This is a single-institution, single-arm, open-label Phase 2 trial evaluating evofosfamide in subjects with M1 CRPC who fail first-line ARSIs. In those progressing after second-line Docetaxel or deemed ineligible to it, the use of alternate ARSI remains the most common line of therapy in our Province, in keeping with recent international recommendations. After baseline molecular imaging (PSMA and fluorodeoxyglucose (FDG) PET/CT), prior to evofosfamide initiation, subjects will be encouraged to undergo biopsy of a dominant lesion: FDG-, PSMA-uptake and/or conventional imaging determined (in order, and according to feasibility). Subjects will then receive the alternate ARSI (i.e., different from the one received in first line) as per current standard practice and Provincial drug plan coverage. Additionally, subjects will receive combinatorial evofosfamide at a dose of 480 mg/m2 intravenously (IV) over 60 minutes on Days 1, 8 and 15 of every 28-day cycle. Therapy will continue until disease progression, unacceptable toxicity as a result of evofosfamide, or subject withdrawal. Assessments during evofosfamide treatment will include history, physical exam, and blood tests at each monthly visit to monitor for toxicity. Response and progression will be evaluated by whole-body PSMA PET/CT scan every 8 weeks (± 3 days) and determined using (PE)RECIST v1.1 criteria. PSA, NE markers (e.g., Serum CHGA, NSE), organ function tests (e.g., liver, kidney) and investigational liquid biopsy samples will be followed every cycle (monthly). FDG PET/CT will be performed at baseline, at 6-10 weeks from the date of signing the informed consent form (ICF), and upon progression, irrespective of treatment discontinuation or initiation of another therapy. Subjects will be followed for survival endpoints following completion of this study treatment until death.