Trodelvy Marks Breakthrough in First-Line mTNBC Treatment with Positive Phase 3 ASCENT-03 Results
Gilead Sciences has announced encouraging topline results from its Phase 3 ASCENT-03 clinical trial evaluating Trodelvy® (sacituzumab govitecan-hziy) in a particularly challenging patient population: individuals newly diagnosed with metastatic triple-negative breast cancer (mTNBC) who are not eligible for immune checkpoint inhibitors, specifically those who are PD-L1 negative or otherwise unable to receive immunotherapy. The study not only met its primary endpoint but did so with what investigators are calling a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) when compared to traditional chemotherapy.
This development represents a potential paradigm shift in the management of first-line mTNBC for a subset of patients who have historically had very limited treatment options. With traditional chemotherapy remaining the mainstay for this group, Trodelvy’s performance in the ASCENT-03 trial is poised to alter treatment strategies in this space.
A Major Advancement in a Historically Stagnant Field
Dr. Javier Cortes, Head of the International Breast Cancer Center in Spain and principal investigator of ASCENT-03, highlighted the urgency for innovation in this setting. “Almost half of the patients diagnosed with metastatic triple-negative breast cancer do not receive treatment beyond first-line, demonstrating an urgent need for innovative treatment options in this early setting,” Dr. Cortes stated. He emphasized the stagnation in treatment advancements for this group, noting that conventional chemotherapy has remained the cornerstone of first-line treatment for decades.
Triple-negative breast cancer, defined by the absence of estrogen receptors, progesterone receptors, and HER2 amplification, is one of the most aggressive forms of breast cancer. It disproportionately affects younger women and is more likely to recur after initial treatment. For patients who cannot benefit from checkpoint inhibitors like PD-1 or PD-L1 antibodies, the treatment outlook has been especially bleak—until now.
Building on a Solid Foundation: Trodelvy’s Expanding Role
The ASCENT-03 results follow closely on the heels of another milestone study, ASCENT-04, which demonstrated positive outcomes for Trodelvy in combination with Merck’s Keytruda® (pembrolizumab) in PD-L1 positive mTNBC patients. Together, these two trials suggest that Trodelvy could become a foundational treatment option in the first-line setting for all patients with metastatic TNBC, regardless of their PD-L1 status.
“These results from ASCENT-03 represent the first clinically meaningful advance for this patient population in over 20 years versus chemotherapy,” said Dr. Dietmar Berger, Chief Medical Officer at Gilead Sciences. “By addressing this aggressive and difficult-to-treat disease earlier, we can potentially improve treatment options for the high unmet need that patients with metastatic triple-negative breast cancer face.”
Safety Profile and Ongoing Evaluation
The safety findings in the ASCENT-03 trial were consistent with previous Trodelvy studies, showing no new safety signals in this patient population. This consistency in the safety profile is important, as it reaffirms the drug’s tolerability and supports its broader use in early-line treatment settings. While progression-free survival was the primary endpoint and was successfully met, overall survival (OS) data were not mature at the time of analysis. However, preliminary findings showed no detriment to OS, and Gilead plans to continue monitoring OS outcomes with longer follow-up and further analyses.
Regulatory and Clinical Implications
While Trodelvy is already approved for use in second-line mTNBC and pre-treated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer, its use in the first-line setting for mTNBC remains investigational. Gilead plans to present detailed results from the ASCENT-03 trial at an upcoming medical conference and will discuss the data with regulatory agencies around the world.
If ultimately approved for first-line use in PD-L1 negative mTNBC, Trodelvy could significantly alter treatment paradigms. Given the high unmet need in this subgroup, regulatory agencies are likely to closely examine the data, particularly in light of the statistically robust PFS benefit and consistent safety outcomes.
A Legacy of Clinical Impact and Real-World Evidence
Trodelvy’s emergence as a major therapeutic player in metastatic breast cancer is underscored by its growing track record. With over five years of clinical and real-world use, the drug has been administered to more than 60,000 patients across more than 50 countries. It is the only antibody-drug conjugate (ADC) to have delivered positive outcomes in four Phase 3 trials across HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH–) metastatic breast cancer, and it remains the only approved Trop-2-directed ADC to show survival benefit in two distinct subtypes of mBC: second-line mTNBC and pre-treated HR+/HER2- mBC.
Trodelvy’s prominence is further validated by its inclusion as a Category 1 preferred treatment option in the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology. It is also the only ADC to receive a maximum score of 5 on the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) for mTNBC, and it holds a score of 4 for HR+/HER2- mBC, indicating substantial clinical benefit across multiple indications.
A Robust Clinical Pipeline Across Tumor Types
Gilead’s commitment to expanding the therapeutic applications of Trodelvy is evident in its extensive clinical trial program. Several Phase 3 studies are currently underway to explore Trodelvy’s role across other breast cancer subtypes and tumor types. These include:
- ASCENT-07, which is evaluating Trodelvy in patients with HR+/HER2- mBC who have previously received endocrine therapy.
- ASCENT-05, which focuses on patients with early-stage triple-negative breast cancer (eTNBC).
In addition to breast cancer, Trodelvy is also being studied in various other solid tumors, including lung and gynecologic cancers, further reinforcing its potential as a broadly applicable anti-cancer therapy.
Gratitude to the Research Community
Gilead expressed deep appreciation for the contributions made by patients, their families, healthcare professionals, and advocacy groups involved in the ASCENT-03 study and the broader Trodelvy research program. “We remain committed to advancing care to address the unmet needs for the breast cancer community,” the company stated.
With the full ASCENT-03 data expected to be presented at an upcoming medical meeting and the ASCO 2025 conference hosting the results of ASCENT-04, Gilead is poised to play a pivotal role in shaping the future of mTNBC treatment. Should regulatory approvals follow, Trodelvy could quickly become the go-to therapeutic backbone for first-line treatment in both PD-L1 positive and negative mTNBC populations.
As it stands, the ASCENT-03 results mark a long-awaited milestone for a patient group that has seen few advancements in more than two decades. Gilead’s continued investment in clinical trials and real-world evidence suggests that Trodelvy is not only a cornerstone of current breast cancer therapy but a key part of the next wave of oncology innovation.
For oncologists and patients facing the realities of metastatic triple-negative breast cancer, the era of relying solely on traditional chemotherapy may soon be over. Trodelvy is offering a new direction—one backed by science, safety, and the promise of meaningful survival benefits.
