can usually also be continued for a much longer period of time than taxanes, which eventually cause neuropathy, or gemcitabine plus carboplatin, which can result in permanent myelosuppression and sometimes allergic reactions with an increasing number of doses.

Hamilton: At ASCO 2025, we saw the late-breaking data from ASCENT-04 testing chemotherapy and pembrolizumab vs sacituzumab govitecan and pembrolizumab in first-line TNBC with PDL1-expression. We have seen a press release for positive data from the PD-L1 negative companion trial, ASCENT-03. ASCENT-03 [randomly assigned] patients to first-line chemotherapy vs sacituzumab govitecan. This means that we will soon likely have approval of ADCs in the first-line setting for TNBC regardless of PDL-1 status.

Tarantino: ASCENT-03 [is evaluating] first-line chemotherapy for patients with metastatic TNBC who cannot receive immunotherapy. Usually, we give taxanes or platinum chemotherapy to these patients, but we really feel that ADCs could lead to improved outcomes.

Mouabbi: This abstract is particularly exciting because it could establish ADCs as the new standard of care for first-line therapy in patients with PD-L1–negative metastatic TNBC, addressing a significant unmet need for those ineligible for immune checkpoint inhibitors.

LBA23 - Sacituzumab tirumotecan (sac-TMT) vs investigator's choice of chemotherapy (ICC) in previously treated locally advanced or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC): results from the randomized, multi-center phase 3 OptiTROP-Breast02 study.

Session time: Saturday 10/18, 10:55 - 11:05 AM CEST

Mouabbi: I'm looking forward to this abstract because it may introduce a fourth ADC option in the metastatic HR-positive, endocrine-refractory breast cancer setting, where patients often face limited effective treatments after prior lines.

Is CDK 4/6 Plus PIK3/mTOR Inhibition a Viable Treatment Strategy Beyond PIK3CA-Mutant Disease?

LBA17 - Gedatolisib (geda) + fulvestrant ± palbociclib (palbo) vs fulvestrant in patients (pts) with HR+/ HER2-/PIK3CA wild-type (WT) advanced breast cancer (ABC): First results from VIKTORIA-1

Session time: Saturday 10/18, 10:25 - 10:35 AM CEST

McCann: Gedatolisib is an intravenous dual PI3K-mTOR inhibitor that was evaluated in the VITKORIA-1 trial in combination with fulvestrant [(Faslodex) with or without] palbociclib [Ibrance] vs fulvestrant alone in [patients with] metastatic HR-positive, HER2-negative breast cancer after progression on a first-line CDK4/6 inhibitor plus aromatase inhibitor.3 Arms A through C [included] patients whose tumors did not have activating mutations in PIK3CA, and arms D to F were in patients whose tumors had activating mutations in PIK3CA. The PI3K-AKT-mTOR pathway can be unregulated and contribute to cancer cell proliferation and endocrine therapy resistance without there being an activating mutation in the pathway. It is well-established that mTOR inhibitor everolimus [Afinitor] can work [irrespective of] whether there is an activating mutation in PIK3CA, so perhaps it is not surprising that gedatolisib can be effective in the absence of a PIK3CA activating mutation.

Mouabbi: Following the success of the [phase 3] INAVO120 trial [NCT04191499], which showed improved outcomes with triplet therapy for [patients with] PIK3CA-mutated [disease], I'm eager to see if gedatolisib in combination with fulvestrant and palbociclib can extend similar benefits to HR-positive metastatic breast cancer cases without PIK3CA mutations.

Tarantino: We already have an mTOR inhibitor approved: everolimus. However, gedatolisib is supposed to be more comprehensive and to target PI3K as well. When it was added to fulvestrant, or fulvestrant plus palbociclib, it improved outcomes with pretty impressive HRs and medians. These data were showcased in an investor call, but we [are excited] to see the full presentation at ESMO 2025.

Will Updated Data Affirm Long-Term CDK 4/6 Inhibitor Benefit in Early Breast Cancer?

LBA13 - monarchE: Primary overall survival (OS) results of adjuvant abemaciclib + endocrine therapy (ET) for HR+, HER2-, high-risk early breast cancer (EBC)

Session time: Friday 10/17, 14:50 - 15:00 AM CEST

Hamilton: The press release has disclosed a survival benefit for the phase 3 monarchE trial [NCT03155997] trial looking at endocrine therapy alone vs endocrine therapy plus abemaciclib [Verzenio] for patients with high-risk node-positive estrogen receptor–positive breast cancer.4 Previously, we had seen with 5 years of follow-up that the benefit in disease-free survival [DFS] was 7.6% with the majority being distant recurrent events. With relatively short follow-up, seeing survival in this population of patients who are very likely to be offered CDK4/6 and have survival in the metastatic setting that is now [over] 5 years is impressive and speaks to the additional patients who are cured with the addition of this therapy.

McCann: Abemaciclib is the first and currently only CDK4/6 inhibitor to show an OS benefit in the adjuvant setting for HR-positive, HER2-negative breast cancer patients at high risk for recurrence. MonarchE included patients with 4 or more positive lymph nodes or 1 to 3 positive lymph nodes plus either a 5-cm or grade 3 tumor. To ameliorate diarrhea on abemaciclib, it is important to consider up-titration per the phase 2 TRADE trial [NCT06533826] presented at ASCO 2025.

Mouabbi: This abstract stands out as the first study to report on OS in patients with early-stage HR-positive breast cancer treated with CDK4/6 inhibitors plus endocrine therapy.

LBA14 - Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes.

Session time: Friday 10/17, 15:00 - 15:10 AM CEST

Mouabbi: The 5-year update from the [phase 3] NATALEE trial [NCT03701334] is crucial for confirming the durability of ribociclib's [Kisqali] benefits when added to adjuvant endocrine therapy

Tarantino: We know that abemaciclib in monarchE improved DFS. Now we expect to see OS data, which has been announced to be positive, alongside the 5-year update of data from NATALEE.

Are There Any Additional Poster Presentations of Interest?

299P - Extended adjuvant neratinib in HER2+/HR+ early breast cancer in clinical routine – final results from the multi-national, prospective, observational study ELEANOR.

Mouabbi: This observational study is important for assessing neratinib's real-world performance in HER2-positive/HR-positive early breast cancer patients previously treated with pertuzumab and/or ado-trastuzumab emtansine [Kadcyla].

310P - Immune-Related Adverse Events in Early Triple Negative Breast Cancer: A Meta-Analysis of Real-World Evidence vs. Clinical Trial Data

311P - Exploring circulating MDSC role in immune-related adverse events (irAEs) in early triple negative breast cancer (eTNBC): a preliminary analysis from the IRIS study.

313P - Tumor Infiltrating Lymphocytes and Residual Cancer Burden following neoadjuvant immunochemotherapy compared to chemotherapy in triple negative breast cancer

315P - SYNERGIA breast cancer - Automated assessment of Tumour Infiltrating Lymphocytes

316P - Blood-based T-cell profiling forecast ICI response in early triple negative breast cancer (eTNBC): preliminary data from IRIS study.

322P - Immune profiling across blood, tumour and lymph nodes to guide patient stratification for neoadjuvant immunotherapy in early-stage TNBC

McCann: Currently, most patients with TNBC are treated with the immune checkpoint inhibitor pembrolizumab in the curative setting as part of the neoPACT or [the phase 3] KEYNOTE-522 trial [NCT03036488]. In KEYNOTE-522, pembrolizumab improved OS at 5 years by [4.9%].5 Compare this with capecitabine [Xeloda], which improved 5-year OS in the curative setting in TNBC by [7.4%] in [the phase 3] CREATE-X trial [UMIN000000843], and it could be argued that the CREATE-X population had a poorer prognosis because a requirement of enrollment was that they hadn’t achieved a pathological complete response with neoadjuvant chemotherapy.6

Chemotherapy remains the crux of TNBC treatment, not checkpoint inhibition. Furthermore, more than half of patients exposed to checkpoint inhibitors will develop an immune-related adverse effect [irAE]; these have been underreported in clinical trials, making real-world data essential to define the incidence of irAEs. We need to develop better markers of which breast cancer patients are likely to respond to immune checkpoint inhibitors and which are likely to develop toxicities to balance the benefits and risks for our patients.

References

1. Enhertu (fam-trastuzumab deruxtecan-nxki) followed by THP before surgery showed statistically significant and clinically meaningful improvement in pathologic complete response in patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 Phase III trial. AstraZeneca. News Release. May 7, 2025. Accessed September 24, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-followed-by-THP-before-surgery-showed-statistically-significant-and-clinically-meaningful-improvement-in-pathologic-complete-response-in-patients-with-high-risk-HER2-positive-early-stage-breast-cancer-in-DESTINY-Breast11-Phase-III-trial.html
2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109
3. Gedatolisib plus fulvestrant with or without palbociclib vs standard-of-care for the treatment of patients with advanced or metastatic HR+/HER2- breast cancer (VIKTORIA-1). ClinicalTrials.gov. Updated June 24, 2025. Accessed September 24, 2025. https://clinicaltrials.gov/study/NCT05501886
4. Lilly’s Verzenio (abemaciclib) increases overall survival in HR+, HER2-, high-risk early breast cancer with two years of therapy. Lilly. News release. August 27, 2025. Accessed September 24, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-verzenior-abemaciclib-increases-overall-survival-hr-her2
5. Schmid P, Cortes J, Dent R, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932
6. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645