Future Directions for Nonhormonal Treatments of VMS

Despite meaningful progress with the development of NK receptor antagonists, important gaps in evidence remain. Carmine Valenza, MD, MPH, PhD(c), identifies long-term oncologic safety and efficacy data as a primary unmet need in this field. Although no mechanistic rationale suggests a detrimental effect of elinzanetant (Lynkuet) on breast cancer outcomes—and preliminary data even suggest a possible benefit related to its effect on systemic estradiol levels—the available follow-up period from OASIS-4 (NCT05587296) is limited by trial design, including the crossover of the placebo arm at week 12. Well-designed, prospective observational studies are needed to evaluate real-world outcomes and longer-term oncologic consequences of NK receptor antagonism in patients with breast cancer.

The use of patient-reported outcomes (PROs) as primary end points represents an evolving and increasingly validated approach in clinical trial design for VMS management. Valenza observes that OASIS-4 has helped establish a precedent by incorporating VMS frequency—as reported by patients—as a co-primary end point, demonstrating that such studies can generate practice-changing evidence based on PROs alone. This framework may prove especially valuable in future studies exploring which nonhormonal approach to initiate first, allowing therapeutic sequencing decisions to be grounded in patient experience and individualized response.

The overarching clinical message from this series is one of therapeutic optimism. Valenza's takeaway for ob-gyns, medical oncologists, and other clinicians managing this population is that effective, evidence-based options now exist to address VMS—and that the primary obligation is to maintain endocrine therapy adherence through active symptom management. Patients should be encouraged to report VMS at every clinical encounter, and clinicians should approach the management of these symptoms as a dynamic, iterative process in which therapeutic strategies are regularly reassessed in partnership with patients. The availability of agents with early onset of action and a favorable tolerability profile provides clinicians with the tools needed to achieve this goal.