From ADCs to Oral SERDs: Practice-Changing Insights from SABCS 2025

Zunairah Shah, MD Roswell Park Comprehensive Cancer Center

Key Points

• HER2–positive disease is entering an era of antibody-drug conjugates (ADCs) as the first-line therapy, although optimal sequencing and treatment duration remain undefined.

• Data from DESTINY-Breast11 and DESTINY-Breast05 are compelling, yet toxicity and the duration of therapy demand careful patient selection and shared decision-making.

• In triple-negative breast cancer (TNBC), treatment strategies are evolving to more refined escalation and de-escalation approaches.

• In HR-positive breast cancer, adjuvant CDK4/6 inhibition remains foundational, oral selective estrogen receptor degraders (SERDs) are moving earlier, and PI3K-pathway targeting is improving outcomes in endocrine-resistant, high-risk PIK3CA-mutant disease.

A Familiar Theme at SABCS 2025: More Options, Harder Choices

Across HER2–positive, triple-negative, and HR-positive breast cancer, the 2025 San Antonio Breast Cancer Symposium (SABCS 2025) emphasized a welcome problem: more active therapies than ever before. The challenge—especially in community settings—remains choosing the appropriate intensity,  sequence, and duration of therapy for each patient, while protecting quality of life and minimizing avoidable toxicity.

During a panel discussion at the conference, Stephanie Graff, MD, of Brown University Health, put it simply, “Isn’t it great to have a wealth of choice for our patients? … And isn’t our life complicated?”

HER2+ Breast Cancer: ADCs Push Earlier, Complexity Increases

Discussion of HER2–positive disease centered on how rapidly T-DXd is moving into curative-intent settings. DESTINY-Breast11, a neoadjuvant clinical trial, raised the possibility of an anthracycline-free path with T-DXd, followed by standard therapy (taxane, trastuzumab, pertuzumab), particularly in high-risk, locally advanced disease. However, the panelists urged caution on immediate practice change.

“The great news is that it would be an anthracycline-free regimen. The complicated news is that we still really don’t know what to do with this data,” said Dr. Graff. She highlighted that DESTINY-Breast11 enrolled a very high-risk population, making generalizability to many screened community populations uncertain.

In the adjuvant setting, DESTINY-Breast05 challenges the long-standing KATHERINE paradigm of ado-trastuzumab emtansine (T-DM1) for residual disease. The signal favoring T-DXd is exciting, but the tradeoffs matter when treatment is given for a full year. “Fourteen cycles of T-DXd is not easy… It’s not just about efficacy, it’s about toxicity and quality of life,” said Susan Dent, BSc, MD, of the University of Rochester Medical Center.

 In current practice, docetaxel, carboplatin, trastuzumab, and pertuzumab, followed by surgery and completion of 1 year of trastuzumab plus pertuzumab, remains the standard for patients achieving a pathologic complete response, while T-DM1 is recommended for residual disease. However, the role of T-DXd is expected to expand as follow-up matures and sequencing questions are clarified.

First-Line Metastatic HER2+: ailor by Biology and Brain Risk

For metastatic HER2–positive disease, the field is moving beyond a single default frontline. DESTINY-Breast09 (T-DXd plus pertuzumab) is reshaping expectations for progression-free survival (PFS), while maintenance strategies are gaining ground based on HER2CLIMB-05 and PATINA.

Two practical selection anchors emerged:

• Central nervous system (CNS) disease drives urgency, with T-DXd strongly favored for patients with brain metastases, Dr. Dent emphasized.
• Maintenance-based approaches that keep shared decision-making in mind may fit some patients better. PATINA may align well with HR-positive, HER2–positive disease, while HER2CLIMB-05 may be more appealing in HR-negative disease or when CNS prevention is prioritized.

Several toxicity considerations are relevant in community practice. With T-DXd, nausea can be clinically significant, and vigilance for interstitial lung disease is essential, including early patient education, a low threshold for symptom evaluation, and established pathways for pulmonary assessment.

For tucatinib-based regimens, diarrhea and elevations in liver function tests require proactive patient counseling and early intervention.

In addition, clinicians should remain attentive to cardiac safety, as Dr. Dent emphasized the importance of maintaining routine cardiac monitoring and cautioned against delayed recognition of left ventricular dysfunction during prolonged therapy.

Early-Stage TNBC: Where to Draw the Neoadjuvant Line

The panel reinforced a pragmatic approach for stage I TNBC: upfront surgery for very small tumors when imaging is confident, but a lower threshold for neoadjuvant therapy as size approaches 1.5–2 cm to enable response-adapted escalation.

Two points particularly relevant for community practice include:

• Axillary ultrasound should be performed before committing patients with presumed stage I TNBC to upfront surgery—upstaging is not rare.
• KEYNOTE-522 intensity should be respected. As Paolo Tarantino, MD, PhD, of Dana-Farber Cancer Institute said, the 2 cm threshold isn’t magical, but it’s a useful guardrail because the regimen is intense and can have life-altering toxicity.

SABCS 2025 also reinforced the relevance of carboplatin in TNBC, while attention increasingly turned to strategies to safely reduce anthracycline exposure. The SCARLET strategy (carboplatin/taxane plus pembrolizumab) reflects where de-escalation research is headed.

Metastatic TNBC: More ADCs, Better Outcomes

In metastatic TNBC, first-line treatment is no longer a single-lane road.

ASCENT-04 (PD-L1–positive) and ASCENT-03 (PD-L1–negative) support moving sacituzumab govitecan earlier, improving PFS versus chemotherapy, with overall survival (OS) interpretation complicated by crossover.

The TROPION-Breast02 study introduced datopotamab deruxtecan (Dato-DXd) as another frontline option in PD-L1–negative disease, reinforcing that ADCs represent a class rather than a uniform toxicity profile. As one panelist emphasized, “Not all ADCs are created equal.” 

With sacituzumab govitecan, alopecia, diarrhea, and neutropenia are common, requiring planning for growth factor use and Day 8 logistics. 

Stomatitis and dry eye are frequent toxicities with Dato-DXd.  A prophylactic steroid mouthwash is critical because once patients stop using mouthwash and develop sores, they are very difficult to get rid of, according to Dr. Hamilton.

Regarding circulating tumor DNA (ctDNA), the consensus in metastatic TNBC was cautious optimism. As Dr. Tarantino said, “We are on the verge—not today, not today,” emphasizing that while ctDNA shows promise, it is not yet ready for routine clinical use.

HR+Breast Cancer: Precision Expands Across Disease Stages

Adjuvant CDK4/6 inhibitor selection is increasingly individualized in HR–positive disease, with panelists emphasizing alignment of therapy with recurrence risk, menopausal status, and tolerability considerations. Abemaciclib’s OS signal supports its role in node–positive higher-risk disease, while ribociclib’s broader eligibility (including some higher-risk node–negative patients) is changing adjuvant conversations.

Emerging early-stage data with oral SERDs, particularly from the phase 3 lidERA trial, were highlighted as a significant advance after decades without a new endocrine monotherapy option. Komal Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center, described the advancement as very exciting, yet she and the other panelists urged caution, as there is a need for longer follow-up and clearer guidance on integration with established adjuvant CDK4/6 inhibitor backbones. 

In the metastatic setting, the panelists praised community oncologists for routinely using liquid next-generation sequencing to identify actionable resistance mutations, including ESR1 and PI3K/AKT/PTEN alterations. For very high-risk endocrine-refractory PIK3CA-mutant disease, the updated PI3K-pathway data (e.g., inavolisib-based strategies) were framed as particularly meaningful because they target a population at high risk of early mortality if left untreated.

Bottom Line

SABCS 2025 delivered practice-informing—and in several areas, practice-changing—data. The most “tomorrow-ready” message for community oncology is this: the winning strategy is no longer only picking the most active drug, but pairing the right regimen with proactive toxicity management, logistics planning, and shared decision-making. With ADCs moving earlier, TNBC first-line expanding, and HR-positive resistance becoming increasingly targetable, the clinics that operationalize these advances safely will see the biggest real-world gains.