Systemic treatment in metastatic penile cancer: current landscape, challenges, and future directions

To evaluate current systemic treatment strategies for metastatic penile squamous cell carcinoma (PSCC), identify limitations in established therapies, and highlight emerging approaches, including immunotherapy, targeted therapies, and combination regimens.

A comprehensive review of international guidelines, prospective and retrospective studies, clinical trials, and case series was conducted. The focus was on first- and second-line systemic cytotoxic therapies, immune checkpoint inhibitors, targeted agents, and novel treatment combinations in metastatic PSCC.

Platinum-based chemotherapy remains the standard first-line treatment with response rates ranging from 30–50%, but high toxicity and limited durability. Novel agents show promise in early studies, although outcomes remain limited beyond first-line treatment. Immune checkpoint inhibitors (ICIs) have shown modest activity (objective response rate [ORR] < 20%) in biomarker-selected populations. Targeted therapies, including EGFR and antibody–drug conjugates, are under early investigation. Combination approaches with immunotherapy and chemotherapy have yielded encouraging preliminary results in small trials. Molecular profiling and human papillomavirus (HPV) status are emerging as potential biomarkers for treatment selection.

Systemic therapy for metastatic PSCC remains suboptimal, with poor long-term outcomes. Novel strategies, including immunotherapy, targeted agents, and biomarker-guided strategies, show promise. Future research should prioritize prospective trials, genomic profiling, and personalized approaches to improve outcomes in this aggressive cancer.