Randomized Study of ONC-392 plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) who Progressed on Androgen Receptor (AR) Pathway Inhibition

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.