Neurokinin Pathways and the Rationale for NK Receptor Antagonism in Treating VMS

Advances in understanding the neuroendocrine regulation of body temperature have provided a compelling mechanistic rationale for a new class of vasomotor symptom (VMS) treatments. In this video, Carmine Valenza, MD, MPH, PhD(c), explains that hypothalamic KNDy neurons—which express kisspeptin, neurokinin B (NKB), and dynorphin—play a central role in thermoregulation and are normally suppressed by circulating estrogen. During physiologic menopause or as a consequence of antiestrogen therapy, declining estradiol levels lead to hyperactivation of these neurons, which in turn triggers the peripheral vasomotor events that manifest as hot flashes and night sweats.

Elinzanetant (Lynkuet) acts as a dual antagonist of the NK1 and NK3 receptors, and Valenza notes that the rationale for targeting both receptors is supported by preclinical and early clinical evidence. Although NK3 blockade addresses the primary thermoregulatory pathway, NK1 inhibition appears to confer additional benefit on sleep quality—a hypothesis derived from preclinical data that has been confirmed in the OASIS-4 clinical trial (NCT05587296). This dual mechanism thus offers the possibility of addressing both daytime hot flashes and nocturnal sleep disturbances within a single therapeutic agent.

The nonhormonal, centrally acting mechanism of NK receptor antagonism has important implications for oncologic safety in patients with breast cancer. Because this pathway does not involve direct modulation of estrogen receptor signaling, Valenza underscores that there is a strong preclinical rationale supporting its safety in this population. Of note, data from studies in healthy women with uterine fibroids suggest that estradiol levels may decrease during treatment with NK receptor antagonists, which could theoretically confer additional benefit in the breast cancer setting—though Valenza acknowledges that longer-term data are needed to determine oncologic impact. Importantly, subgroup analyses from OASIS-4 confirm that the efficacy of elinzanetant is consistent across all types of endocrine therapy, including tamoxifen, aromatase inhibitors, and ovarian function suppression.