This clinical trial was done to show whether a radioactive drug (I-131-1095) that binds to prostate-specific membrane antigen (PSMA) is useful in treating metastatic prostate cancer that is positive for PSMA. The trial enrolled men whose PSMA-positive metastatic prostate cancer had progressed while they were taking abiraterone. During the trial, all of the men took enzalutamide (standard-of-care therapy) once a day. However, some of the men also had up to 4 doses (8 weeks apart) of I-131-1095 (in addition to taking enzalutamide once a day). At specified times during the trial, all of the men had blood tests (to measure levels of prostate-specific antigen [PSA]) and imaging studies (to assess tumor status). The two groups of men were then compared in several ways. The main comparison was the percentage of men in each group with at least a 50% decrease in PSA levels. Other comparisons involved the response of the tumors (as seen on imaging) and overall survival. To assess safety, the number of adverse events in both groups were also compared.

This phase 2 clinical trial (conducted in the United States and Canada) enrolled chemotherapy-naïve men whose PSMA-positive (as shown by piflufolastat F18 imaging) metastatic prostate cancer had progressed during treatment with abiraterone. The participants were stratified by risk factors at Screening and then randomized 2:1 either to receive PSMA radioligand therapy (up to four 8-week cycles of I-131-1095) plus standard treatment with enzalutamide or to receive standard treatment with enzalutamide as monotherapy. The prostate-specific antigen (PSA) levels and radiographic response or progression (RECIST v1.1 criteria for soft tissue and PCWG3 criteria for bone) were then monitored for up to 53 weeks of randomized treatment. The primary outcome measure was PSA response rate (percentage of participants with a confirmed ≥50% decrease in serum PSA). Other outcome measures included percentage of participants with partial or complete response (radiographic), duration of response, time to progression (PSA or radiographic), time to next treatment for prostate cancer, and overall survival.

Inclusion Criteria:

1. Male ≥ 18 years of age

2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis

3. Castration-resistant prostate cancer, with serum testosterone ≤ 50 ng/dL at Screening

4. Radiographic evidence of metastatic disease prior to Randomization or up to 21 days prior to Screening

5. Disease progression on prior abiraterone therapy as defined by meeting at least one of the following criteria per the investigator:

   1. PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart
   2. Soft tissue disease progression defined by RECIST 1.1
   3. Bone disease progression defined by two or more new lesions on bone scan

6. Planned to receive treatment with enzalutamide

7. Subjects who are ineligible or choose not to receive taxane-based chemotherapy based on personal preference or physician opinion. Examples of conditions that could make a patient ineligible or refuse to receive taxane-based chemotherapy, but would allow them to still be eligible to receive I-131-1095 include the following:

   1. Poor performance status
   2. Prior intolerance to cytotoxic agents
   3. History of another malignancy suspected for recurrence or metastases
   4. Other serious medical conditions such as symptomatic peripheral neuropathy CTCAE Grade 2 or higher; or clinically significant cardiovascular disease per the Investigator or treating physician

8. Subjects receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Randomization

9. ECOG performance status 0-2

10. If sexually active, agree to use a medically acceptable method of birth control or sexual abstinence from the time of dosing through 28 days after the last dose of I-131-1095. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.

11. Estimated life expectancy of at least 6 months as determined by the Investigator.

12. Able and willing to provide signed informed consent and comply with protocol requirements

Exclusion Criteria:

1. Received any anti-tumor therapy within 4 weeks of Randomization, with the exception of abiraterone, GnRH therapy and non-radioactive bone-targeted agents

2. Received prior chemotherapy for castration-resistant prostate cancer

3. Superscan as evidenced on baseline bone scan

4. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Randomization

5. Prior hemi-body irradiation

6. Prior PSMA-targeted radioligand therapy

7. Major surgery within 4 weeks of Randomization

8. Impaired organ function as evidenced by the following laboratory values at Screening:

   1. Absolute neutrophil count < 1500 μL
   2. Platelet count < 100,000/μL
   3. Hemoglobin < 9.5 g/dL
   4. Albumin < 3.0 g/dL (30 g/L)
   5. Total bilirubin > 2 x ULN unless in instances of known or suspected Gilbert's disease
   6. AST or ALT > 2.5 x ULN
   7. Calculated creatinine clearance (CrCL) < 30 mL/min (Cockroft-Gault equation), or currently on renal dialysis.

9. QT interval corrected for heart rate (QTc) > 470 msec

10. Previous use of enzalutamide for more than 7 days prior to consent

11. Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study

12. History or risk of seizure (i.e., clinically significant neurological disorder) or any other condition that contraindicates treatment with enzalutamide

13. Gastrointestinal disorder affecting absorption of oral medications

14. Known or suspected brain metastasis or active leptomeningeal disease

15. Active malignancy other than prostate cancer, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or non-muscle invasive bladder/urothelial cancer

16. Subjects with any medical condition or other circumstances that, in the opinion of the investigator, compromise obtaining reliable data, achieving study objectives, or completing the study.