Beyond Chemo: Dr Ana Garrido-Castro on the Evolving TNBC Landscape

The landscape of triple-negative breast cancer (TNBC) is shifting rapidly. What was once a landscape dominated by standard cytotoxic chemotherapy is now a complex map of immunotherapy, PARP inhibitors, and a rapidly expanding fleet of antibody-drug conjugates (ADCs).

At the forefront of these discussions is Ana Garrido-Castro, MD, medical oncologist at Dana-Farber Cancer Institute and assistant professor of Medicine at Harvard Medical School. In an interview with Targeted Oncology regarding the state of the field, Garrido-Castro highlighted the clinical triumphs of the last few years while casting a candid eye on the unmet needs that still occupy oncologists and researchers.

The Challenge of Early Relapse

While the standard of care for stage II or III TNBC now typically involves a combination of chemotherapy and immunotherapy, a specific subset of patients remains particularly vulnerable. Garrido-Castro noted that for many, the curative intent of neoadjuvant and adjuvant therapy is successful, but for others, particularly those with residual disease at surgery, the risk of recurrence is higher.

"There is still a proportion of patients who experience a recurrence after treatment with chemotherapy plus immunotherapy in the early stage setting," Garrido-Castro explained. "For those patients who do experience relapse, that tends to happen early on, within the first 6 to 12 months of having completed adjuvant therapy treatment in the curative setting."

This early relapse group represents a significant hurdle in modern oncology. Because these patients have already been exposed to multiple chemotherapy agents and immunotherapy, their remaining options are sparse. Furthermore, as Garrido-Castro added, "many of these patients with early relapse... are excluded from clinical trials." There is a clear, urgent need to develop new combinations that can intervene during this short disease-free interval.

The Rise of the ADCs

The emergence of TROP2-directed ADCs has brought a notable shift in the treatment landscape.Data presented at recent conferences have signaled a potential sea change in how oncologists approach first-line treatment for metastatic TNBC.

"At ESMO last year, we saw data from two randomized phase III trials comparing a TROP2 ADC, sacituzumab govitecan [Trodelvy]¹ (ASCENT-03) or datopotamab deruxtecan [Dato-DXd; Datroway]² (TROPION-Breast02) to chemotherapy of physician’s choice in the first-line setting for patients with metastatic TNBC who are not candidates for immune checkpoint inhibition, primarily due to PD-L1–negative status. Both trials met their primary endpoint(s), demonstrating an improvement in outcomes with TROP2 ADC compared to standard chemotherapy," said Garrido-Castro.

She also highlighted the ASCENT-04 (NCT05382286)³data, which combined sacituzumab govitecan with pembrolizumab (Keytruda) for patients with metastatic PD-L1–positive TNBC, showing improved progression-free survival over the current standard regimen of chemotherapy plus pembrolizumab. These results have sparked significant "enthusiasm about looking at TROP2 ADCs and perhaps combinations with other agents" to move these therapies even earlier into the treatment timeline.

The Sequencing Dilemma: Target vs Payload

As more ADCs gain approval, the question for clinicians is no longer just if to use them, but when and in what order.

Currently, Garrido-Castro noted that sacituzumab govitecan is often positioned first for TNBC due to the existing data from several phase 3 trials conducted specifically in the triple-negative population. However, for the roughly 40% of patients with TNBC who have HER2-low tumors, trastuzumab deruxtecan (T-DXd; Enhertu) remains a treatment option based on the exploratory analysis from the DESTINY-Breast04 trial in which approximately 10% of the patient population had hormone receptor-negative/HER2-low metastatic breast cancer.

After progressive disease develops with an ADC, the challenge lies in the diminishing returns of sequential ADC therapy. "The take-home message from several real-world retrospective studies reported to date is that the second ADC tends to have a shorter time to progression than the first ADC," she warned. "However, there are some patients who appear to derive similar or greater benefit from the second ADC. Then the question is, how do we identify who those patients are? And that’s again, where going back to biomarkers and understanding how resistance develops is key."

Research is currently pivoting to determine whether resistance stems from a decrease in the target expression (eg, TROP2 or HER2) or resistance to the payload or other mechanisms. Garrido-Castro points to the TRADE DXd study (NCT06533826) as a vital step in answering this, as it looks at switching targets while keeping the payload similar.

However, she added that we must look further: "Developing new ADCs that have new payloads beyond topoisomerase I-inhibitors, such as microtubule inhibitors or new mechanisms that are being studied, will also be key."

Is Chemotherapy Still the Foundation?

With ADCs "poised to replace standard chemotherapy in the first-line setting for metastatic TNBC," oncologists might wonder if the era of traditional chemotherapy is ending. According to Garrido-Castro, chemotherapy remains available in later lines of therapy or as a strategic partner in the neoadjuvant or adjuvant settings.

"We see chemotherapy as an option in the second line and beyond for metastatic TNBC," she noted. "There is a need to develop better drugs that will help improve outcomes in an ADC-refractory patient population."

In the early-stage setting, anthracyclines and taxanes remain the backbone of treatment, often with platinum for high-risk TNBC. The goal isn't necessarily to eliminate chemotherapy, but to optimize its use through smarter delivery systems.

Looking Ahead

The speed of change in TNBC research is, in Garrido-Castro's view, the most important takeaway for her colleagues. With ADCs moving into the frontline and trials exploring their use in neoadjuvant and adjuvant settings, the standard approach is in a state of constant evolution.

"The landscape is changing very quickly... with many studies ongoing in the early stage setting to look at the potential activity of these agents,” she concluded.

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). Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin Germany. Abstract LBA20.

2. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.

3. Tolaney SM, de Azambuja E, Kalinsky K, et al; ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959