Antibody-Drug Conjugates (ADCs) Take Center Stage

The 42nd Annual Miami Breast Cancer Conference, held in March 2025, showcased promising advancements in breast cancer treatment, with a strong emphasis on antibody-drug conjugates (ADCs), novel therapies targeting estrogen signaling, and the critical importance of patient-centered care.ADCs,designed too selectively deliver cytotoxic agents to cancer cells,have emerged as a powerful tool in the oncologist’s arsenal.

The conference spotlighted ADCs targeting TROP2, HER2, and HER3, key proteins overexpressed in various breast cancer subtypes.TROP2, in particular, garnered meaningful attention, with discussions focusing on datopotamab deruxtecan-dlnx (Dato-DXd; Datroway) and sacituzumab govitecan-hziy (Trodelvy). TROP2’s prevalence in breast cancer cells,coupled with its limited expression in normal tissues,makes it an ideal target for these innovative therapies.

TROPION-Breast01 Trial: Dato-DXd Shows Promise

The phase 3 TROPION-Breast01 trial (NCT05104866) revealed that Dato-DXd significantly improved progression-free survival (PFS) compared to standard chemotherapy in patients with metastatic hormone receptor–positive (HR+), HER2-negative breast cancer that had progressed after hormone therapy and up to two lines of chemotherapy. The hazard ratio (HR) was 0.63 (95% CI, 0.52-0.76; P <.0001).While overall survival (OS) data were still preliminary, a trend favoring Dato-DXd was observed (HR, 0.84; 95% CI, 0.62-1.14).

However, clinicians should be aware of the unique adverse effect (AE) profile of Dato-DXd, which includes stomatitis, nausea, neutropenia, and ocular effects like dry eye and keratitis. Managing these side effects will be crucial for optimizing patient outcomes. For example,proactive oral hygiene protocols and early intervention for ocular symptoms can definitely help mitigate the severity of these AEs,improving patients’ tolerance and adherence to treatment.

Sacituzumab Govitecan: An Established Option

Sacituzumab govitecan, the first TROP2-directed ADC approved for metastatic breast cancer, was also a key topic.Data from the phase 3 TROPiCS-02 trial (NCT03901339) and the phase 3 ASCENT trial (NCT02574455) have previously demonstrated superior PFS and OS with sacituzumab govitecan compared to standard chemotherapy in HR+ and triple-negative metastatic breast cancer, respectively.

A crucial distinction between Dato-DXd and sacituzumab govitecan lies in their AE profiles and administration schedules. Dato-DXd is administered every three weeks, while sacituzumab govitecan is given on days 1 and 8 of a 21-day cycle. These practical differences underscore the importance of shared decision-making between physicians and patients. “The approvals of both TROP-2-directed ADCs in HR+ breast cancer provide additional treatment options for our patients and highlight the importance of mutual decision-making when considering practical differences between both options,” experts noted at the conference.

HER2 and HER3-Targeted ADCs: Expanding the Horizon

The conference also addressed other ADCs targeting HER2 and HER3,including fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and patritumab deruxtecan (HER3-DXd),respectively. Panel discussions emphasized the benefits of using T-DXd earlier in the treatment course, demonstrating its superiority over standard chemotherapy in both HER2-amplified and HER2-low settings.

DESTINY-Breast09 Trial: A Potential Paradigm Shift?

The fully accrued phase 3 DESTINY-Breast09 trial (NCT04784715), which compared first-line T-DXd against the current standard of care (taxane, trastuzumab [Herceptin], and pertuzumab [THP]) for HER2-amplified metastatic breast cancer, was a major point of interest. While THP remains the current standard, the results from DESTINY-Breast09 are eagerly awaited and could potentially redefine the treatment landscape.

However, recently reported data from the phase 3 PATINA trial (NCT02947685) demonstrated significantly improved PFS when the CDK4/6 inhibitor palbociclib (Ibrance) was added to endocrine therapy plus trastuzumab and pertuzumab (HP) after response to taxane therapy with HP. These data may fuel the potential dilemma of choosing an induction/maintenance approach vs first line T-DXd with continuation until progression if the DESTINY-BREAST09 trial is positive. A patient-centered approach with mutual decision-making will likely be critical for navigating this potential dilemma.

HER3-DXd: A Promising New Avenue

Targeting HER3 with ADCs like HER3-DXd represents another promising avenue.HER3 is frequently overexpressed in various cancers, including breast cancer, and early phase 2 data suggest that HER3-DXd has significant clinical activity in metastatic breast cancer. The growth of ADCs with different cytotoxic payloads and antibody targets is crucial for overcoming resistance and maintaining efficacy when sequencing these therapies and this approach is notably relevant given the potential for cross-resistance between different ADC therapies.

Novel Endocrine therapies: Disrupting Estrogen Signaling

The conference also highlighted the integration of novel endocrine therapies into breast cancer treatment.The phase 3 EMERALD trial (NCT03778931) led to the approval of elacestrant (Orserdu), the first oral selective estrogen receptor degrader (SERD), for HR+, HER2-negative metastatic breast cancer with an ESR1 mutation. “Elacestrant represents a significant advancement, offering a more convenient oral option for patients with ESR1 mutations,” a leading oncologist stated.

Several other SERDs are currently in development, alongside therapies with diverse mechanisms of action, including selective estrogen receptor modulators, proteolysis targeting chimeras (PROTACs), selective estrogen receptor covalent antagonists, and complete estrogen receptor antagonists. Vepdegestrant, a novel PROTAC, has shown greater estrogen receptor (ER) degradation compared to fulvestrant in preclinical models. In the phase 1/2 VERITAC trial (NCT04072952), vepdegestrant demonstrated a favorable safety profile, and results from the phase 3 VERITAC-2 trial (NCT05654623) are eagerly anticipated and the efficacy of vepdegestrant is of particular interest due to its novel mechanism of action and the potential for improved ER degradation.

Patient-Centered Care: A Cornerstone of Treatment

Patient-centered care emerged as a central theme, with sessions featuring clinicians and patient advocates discussing quality of life and compassionate care. These discussions served as a crucial reminder that, despite the excitement surrounding new therapies, minimizing toxicity remains a top priority. The growing number of treatment options necessitates transparency regarding AEs and collaborative decision-making.Whole-person care, encompassing lifestyle and mental health support, is an indispensable component of cancer treatment plans and leads to improved outcomes.

For community practices with limited resources, providing complete lifestyle and whole-person care can be challenging. Innovative solutions, such as the Dawn Oncology telehealth lifestyle and survivorship clinic, offer a way to integrate these essential services into existing clinical practices. Such telehealth programs hold promise for expanding access to specialized supportive care, particularly in rural or underserved communities. The Dawn Oncology model can be integrated into existing practices.⁹

The Path forward

The Miami Breast Cancer Conference provided a valuable forum for discussing the integration of emerging and recently approved therapies into clinical practice. In the rapidly evolving landscape of breast cancer treatment, ongoing dialog is essential for contextualizing new data and equipping oncology clinicians to deliver the best possible care to their patients. This includes access to cutting-edge therapies and comprehensive patient support services.