Tinengotinib with a novel endocrine therapy for metastatic castration-resistant prostate cancer

Inclusion Criteria:

1. Male aged \>= 18 years at the time of signing the informed consent form (ICF).
2. Histologically or cytologically confirmed prostate adenocarcinoma; neuroendocrine differentiation after prior treatment is permitted (patients with de novo neuroendocrine prostate cancer at initial diagnosis are excluded).
3. Baseline imaging confirming metastatic lesions in bone (\>=2 bone lesions) or soft tissue; lesions identified only by PET imaging are not acceptable.
4. Receipt of continuous medical castration for \>=90 days or prior surgical castration, with serum testosterone \< 50 ng/dL (1.73 nmol/L) within 28 days prior to the first dose. Participants receiving medical castration with a luteinizing hormone-releasing hormone (LHRH) analogue must continue treatment throughout the study.
5. Documented disease progression (per RECIST v1.1 and/or PCWG3) after \>1 month of prior novel endocrine therapy (including abiraterone and AR inhibitors).

   Cohort B: Prior exposure to only one type of novel endocrine therapy.
6. Disease failure after \<=1 line of chemotherapy administered during the castration-resistant phase (chemotherapy duration \<=1 month and ADC agents are not counted as systemic chemotherapy).
7. ECOG performance status \<= 1.
8. Adequate organ and bone marrow function (no hematopoietic growth factors, blood transfusion or related blood products within 14 days before the first dose).
9. Must agree not to donate sperm or cryopreserve sperm for future assisted reproduction during study treatment and for 3 months after the last dose of study treatment. If the participant is spermatogenic and his female partner is of childbearing potential, highly effective contraception must be used.
10. Able to provide informed consent and comply with study procedures.

Exclusion Criteria:

1. Prior treatment with tyrosine kinase inhibitors (TKIs).
2. Prior treatment with darolutamide or enzalutamide (except for treatment duration \<= 1 month).
3. Uncontrolled hypertension (systolic blood pressure \>=150 mmHg or diastolic blood pressure \>=100 mmHg; repeat measurement is permitted after an interval of \>=10 minutes if abnormal), or a medical history of hypertensive crisis/hypertensive encephalopathy. Uncontrolled is defined as failure to achieve blood pressure control despite antihypertensive therapy with stable type/dose for at least 1 week.
4. Concurrent central nervous system (CNS) metastases with radiological or symptomatic progression within 28 days prior to study treatment initiation.
5. Concurrent other malignancies requiring active treatment. Malignancies not requiring treatment within 5 years and cured localized tumors such as basal cell carcinoma of the skin, papillary thyroid carcinoma, etc., are excluded from this criterion.
6. Prior administration of other anti-tumor therapies within \<=5 half-lives or 14 days (whichever is shorter) before initiation of study treatment, or failure to recover from adverse events of prior therapy (except for adverse events \<= Grade 1 or \<= Grade 2 adverse events judged by the investigator not to pose a safety risk). Sex hormone therapies other than LHRH agents must be discontinued \>=7 days before study drug administration.
7. Receipt of extensive radiotherapy within 4 weeks prior to study treatment initiation, or palliative local radiotherapy within 2 weeks, or failure to recover from adverse events of prior therapy. (If the investigator considers that early initiation of study drug is in the participant's best interest based on benefit-risk assessment, study drug treatment may be started during the washout period upon sponsor approval.)
8. Major surgery within 4 weeks prior to study treatment initiation, or failure to recover from surgical adverse events (except for adverse events \<= Grade 1 or \<= Grade 2 adverse events judged by the investigator not to pose a safety risk). 9. History of severe cardiovascular or cerebrovascular diseases.

10\. Severe gastrointestinal disease or gastrointestinal dysfunction that may alter the absorption, metabolism or excretion of the study drug; eligibility will be determined by investigator assessment (including but not limited to total gastrectomy, short bowel syndrome, etc.).

11\. Bleeding disorders, thrombotic disorders, or therapeutic anticoagulation requiring INR monitoring, such as warfarin or any other coumarin derivative anticoagulants.

12\. Use of strong CYP3A4 inhibitors and other agents that may affect the metabolism of the study drug within \<=2 weeks or 5 half-lives (whichever is shorter) prior to study treatment initiation. Other agents that may affect the concomitant medications are as follows: (1) Participants receiving enzalutamide combination therapy: use of strong CYP2C8 inhibitors; (2) Participants receiving darolutamide combination therapy: use of rosuvastatin, strong P-gp inhibitors and inducers.

13\. Positive human immunodeficiency virus (HIV) test. 14. Active HBV infection (abnormal HBV serology other than positive hepatitis B surface antibody; HBV DNA copy number testing is required to confirm activity) and/or HCV infection (HCV RNA copy number testing is required to confirm activity if HCV antibody is positive).

15\. Inability to swallow or tolerate oral medication. 16. Other conditions judged by the investigator to make the participant unsuitable for study participation.