Inclusion
Age ≥ 18 years
Histological confirmation of squamous cell carcinoma of the penis (PSCC): NOTE: Biopsy confirmation of at least one site of metastasis is encouraged but not required.
At least one site of metastatic or unresectable PSCC. NOTE: Prior therapy is not required for patients whose treatment is considered palliative (for example, presence of distant metastasis). NOTE: Patients who are potentially curable (any T, N1 - N3, M0) must have had tumor progression after standard chemotherapy, radiotherapy, or surgery, or be unable to receive such treatment. Eligible stages include:
Any T, N1 (i.e., a palpable mobile unilateral inguinal lymph node), M0 OR
Any T, N2 (i.e., palpable mobile multiple or bilateral inguinal lymph nodes), M0 OR
Any T, N3 (i.e., fixed inguinal nodal mass or any pelvic lymphadenopathy), M0 OR
Any T, any N, M1
Patients with clinical N1, M0 mPSCC at protocol entry must be ineligible for surgery because of comorbidities or clinical T4 disease, or have refused surgery
Patients with clinical N1 - N3, M0, and no prior systemic therapy must be:
Unable to receive neoadjuvant (paclitaxel + ifosfamide + cisplatin) TIP because of comorbidities or refused TIP; AND
Unable to receive radiotherapy with curative intent, or refused radiotherapy
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Prior therapy is allowed. Patients may be treatment-naïve or have had any number of prior anti-cancer treatments
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Hemoglobin ≥ 9.0 g/dL obtained ≤15 days prior to registration
Absolute neutrophil count (ANC) ≥ 1000/mm\^3 obtained ≤ 15 days prior to registration
Platelet count ≥ 100,000/mm\^3 obtained ≤ 15 days prior to registration
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN for patients with Gilbert's disease obtained ≤ 15 days prior to registration
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN obtained ≤ 15 days prior to registration
Glomerular filtration rate (GFR) or calculated creatinine clearance ≥ 30 ml/min as estimated using the Cockcroft-Gault formula or as measured by 24-hour urine collection obtained ≤ 15 days prior to registration
Provide written informed consent
Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
Exclusion
Pure verrucous carcinoma of the penis
Non-squamous malignancy of the penis
Squamous carcinoma of the urethra
Preexisting sensory or motor neuropathy ≥ grade 2
Active central nervous system (CNS) metastases. Exception: Treated CNS metastases are allowed if all of the following are true:
CNS metastases are clinically stable for ≥ 6 weeks prior to registration
If needed, steroid dose is stable and ≤ 20 mg/day of prednisone or equivalent for ≥ 2 weeks prior to registration
Baseline imaging shows no evidence of new or enlarged brain metastasis
No leptomeningeal disease
History of uncontrolled diabetes mellitus ≤ 3 months prior to registration NOTE: Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8.0% or HbA1c 7.0-7.9% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
Failure to recover from any of the following therapies prior to registration:
Major surgery
Radiotherapy, chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy
Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive
Uncontrolled intercurrent illness including, but not limited to:
Ongoing or active infection requiring systemic treatment
History of cerebral vascular event (stroke or transient ischemic attack)
Myocardial infarction or symptomatic congestive heart failure (New York Heart Association \[NYHA\] Class III-IV) ≤ 6 months prior to registration
Unstable angina pectoris
Cardiac arrhythmia
Or psychiatric illness/social situations that would limit compliance with study requirements (e.g., history of substance abuse)
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Currently receiving systemic antimicrobial treatment for viral, bacterial or fungal infection. NOTE: Routine antimicrobial prophylaxis is allowed
Known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or active hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid (RNA) \[qualitative\] is detected)
Known active keratitis or corneal ulcerations. NOTE: Superficial punctate keratitis is allowed if the disorder is being adequately treated
Known hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate and polysorbate 20) OR subject has known hypersensitivity to biopharmaceutical produced in Chinese hamster ovary cells
Other active malignancy ≤ 2 years prior to registration. EXCEPTIONS: Locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, or carcinoma in situ of the breast or low risk Gleason 6 prostate cancer.
History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Patients who are sexually active and unwilling to use effective contraception (if they are not already surgically sterile)
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Chemotherapy-naïve patients who are potentially curable (any T, N1 - N3, M0) in the absence of any condition that precludes cisplatin-based chemotherapy, such as low GFR, peripheral neuropathy, hearing impairment, or psychosocial considerations