Potential Risk of Neoplasms with Fezolinetant: Clinical Evidence, Mechanisms, and Post-Marketing Implications

Abstract In 2023, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved fezolinetant (Veozah® in the US, Veoza® in Europe), a novel neurokinin 3 receptor (NK3R) antagonist and first-in-class non-hormonal drug for treating moderate to severe menopausal vasomotor symptoms (VMS). While its efficacy and safety have been demonstrated through the SKYLIGHT and MOONLIGHT programs, concerns were highlighted regarding a potential increased risk of neoplasms. Although regulatory agencies initially dismissed that risk, emerging data from meta-analysis and pooled analysis consistently showed a significant increase in the risk of non-benign neoplasms. These findings raise important questions regarding a potential causality link between NK3R antagonists and cancer. By blocking NK3R, fezolinetant can reduce kisspeptin secretion, a ubiquitous peptide known for its anti-metastasis function. Furthermore, NK3R blockade may induce compensatory activation of the neurokinin 1 receptor (NK1R), which has been implicated in tumor proliferation, angiogenesis, and metastasis. Because of these mechanistic concerns, long-term safety studies and investigations on the NK3R pathway are essential to clarify the neoplastic risk profile of fezolinetant. This review is based on a PubMed/MEDLINE search using specific keywords, complemented by screening of regulatory documents and citation tracking.