The goal of this clinical trial is to examine the safety and efficacy of ONC-392 in combination with lutetium Lu 177 vipivotide tetraxetan in metastatic castration resistant prostate cancer patient who have disease progressed on androgen receptor pathway inhibition. The main questions it aims to answer are (1) whether it is safe to combine ONC-392 with lutetium Lu 177 vipivotide tetraxetan, (2) whether the combination increases the radiographic progression free survival (rPFS).

Participants will be randomized to two arms in 2:1 ratio. In experimental arm, they will be given ONC-392 10 mg/kg IV infusion, once every 4 weeks for up to 13 cycles or approximately one year, together with lutetium Lu 177 vipivotide tetraxetan 7.4 GBq IV, once every 6 weeks for up to 6 cycles. In active control arm, they will be given standard of care treatment with lutetium Lu 177 vipivotide tetraxetan 7.4 GBq IV, once every 6 weeks for up to 6 cycles.

In this Phase 2 study, mCRPC patients with PSMA positive scans who progressed on prior ARTA and 1 or more cycle of taxanes, and are naïve to lutetium Lu 177 vipivotide tetraxetan, will be enrolled. Patients will be randomized in a 2:1 ratio to Arm A or Arm B.

• Arm A receives ONC-392, 10 mg/kg, Q4W for up to 13 doses, plus lutetium Lu 177 vipivotide tetraxetan 7.4 GBq (200 mCi), Q6W for up to 6 doses.
• Arm B receives lutetium Lu 177 vipivotide tetraxetan 7.4 GBq (200 mCi), Q6W for up to 6 doses.

The study is open-label and patients will be monitored throughout the study period for survival, disease progression, and adverse events.

Inclusion Criteria:

1. Adult (≥ 18 years), capable of signing informed consent.
2. ECOG score 0 or 1. Life expectancy > 6 months. Adequate organ functions.
3. Histologically- or cytologically- confirmed diagnosis of metastatic prostate adenocarcinoma.
4. Patients must have a positive PSMA PET/CT scan.
5. Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L).
6. Patients must have received at least one second generation AR-targeting agents (such as enzalutamide and/or abiraterone).
7. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if:
   1. The patient is not willing to receive a second taxane regimen, or
   2. The patient's physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation or intolerance).
8. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:
   1. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 1.0 ng/mL.
   2. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions.
   3. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (PCWG3 criteria).

Patients must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to beginning study therapy.

Exclusion Criteria:

1. Patients who have not recovered to NCI CTCAE grade≤ 1 from an adverse event (AE) due to prior cancer therapeutics.
2. Receiving other anti-cancer agent or device, or participating in other clinical trial, within 28 days of first dose of study treatment.
3. 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 of immunosuppressive medication.
4. Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation within 6 months prior to randomization. Previous PSMA-targeted radioligand therapy is not allowed.
5. Symptomatic brain metastasis, symptomatic cord compression, or clinical or radiological findings indicative of impending cord compression.
6. Active GI disease, including peptic ulcer disease, pancreatitis, diverticulitis, or inflammatory bowel disease.
7. Active infections.
8. Impaired heart function.
9. Active or previously documented autoimmune disease and/or current use of immunosuppressive agents. Use of endocrine replacement therapy (e.g., thyroxine, insulin, low dose of steroid, etc.) is allowed.
10. Diagnosed with other malignancies that having ant-cancer treatment within 2 years.