Efficacy and Safety of Disitamab Vedotin Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer：a Phase II Study

Inclusion criteria

• Patients are able to understand and voluntarily sign the informed consent form (ICF); judged by the investigator to be capable of complying with the protocol.
• Male patients of ≥18 years or older at the time of ICF signature.
• Patients with ECOG performance status 0-1.
• Patients with an expected survival of 3months or more.
• Patients who are histologically or cytologically confirmed prostatic adenocarcinoma with HER2 expression (IHC 1+, 2+ or 3+) in archival or fresh tumour tissue.
• Patients with documented castration-resistant prostate cancer (CRPC): serum testosterone <1.73 nmol/L (50 ng/dL) at screening; patients on medical castration must continue LHRH agonist/antagonist therapy throughout the study.
• Patients with evidence of metastatic disease by bone scan (bone lesions) and/or CT/MRI (soft-tissue lesions).
• Patients with adequate organ function as defined below:

• Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
• Platelet count (PLT) ≥100 × 10⁹/L
• Hemoglobin (Hb) ≥100 g/L
• Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN); ≤2 × ULN if liver metastases present
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 × ULN; ≤2 × ULN if liver metastases present
• Serum creatinine (Cr) ≤1.5 × ULN or calculated creatinine clearance (CrCl) ≥60 mL/min (Cockcroft-Gault formula; calculate only if Cr >1.5 × ULN)
• Urinalysis protein <2+; if ≥2+, 24-h urine protein must be <1 g or urine protein/creatinine ratio <0.5
• For patients not on anticoagulation: INR and aPTT ≤1.5 × ULN; patients on stable-dose anticoagulation are eligible
• Left ventricular ejection fraction (LVEF) ≥50% or ≥local lower limit of normal (LLN), whichever is lower
• QTcF interval <470 ms
• Male patients with partners of child-bearing potential must use a medically acceptable contraceptive method from the first study dose until 3 months after the last dose.

Exclusion criteria

• Patients who are known hypersensitivity to any component of disitamab vedotin or abiraterone.
• Patients with other malignancies within 3 years before screening, except early-stage malignancies considered clinically cured (carcinoma in situ or stage I tumors), e.g., basal-cell or squamous-cell skin carcinoma or superficial bladder cancer.
• Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with treated brain metastases may enroll if lesions have been stable for ≥1 month, there is no evidence of new or enlarging CNS disease, and systemic corticosteroids have been discontinued ≥3 days before the first study dose.
• Patients who are clinically significant pericardial effusion, or pleural/peritoneal/pelvic effusions that are poorly controlled or require drainage within 2 weeks before the first dose.
• Patients with major surgical intervention (any grade 3 or 4 procedure per the 2009 Chinese Regulation on Clinical Application of Medical Technologies) within 4 weeks before the first dose, or incomplete post-operative recovery that, in the investigator's judgment, poses a risk to trial participation.
• Patients who are prior PSMA-targeted therapy.
• Patients within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before the first dose: any antineoplastic chemotherapy (except castration therapy), radiotherapy (>1 week of local palliative radiotherapy permitted), endocrine therapy (estrogens or anti-androgens; bicalutamide or nilutamide require 6-week washout), targeted therapy, immunotherapy, or participation in another interventional clinical trial (observational studies or post-trial follow-up are allowed).

• Patients with stable-dose denosumab or bisphosphonates for bone metastases are permitted.
• mCRPC patients must not have used PSA-lowering herbal agents (e.g., saw palmetto) or systemic corticosteroids (except short courses for allergy prophylaxis/treatment) within 4 weeks before the first dose, nor plan to use such agents during the study.
• Patients with use of antineoplastic traditional Chinese medicine (TCM) prescriptions or proprietary TCM within 1 week, or receipt of blood transfusion/blood products, hematopoietic growth factors, or other agents to correct blood cell counts within 2 weeks before first study dose.
• Patients with toxicities from prior antineoplastic therapy that have not resolved to baseline, CTCAE v5.0 grade 0-1 (except alopecia and pigmentation), or to the levels specified in the inclusion/exclusion criteria; unhealed wounds. Irreversible toxicities not expected to worsen with study drug (e.g., hearing loss) are permitted.
• Patients with unexplained fever >38.5 °C (tumor-related fever may be allowed per investigator judgment); active or persistent infection; HIV antibody positive; HBsAg positive with HBV DNA > site ULN, or HBsAg-negative/HBcAb-positive with HBV DNA > site ULN after treatment; HCV antibody positive with HCV RNA > site ULN; active syphilis (except adequately treated, cured, or stable syphilis).
• NYHA class III/IV congestive heart failure; uncontrolled arrhythmia despite treatment/intervention; risk of QT prolongation or use of drugs known to prolong QT; refractory hypertension (hypertension controlled to <140/90 mmHg on medication is allowed).
• Patients with clinically significant vascular events within 6 months before first dose, including acute arterial/venous thromboembolism, thrombotic arteritis, thrombophlebitis, acute pulmonary embolism, acute coronary syndrome (MI, unstable angina, etc.), acute cerebrovascular events, or disseminated intravascular coagulation.
• Patients with tumor metastases with clear invasion of major arteries posing a high bleeding risk.
• Patients with interstitial pneumonitis, pulmonary fibrosis, or other severe pulmonary disease requiring treatment; hemoptysis >2.5 mL per episode within 3 weeks before first dose.
• Patients with active gastro-intestinal ulcer, perforation, and/or fistula requiring treatment within 6 months; GI bleeding (hematemesis, melena, or hematochezia) within 3 months without endoscopic/colonoscopic evidence of complete healing.
• Patients with uncontrolled concurrent disease >CTCAE v5.0 grade 2 (e.g., diabetes).

Uncontrolled concurrent disease >CTCAE v5.0 grade 2 (e.g., diabetes).

• Patients with CTCAE v5.0 grade >2 peripheral neuropathy, prior epilepsy, psychiatric disorders; history of drug abuse within 6 months or alcohol abuse within 3 months (alcohol abuse defined as >14 units/week: 1 unit = 285 mL beer, 25 mL spirits, or 80 mL wine).
• Patients with autoimmune disease, immunodeficiency, or organ transplantation.
• Patients with any condition, therapy, or laboratory abnormality that, in the investigator's opinion, could confound results, interfere with trial participation, or be not in the subject's best interest.