Findings from recently presented studies support an upfront integration of ADCs in the treatment course, but some key questions are pending
At the 2025 ASCO Annual Meeting, a defining theme in breast cancer was the integration of antibody-drug conjugates (ADCs) into the first-line treatment for metastatic breast cancer, with findings from three key studies contributing to this evolving landscape.
The phase III DESTINY-Breast09 trial was the most anticipated study in HER2-positive metastatic breast cancer (J Clin Oncol 43, 2025, suppl 17; abstr LBA1008). It compared first-line trastuzumab deruxtecan (T-DXd) plus pertuzumab with the long-standing standard combination of trastuzumab, pertuzumab and taxane (THP). The trial met its primary endpoint, showing a significant and clinically meaningful improvement in progression-free survival with the antibody-drug conjugate which positions T-DXd/pertuzumab as a new first-line treatment option, pending regulatory and guideline updates.
However, important questions remain. Firstly, no data is available from the third arm of the trial (T-DXd monotherapy) yet, leaving unanswered the question of the impact of pertuzumab on the overall benefit. Secondly, sites of first progression are not available yet, but will be critical; the hope is that first-line T-DXd may reduce intracranial progressions compared to THP. Also, crossover to T-DXd in the control arm of the study was extremely limited (10%), not resolving the uncertainty about the impact of first versus second-line use of T-DXd for this disease.
In DESTINY-Breast09, toxicity was higher with T-DXd/pertuzumab as expected, including 5 treatment-related deaths (vs. 1 with THP). Overall, the THP regimen allowed patients to maintain an optimal quality of life (QoL) during the maintenance HP phase, something which may be more challenging during the receipt of continued T-DXd/P treatment. The future presentation of QoL data from the trial will help address this particular aspect.
Finally, the PATINA trial showed outstanding progression-free survival (PFS) with maintenance treatment with palbociclib plus anti-HER2 therapy plus endocrine therapy in the triple-positive setting. Once both regimens are available (DB09 and PATINA regimens), it will be important to discuss adequate implementation of the two studies’ regimens to treat patients in the real world.
Also presented at ASCO 2025, the ASCENT-04 trial addressed first-line treatment for patients with PD-L1-positive advanced triple-negative breast cancer (TNBC), a population typically treated with chemo-immunotherapy (J Clin Oncol 43, 2025; suppl 17; abstr LBA109). The study compared sacituzumab govitecan (SG) plus pembrolizumab to physician’s choice chemotherapy plus pembrolizumab, and included built-in crossover, strengthening the interpretability of the results. The trial showed a significant and clinically meaningful improvement in PFS, with most survival benefit observed in patients with recurrent disease (vs. de novo metastatic) - which is the population where moving SG to the first line is expected to be most critical. In the study, a higher rate of serious adverse events and grade 5 events was observed in the SG arm, highlighting the importance of a proactive toxicity management with this compound (with many patients expected to benefit from prophylactic growth factor support to minimize the impact of neutropenia).
Interesting results were also reported from the OPTI-TROP-Breast05, a single-arm phase 2 trial which explored the first-line use of sacituzumab tirumotecan for metastatic TNBC (J Clin Oncol 43, 2025; suppl 16; abstr 1019). The compound showed impressive activity, with an objective response rate (ORR) of 70% and a median PFS of 13.4 months. The toxicity was in line with what was previously observed with SG (i.e. neutropenia, fatigue) and Dato-DXd (i.e. stomatitis, ocular toxicity), but there were no deaths and few discontinuations. Although the findings are very promising, the study was only conducted in Asian patients, and we are still awaiting data on Western patients and multiple global phase III trials are ongoing with this compound.
Besides the first-line metastatic trials, new data was also presented with ADCs in the early-stage setting, with a presentation from the NeoSTAR trial (J Clin Oncol 43, 2025; suppl 16; abstr 511). This phase II trial evaluated neoadjuvant SG plus pembrolizumab in patients with early-stage TNBC. The study reported a pathologic complete response (pCR) rate of 32% after SG plus pembro for 4 cycles, and up to 50% when SG plus pembro was followed by additional chemotherapy. Overall, the pCR rate compares unfavorably with KEYNOTE-522 (>60%) (N Engl J Med. 2024 Nov 28;391(21):1981-1991), yet it may be underestimated in the trial, due to its design. The reported safety profile was as expected.
The common thread across these studies is clear: ADCs are moving earlier in the treatment pathway. Yet, questions remain, particularly regarding the impact on long-term outcomes of an upfront integration of ADCs, which is best addressed by trials like ASCENT-04 with robust crossover design, and less so by DESTINY-Breast09. Furthermore, biomarkers are urgently needed to optimise patient selection.
