ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With mCRPC

Inclusion Criteria:

1. Patients must be ≥ 18 years of age and have the ability to understand and sign anapproved informed consent form (ICF).

2. Patients must have an ECOG performance status of 0 or 1.

3. Patients must have a life expectancy > 6 months.

4. Patients must have histological or cytological confirmation of prostateadenocarcinoma.

5. Patients must have a positive PSMA in an FDA-approved PSMA PET scan. A positive PSMAis defined as at least one tumor lesion with PSMA uptake greater than normal liver.

6. Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy anda castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L).

7. Patients must have received at least one second generation AR-targeting agents (suchas apalutamide, darolutamide, enzalutamide and/or abiraterone).

8. Patients should have prior treatment of up to two taxane regimens, or are unfit for,or refuse taxane chemotherapy. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. Note: Taxane chemotherapy administered in the CastrationSensitive Prostate Cancer (CSPC) or Castration Resistant Prostate Cancer (CRPC)setting is allowed.

9. Patients must have progressive mCRPC. Documented progressive mCRPC will be based onat least 1 of the following criteria:

10. Serum PSA progression defined as 2 consecutive increases in PSA over a previousreference value measured at least 1 week prior. The minimal start value is 1.0ng/mL.

11. RECIST v1.1 soft-tissue progression

12. Progression of bone disease: 2 or more new metastatic bone lesions by bone scanper PCWG3 criteria.

13. Patients must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, orbone scan imaging obtained ≤ 42 days prior to beginning study therapy.

14. Patients must have adequate organ function.

15. Patients with or without concomitant bisphosphonate or denosumab regimen for ≥ 30days prior to randomization are eligible.

16. For patients who have partners of childbearing potential: Partner and/or patientmust use adequate methods of birth control with barrier protection, deemedacceptable by the principal investigator during the study and for 3 months afterlast study drug administration.

Exclusion Criteria:

1. Patients who have not recovered to NCI CTCAE grade ≤ 1 from an adverse event (AE)due to prior cancer therapeutics except neuropathy or endocrinopathy with Gr 2 orless.

2. Any systemic anti-cancer therapy within 5 half-lives or 14 days, whichever isshorter (small molecule drugs) or within 28 days for antibody based therapy, priorto starting study treatment.

3. Known hypersensitivity to the components of the study therapy or its analogs.

4. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, orinvestigational therapy.

5. Transfusion within 14 days of first day of study treatment

6. PSMA-negative lesions are defined as lesions with PSMA uptake equal to or lower thanthat of liver parenchyma. Patients with PSMA-negative lesions in any lymph node witha short axis of ≥ 2.5 cm, in any metastatic solid-organ lesions with a short axis of ≥ 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of ≥ 1.0 cmin the short axis are ineligible.

7. Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188,Radium-223 or hemi-body irradiation within 6 months prior to randomization. PreviousPSMA-targeted radioligand therapy is not allowed.

8. Patients with a history of CNS metastases must have received therapy (surgery,radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and notreceiving corticosteroids for the purposes of maintaining neurologic integrity.Patients with epidural disease, canal disease and prior cord involvement areeligible if those areas have been treated, are stable, and not neurologicallyimpaired. For patients with parenchymal CNS metastasis (or a history of CNSmetastasis), baseline and subsequent radiological imaging must include evaluation ofthe brain (MRI preferred or CT with contrast).

9. A superscan as seen in the baseline bone scan.

10. Symptomatic cord compression, or clinical or radiologic findings indicative ofimpending cord compression.

11. Concurrent serious (as determined by the Principal Investigator) medical conditions,including, but not limited to, myocardial infarction within 6 months, New York HeartAssociation class III or IV congestive heart failure, history of congenitalprolonged QT syndrome, or unstable arrhythmia within 3 months, uncontrolledinfection, active hepatitis B or C, or other significant co-morbid conditions thatin the opinion of the investigator would impair study participation or cooperation.

12. Active concurrent malignancy (with the exception of non-melanomatous skin cancer).Patients with carcinoma in situ of any origin and patients with prior malignancieswho are in remission and/or whose likelihood of recurrence is very low perinvestigator's judgment are eligible for this study.

13. Receiving systemic steroid therapy with > 10 mg/day prednisone or equivalent within 7 days prior to the first dose of study treatment or receiving any other form ofimmunosuppressive medication.

14. Active GI disease, including peptic ulcer disease, pancreatitis, diverticulitis, orinflammatory bowel disease.

15. Active or previously documented autoimmune disease and/or current use ofimmunosuppressive agents. Use of endocrine replacement therapy (e.g., thyroxine,insulin, low dose of steroid, etc.) is allowed.