# Update on Systemic Therapies for Metastatic/Unresectable Pheochromocytomas and Paragangliomas and Future Directions

## TL;DR

This review discusses current and emerging treatments for metastatic pheochromocytomas and paragangliomas, emphasizing personalized approaches and new targeted therapies.

## Contribution

The paper highlights the recent approval of belzutifan and the shift toward precision medicine in treating metastatic PPGLs.

## Key findings

- Radiopharmaceuticals like 131I-MIBG and 177Lu-DOTATATE remain key for disease control.
- Belzutifan, a HIF-2α inhibitor, is the first oral targeted therapy for advanced PPGLs.
- Treatment strategies are increasingly tailored to genotype, tumor behavior, and imaging phenotype.

## Abstract

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms characterized by excess catecholamine production and secretion. This review summarizes current systemic therapy options and emerging strategies. Radiopharmaceuticals (131I-MIBG, 177Lu-DOTATATE) and cytotoxic regimens (CVD, temozolomide) remain cornerstone treatment options for disease control. Multi-targeted tyrosine kinase inhibitors (sunitinib, cabozantinib, axitinib) and the recently approved HIF-2α inhibitor belzutifan offer other targeted options, particularly for some PPGLs. Immune checkpoint inhibitors have modest activity, but combination approaches with TKIs or PARP inhibitors are currently under investigation. It is increasingly recognized that treatment for these tumors should be individualized based on tumor kinetics, genotype, and functional imaging phenotype, with multidisciplinary involvement and clinical trial participation being encouraged.

Metastatic or unresectable pheochromocytomas and paragangliomas (PPGLs) remain rare but clinically challenging neuroendocrine neoplasms with limited curative options. Traditionally managed with surgery, radionuclide therapy, or cytotoxic chemotherapy, systemic treatments have historically achieved disease stabilization, rather than durable remissions. In recent years, however, the therapeutic landscape has evolved substantially. Radiopharmaceuticals such as 131I-MIBG and 177Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors. Immunotherapy has yielded modest responses with checkpoint inhibitor monotherapy, but ongoing studies of dual checkpoint blockade and TKI–ICI combinations hold promise. Novel approaches, including PARP inhibition, metabolic targeting strategies, and cancer vaccines, are under investigation, especially for aggressive SDHB-related disease. Optimal sequencing of these therapies is emerging as a central challenge, with treatment strategies increasingly tailored to molecular genotype, tumor behavior, and functional imaging phenotype. This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a more manageable chronic disease with improved survival and quality of life.