Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and historically poor outcomes. Prior to the emergence of antibody–drug conjugates (ADCs), palliative sequential single-agent chemotherapy was the mainstay of treatment for metastatic TNBC (mTNBC), offering limited response and survival. In an interview with MIMS Oncology, Dr Rodrigo Sánchez-Bayona from the Universitary Hospital 12 de Octubre, Madrid, Spain, discussed how Trop-2–targeted ADCs have changed the treatment landscape of mTNBC and predicted their future role in the changing treatment paradigm. He highlighted data on sacituzumab govitecan (SG), an ADC that has demonstrated efficacy regardless of Trop-2 expression status or presence of biomarkers while maintaining quality of life (QoL), and shared a patient case with rapidly progressing mTNBC effectively treated with SG.
ADCs: Game changers in mTNBC
Early relapse or rapid progression is common in TNBC, affecting nearly half of the patients and often occurring within 12 months after completing neoadjuvant or adjuvant ([neo]adjuvant) therapy. “Patients with TNBC who relapse early either exhibit primary resistance or develop early resistance to cytotoxic chemotherapy,” noted Sánchez-Bayona. “This highlights an urgent unmet clinical need, as rechallenging with chemotherapy or chemo-immunotherapy, especially in PD-L1–positive patients, may no longer be a feasible option due to mechanisms of cross-resistance.” [NPJ Breast Cancer 2022;8:72; Eur J Cancer 2023;189:112935; Int J Mol Sci 2022;23:1665]
“Switching to an ADC such as SG, a first-in-class ADC consisting of an anti–Trop-2 antibody conjugated to SN-38, a topoisomerase-1 inhibitor, offers a promising strategy due to its novel mechanism of action and enhanced antitumour potency,” said Sánchez-Bayona.
“SG targets Trop-2, which is highly overexpressed in aggressive tumours, and delivers a high chemotherapeutic payload directly to cancer cells while sparing healthy tissue and minimizing toxicities,” he explained. “ADCs’ novel mechanism of action could also bypass resistance mechanisms and mutations that tumours acquire under therapeutic pressure [after multiple lines of treatment], maximizing antitumour effects. Instead of rechallenging with taxanes or platinum salts at relapse, both the target and the cytotoxic load are changed with ADCs, offering a strong biological rationale for adopting a different mode of action.” [Breast 2022;66:169-177]
“Furthermore, because anti–Trop-2 ADCs are effective regardless of biomarker status, they eliminate the need for extensive testing, saving time and costs,” Sánchez-Bayona added.
SG: Guideline-recommended ADC addressing an unmet need
The current European Society for Medical Oncology (ESMO) guideline recommends using SG in patients with mTNBC (regardless of germline BRCA status) with recurrence ≤6–12 months after completing (neo)adjuvant immune checkpoint inhibitor therapy or second and later lines of therapy. While in patients with germline BRCA mutation, SG can be used following disease progression on poly (ADP-ribose) polymerase (PARP) inhibitors or chemotherapy, in patients with wild-type mTNBC, SG can be commenced immediately in the event of such recurrence. [ESMO Living Guideline, Metastatic Breast Cancer, v1.2, April 2025]
“SG scores a 5 [highest level of clinical benefit in the noncurative (palliative) setting] in the ESMO–Magnitude of Clinical Benefit Scale [ESMO-MCBS] as it demonstrated substantial overall survival [OS] and progression-free survival [PFS] benefits vs standard chemotherapy, balanced by improvements or delayed deterioration in QoL, evidenced by the promising results of the pivotal phase III ASCENT study,” Sánchez-Bayona highlighted.
In the ASCENT trial (n=468), SG prolonged median PFS vs chemotherapy in patients with relapsed or refractory mTNBC who had progressed after ≥2 prior standard chemotherapy regimens. (Figure 1) Median OS also improved with SG vs chemotherapy (11.8 vs 6.9 months; hazard ratio, 0.51; 95 percent confidence interval, 0.42–0.63), while a health-related QoL analysis showed that SG delayed worsening of physical functioning (22.1 vs 12.1 weeks; p<0.001), role functioning (11.4 vs 7.1 weeks; p<0.001), fatigue (7.7 vs 6.0 weeks; p<0.05) and pain (21.6 vs 9.9 weeks; p<0.001). [N Engl J Med 2021;384:1529-1941; J Clin Oncol 2024;42:1738-1744; Eur J Cancer 2023;178:23-33]
“Over the past decade, no drug has shown an ability to both improve survival outcomes and delay QoL deterioration. That’s why SG is a practice-changing treatment option and will likely systematically replace chemotherapy in this heavily pretreated population,” Sánchez-Bayona remarked.
Evolving mTNBC treatment landscape with ADCs
“SG is also anticipated to play an increasingly prominent role in first-line treatment of mTNBC. Results from two latest phase III SG trials, ASCENT-03 and ASCENT-04, promise to reshape the treatment algorithm for first-line mTNBC,” noted Sánchez-Bayona. (Figure 2) [ESMO Living Guideline, Metastatic Breast Cancer, v1.2, April 2025]
“With significant improvements in PFS observed in both trials, SG has become a potential first-line treatment for both PD-L1–positive and PD-L1– negative mTNBC. Further research is required on optimal ADC sequencing,” Sánchez-Bayona noted. [N Engl J Med 2025;doi:10.1056/NEJMoa2511734; J Clin Oncol 2025;43:LBA109]
Factors to consider when choosing ADCs
“When deciding between SG and trastuzumab deruxtecan [T-DXd], physicians should balance between efficacy and toxicity, adapting to patient needs,” Sánchez-Bayona suggested.
“Although both ADCs are potent with a low rate of febrile neutropenia, SG has a higher rate of neutropenia than T-DXd. T-DXd may be a preferable option in patients with a history of recurrent neutropenia with chemotherapy,” he explained. “On the other hand, if a patient has pre-existing airway issues, SG may be preferable as T-DXd is associated with an increased risk of pneumonitis and interstitial lung disease, which is more frequent in Asian vs Caucasian populations and requires discontinuation at grade 2. Importantly, patients should be involved in decision-making, and the pros and cons of these treatment options should be discussed with them.” [Cancer Treat Rev 2025;132:102865, N Engl J Med 2022;387:9-20; Enhertu SmPC]
AE management: Proactive strategies for improved outcomes
“It is essential to educate patients and manage expectations of any potential chemotherapy-like side effects, such as alopecia, diarrhoea and neutropenia, to ensure they are well prepared for treatment,” emphasized Sánchez-Bayona. “Proactive implementation of prophylactic measures for clinically relevant adverse events [AEs] optimizes tolerability and enhances adherence to treatment. If patients tolerate initial cycles well, they are more likely to adhere to long-term treatment.”
”For example, primary prophylaxis with doublets or triplets of antiemetic drugs, including dexamethasone and ondansetron, is recommended, especially in patients who have a history of significant nausea and vomiting with chemotherapy,” he suggested. “Primary prophylaxis with low-dose loperamide, with or without subcutaneous atropine, has been shown to significantly reduce treatment discontinuation rates with ADCs and should be used systematically in all patients, at least for the first two cycles.” [Mol Cancer Ther 2022;22:102-111; Breast Cancer 2025;32:278-285; Oncologist 2021;26:827-834]
Prophylaxis with granulocyte colony–stimulating factor (G-CSF) significantly reduces the incidence and severity of neutropenia, and is highly encouraged for 2 days following treatment infusion. This is particularly important in elderly or frail patients and those with a prior history of grade ≥3 neutropenia with chemotherapy. [eClinicalMedicine 2025;85:103309]
Conclusion
“SG represents an important advance in heavily pretreated mTNBC, with emerging data supporting its use as early as possible for maximum benefit. Additional research is needed to determine optimal ADC sequencing and for translating precision medicine into personalized treatment strategies,” Sánchez-Bayona noted.
