Subsequent-line Systemic Therapy for Metastatic or Recurrent Penile Cancer: A Systematic Review of Efficacy, Toxicity, and Outcomes.

Treatment options for metastatic or recurrent penile squamous cell carcinoma (PSCC) progressing after first-line platinum-based chemotherapy are limited, and no standard subsequent-line systemic therapy exists. We systematically reviewed the efficacy, safety, and survival outcomes of second- and later-line systemic treatments in this setting. A systematic review, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, was performed across PubMed, Scopus, Embase, Medline, Web of Science, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and International Clinical Trials Registry Platform (from inception to June 2025). Eligible studies enrolled adult males receiving systemic chemotherapy, immunotherapy, or targeted therapy after progression on first-line treatment. The primary outcomes were overall (OS) and progression-free (PFS) survival; the secondary outcomes included objective response rate, disease control rate, duration of response, adverse events (AEs), and quality of life (QoL). Seventeen studies (seven nonrandomized trials and ten case series; 367 patients) were included. Evidence quality was low due to small cohorts, heterogeneity, and potential bias. The reported median OS ranged from 4.3 to 9.5 mo and PFS ranged from 1.3 to 4.8 mo. Targeted therapies showed the most favorable OS (6.7-9.5 months) and lowest grade 3-4 AE rates (0-30%), followed by immunotherapy and chemotherapy. Biomarker-driven benefit was observed in patients with human papillomavirus positivity, programmed death-ligand 1 expression, or actionable genomic alterations (eg, PIK3CA, RAD51, and NOTCH1). QoL data were reported in only two studies, underscoring a major evidence gap. Interpretation is limited by the absence of randomized studies, inconsistent reporting, and the inability to distinguish second-line from later-line therapies in most studies. No standard systemic therapy exists beyond first-line treatment for metastatic or recurrent PSCC. Targeted agents and immune checkpoint inhibitors show encouraging activity in biomarker-selected subgroups. Prospective biomarker-guided trials and international collaborations are needed, while multidisciplinary management and clinical trial enrollment remain essential for optimizing outcomes for this rare malignancy.