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.

Evofosfamide at a dose of 480 mg/m2 IV over 60 minutes on Days 1, 8 and 15 of every 28-day cycle. Additionally, subjects will receive standard-of-care castration (medical or surgical) plus ARSI. On days when both an ARSI and evofosfamide are administered, the ARSI should be administered at least 2 hours before or at least 2 hours after completion of the evofosfamide infusion. The preferred order of administration is evofosfamide administered first, with the ARSI administered at least 2 hours following the completion of evofosfamide infusion.

Inclusion Criteria:

1. At least 18 years of age;
2. Ability to understand the purposes and risks of the trial and has signed a written ICF approved by the investigator's REB;
3. CRPC stage M1 based on conventional imaging (CT and/or bone scan) or PSMA PET;
4. Progression (i.e., PSA rise of 25% or more, and absolute increase of 2 ng/mL or more from the nadir) to first-line ARSIs (Abi or Enza or Daro or Apa monotherapy) and subsequent docetaxel or deemed ineligible for it;
5. Ongoing castration therapy (e.g., surgical or medical with LHRH agonists/antagonist), with baseline testosterone level <50ng/dL;
6. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2;
7. In subjects with known significant pulmonary disease (severe chronic obstructive or other pulmonary disease with hypoxemia), measure oxygen saturation using pulse oximeter after a 2-minute walk. Subjects must have oxygen saturation ≥90% to be eligible for the trial.

Exclusion Criteria:

• 1. ANC <1,000/mm3, and/or hemoglobin <9.0 g/dL, and/or platelet count <100,000/mm3; independent of transfusion and/or growth factors 2. Liver dysfunction: total bilirubin, serum glutamic oxaloacetic transaminase (SGOT; aspartate aminotransferase [AST]) and/or serum glutamic-pyruvic transaminase (SGPT; alanine aminotransferase [ALT]) >1.5 × upper normal limit (UNL); 3. Inadequate renal function: creatinine >1.5 × UNL, or eGFR <40 mL/min; 4. Any Grade 3 or greater toxicity experienced during treatment with prior ARSI; 5. Severe, active co-morbidity defined as follows:

  1. Myocardial infarction within 6 months prior to date of enrollment.

  2. Current severe or unstable angina.

  3. New York Heart Association Functional Classification III/IV. (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)

  4. Severe chronic obstructive or other pulmonary disease with hypoxemia at rest (requires supplementary oxygen, symptoms due to hypoxemia).

  5. History of any condition that in the opinion of the investigator, would preclude participation in this study.

     6. Known liver metastases based on conventional imaging (i.e., abdominal CT and/or MR).

     7. Known brain, leptomeningeal or epidural metastases (unless treated, well controlled, and not requiring steroidal therapy for at least 3 months).

     8. Major surgery (other than diagnostic surgery), open biopsy, or significant traumatic injury, ≤28 days prior to the date of signing informed consent. Subject must have completely recovered from surgery.

     9. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.

     10. Treatment of PCa with radiation therapy or surgery ≤28 days prior to the Cycle 1 Day 1.

     11. Prior therapy with a hypoxic cytotoxin. 12. HIV-infected patients with detectable viral load and/or on effective anti-retroviral therapy (ART) with undetectable viral load for less than 6 months. Note: HIV testing is not required for eligibility for this protocol. Drug-drug interactions with ART occur via many mechanisms, with cytochrome P450 CYP3A4-mediated interactions being the most common. Patients who are using concurrent strong or moderate CYP3A4 inhibitors (e.g., ritonavir, cobicistat) or strong or moderate CYP3A4 inducers must be switched to an alternate effective ART regimen ≥4 weeks before study enrollment or should be excluded from the study if their regimen cannot be altered.

     13. Active infection with hepatitis B or hepatitis C (i.e., detectable viral load) with or without active treatment in patients with previously known infection. Note: Only Hepatitis B testing is required for eligibility for this protocol as per standard practice prior to systemic therapy.

     14. Subjects who have exhibited allergic reactions to a structural compound similar to evofosfamide or the drug product excipients.

     15. Subjects who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (see Appendix A).

     16. Subjects with a QTc interval calculated according to Fridericia formula (QTC = QT / RR1/3) of >450 msec based on screening electrocardiogram (ECG).

     17. Subjects with a history of long QT syndrome. 18. Subjects taking a medication that is a moderate or strong inhibitor or inducer of CYP3A4within 14 days or 5 half-lives (whichever is longer) prior to signing of ICF. (see Appendix B).

     19. Subjects taking a medication that is a sensitive substrate or substrates with a narrow therapeutic index of CYP3A4, CYP2D6, or CYP2C9 (see Appendix C).

     20. Any other significant concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this trial.

     21. Unwillingness or inability to comply with the study protocol for any reason.