Review of Phase 3 Data on Investigational Endocrine Agents: VERITAC (ASCO 2025)
Panelists discuss recent phase 3 trials introducing novel endocrine agents such as proteolysis-targeting chimeras (PROTACs) that target estrogen receptors through new mechanisms, highlighting modest progression-free survival benefits—especially in patients with ESR1-mutated disease—and generally favorable tolerability profiles, while underscoring the importance of monitoring unique adverse effects and the potential for these therapies to advance treatment of endocrine-resistant metastatic breast cancer.
Several recent phase 3 trials have introduced novel endocrine agents that challenge current treatment paradigms for metastatic hormone receptor–positive breast cancer. One such trial investigated a drug known as a proteolysis-targeting chimera (PROTAC)PROTAC, which degrades the estrogen receptor through a distinct mechanism. This agent was tested in patients previously treated with CDK4/6 inhibitors and demonstrated a modest overall progression-free survival benefit compared to with fulvestrant. Notably, the drug showed greater efficacy in patients harboring ESR1 mutations, with median progression-free survival roughly doubling in that subgroup. While the overall benefit was limited, the favorable safety profile and activity in biomarker-selected patients were promising.
Another interesting aspect of these novel agents is their generally favorable tolerability, although each comes with unique side adverse effect considerations. For example, some have reported QTc prolongation, which is a cardiac conduction delay not typically seen with older endocrine therapies. This highlights the importance of monitoring and managing novel toxicities as these new treatments become integrated into clinical practice. Despite these differences, most of these drugs maintain the advantage of being well tolerated compared to with traditional chemotherapy, allowing patients to remain on therapy longer with a better quality of life.
Together, these phase 3 trials represent a significant step forward in targeting endocrine resistance in metastatic breast cancer. The ability to better tailor treatment based on ESR1 mutation status and to offer safer, more effective options is a meaningful advance. As these agents move toward regulatory approval and clinical use, ongoing research will clarify their optimal sequencing and combination with other targeted therapies, ultimately aiming to improve outcomes beyond the current progression-free survival plateaus.
