[Personalized systemic therapy of penile cancer: molecular targets and new therapeutic horizons]

Penile cancer is a rare urological malignancy with approximately 36,000 new cases worldwide each year. In the first-line setting of locally advanced or metastatic disease, platinum-based chemotherapy is recommended, but it yields only moderate response rates, short remission durations, and considerable toxicity. Effective second-line treatment options are largely lacking, underscoring the urgent need for innovative therapeutic approaches.

This article aims to summarize current evidence on immunotherapeutic and targeted treatment strategies in advanced penile cancer.

A systematic literature search was conducted in PubMed, complemented by recent abstracts and presentations from major congresses (American Society of Clinical Oncology, ASCO; ASCO Genitourinary, ASCO GU; European Society for Medical Oncology, ESMO) and clinical trial registries (clinicaltrials.gov).

Immune checkpoint inhibitor monotherapy demonstrates response rates of 13-17% in unselected cohorts, with improved outcomes in patients with high tumor mutational burden or exclusively nodal metastases. In combination with chemotherapy, response rates increased to around 40%. Epidermal growth factor receptor (EGFR)-targeted antibodies achieved remissions in approximately one third of patients, albeit generally of short duration. Based on expression patterns of various surface proteins (EGFR, HER2, Nectin‑4, Trop-2), several antibody-drug conjugates are currently being evaluated in phase II trials. Moreover, poly ADP ribose polymerase (PARP) inhibition may represent a rational option in tumors harboring alterations in homologous recombination repair genes.

Immuno- and targeted therapies open new perspectives for the management of advanced penile cancer. Because of the rarity of this malignancy, international collaborations are crucial to ensure adequate trial recruitment. Such efforts are essential to render innovative approaches accessible to a broader patient population and to strengthen the evidence base for future treatment strategies.