FDA approval of the selective HIF2α inhibitor belzutifan for advanced phaeochromocytoma and paraganglioma (PPGL) is an important milestone in precision oncology. This achievement underscores the power of scientific collaboration in establishing HIF2α as a central driver of PPGL pathogenesis and offers hope for a historically underserved group of patients.
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References
Gatta, G. et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur. J. Cancer 47, 2493–2511 (2011).
Dahia, P. L. M. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat. Rev. Cancer 14, 108–119 (2014).
Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).
Arenillas, C. et al. Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes. Cancer Discov. 15, 1037–1062 (2025).
Toledo, R. A. New HIF2α inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas. Endocr. Relat. Cancer 24, C9–C19 (2017).
Toledo, R. A. et al. Hypoxia-inducible factor 2 alpha (HIF2α) inhibitors: targeting genetically driven tumor hypoxia. Endocr. Rev. 44, 312–322 (2023).
Kamihara, J. et al. Belzutifan, a potent HIF2α inhibitor, in the Pacak-Zhuang syndrome. N. Engl. J. Med. 385, 2059–2065 (2021).
Baudin, E. et al. Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial. Lancet 403, 1061–1070 (2024).
Choueiri, T. K. et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat. Med. 27, 802–805 (2021).
Srinivasan, R. et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 26, 571–582 (2025).
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C.A. and R.A.T. are members of the Pheochromocytoma and Paraganglioma (PPGL) Working Group of the European Network for the Study of Adrenal Tumors (ENS@T). R.A.T receives research funding from the Paradifference Foundation and Pheipas Association to support research on metastatic PPGL.
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Advanced RCC FDA approval: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma
Paradifference Foundation: https://www.paradifference.org
PPGL FDA approval: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
VHL FDA approval: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease
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Arenillas, C., Toledo, R.A. FDA fast-track approval of belzutifan is a milestone in rare cancer therapy. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01183-z
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DOI: https://doi.org/10.1038/s41574-025-01183-z
