DEPECA-1 (Defeating Penile Cancer 1): A phase II study to evaluate a first-line systemic therapy with enfortumab vedotin plus avelumab for advanced and metastatic penile carcinoma.

Abstract

TPS5133 Background: Squamous cell carcinoma of the penis (PeCa) is a rare malignancy with unfavorable outcomes in advanced stage. Since the 1990s, platinum-based chemotherapy has been the standard of care for the first-line treatment of metastatic disease. Unfortunately, it is characterized by a response rate of 30-40%, overall survival (OS) of 17 months and progression free survival (PFS) of 6 months at most. Thus, there is a critical medical need to assess novel systemic strategies for PeCa in the first-line setting, given that current regimens are of a limited clinical benefit while exposing patients to considerable chemotherapy-associated toxicities. In this context, the PD-1 inhibitor pembrolizumab yielded a promising activity in squamous cell carcinomas of various origins. Meanwhile, enfortumab vedotin (EV), a Nectin-4 directed antibody-drug-conjugate, in combination with pembrolizumab has been recently approved for the treatment of metastatic urothelial cancer. The incidence of ≥3 grade adverse events with this regimen was > 55%. Notably, a PD-L1 inhibitor avelumab provided a comparable activity as pembrolizumab but a lower overall rate of endocrine adverse events in patients with urothelial carcinoma. Avelumab monotherapy yielded a response rate of 17% and a median duration of response of 16 months in males with a platinum-refractory PeCa or those unfit for platinum chemotherapy in ALPACA trial. Given that approximately 60% of PeCa tissues express both PD-L1 and Nectin-4, the combination of EV with avelumab represents a potentially synergistic therapeutic strategy, leveraging both direct cytotoxicity and immune-mediated anti-tumor activity through complementary mechanisms of action. Methods: The DEPECA-1 trial is an investigator-initiated, open label, single-arm, multicenter phase II trial, enrolling 25 males with locally advanced or metastatic PeCa at 10 sites in Germany. Patients must be ineligible for curative surgery and not have received any prior systemic palliative therapy. Participants (ECOG ≤ 2) will receive 1200 mg avelumab on day 1 and EV (1,25 mg/kg) on day 1 and day 8 in a 3-week -cycle for a maximum of 24 months and 32 cycles. Primary endpoint is the objective response rate (ORR) assessed per RECIST 1.1. Secondary endpoints include PFS, OS, duration of response (DOR), disease control rate (DCR) and patient-related outcomes. Exploratory analysis comprises tumor biomarker profiling. DEPECA-1 has received regulatory approval on 29 th October 2025. First patient was enrolled on December 16, 2025. Registration IDs: EU CT No. 2025-521644-37-00/NCT07110038. Clinical trial information: NCT07110038 .