Sacituzumab Tirumotecan as Second-Line Treatment for Penile Cancer

This is a single-arm, Phase 2 clinical trial (PERSEUS TRIAL / LACOG 1924) evaluating the efficacy, safety, and tolerability of sacituzumab tirumotecan (sac-TMT; MK-2870) as a second-line treatment for patients with advanced or metastatic penile cancer. Penile squamous cell carcinoma (PSCC) is a rare and aggressive cancer with limited treatment options once disease progression occurs after initial platinum-based chemotherapy. Sacituzumab tirumotecan is an antibody-drug conjugate (ADC) designed to target TROP-2, a protein frequently expressed at high levels on penile cancer cells. By binding to TROP-2, sac-TMT delivers a anti-cancer payload directly to the tumor cells. All participants in this trial will receive sacituzumab tirumotecan administered via intravenous (IV) infusion every 2 weeks. The main goal of this study is to determine the percentage of patients whose tumors shrink or disappear after receiving sacituzumab tirumotecan (Objective Response Rate).

Inclusion Criteria: * Histologically- or cytologically confirmed diagnosis of penile squamous cell carcinoma. * Metastatic or locally advanced disease not amenable to curative intent-therapy (e.g., surgery, radiotherapy, chemoradiotherapy) in the opinion of the investigator. * Measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology (lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions). * Disease progression on first-line platinum-based chemotherapy for locally advanced/metastatic disease or disease progression within 12 months of (neo) adjuvant chemotherapy completion. * Male participant at least 18 years of age at the time of providing informed consent. * Male Participants (Reproductive Potential): If capable of producing sperm, agrees to refrain from donating sperm and use a penile/external condom when having intercourse with a partner of childbearing potential, plus partner use of an additional contraceptive method, during the intervention period and for at least 120 days after the last dose of study intervention. * The participant (or legally acceptable representative if applicable) provides written informed consent for the study. * Life expectancy of at least 12 weeks. * Provide an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site not previously irradiated; formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides (recommended 22-28 slides). * Recovery from AEs due to previous anticancer therapies to Grade \= 1,500/uL * Platelets \>= 100,000/uL * Hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/L * Measured or calculated Creatinine Clearance \> 30 mL/min * Total Bilirubin \ 1.5 x ULN * AST (SGOT) and ALT (SGPT) \350 cells/mm3, confirmed HIV RNA \