A Study of ARV-766 Given by Mouth in Men With Metastatic Prostate Cancer

Prior treatment

• Known symptomatic brain metastases requiring steroids (above physiologic replacement doses)
• Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ or other low grade localized cancer. Eligibility for exception requires Sponsor approval
• Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease
• Active inflammatory gastrointestinal disease, chronic diarrhea, diverticulitis, or previous gastric resection or lap band surgery
• Participants taking sensitive BCRP and P-glycoprotein (P-gp) substrates or substrates with narrow therapeutic indices, strong CYP3A4 inhibitors and inducers, restricted medications described in the study protocol and the Investigator's Brochure, and additionally for Part C, CYP2D6 substrates with a narrow therapeutic index
• Prior treatment with a second-generation NHA such as abiraterone, enzalutamide, darolutamide, or apalutamide (Part C only). Note: prior chemotherapy is allowed.
  • Other inclusion/exclusion criteria may apply.

Lab values

• Any of the following in the previous 6 months: congenital long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior hemiblock (bifascicular block). Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation). Anticoagulation (heparin/lovenox only) can be allowed if indicated
• Inadequate bone marrow function defined as follows (with no transfusion of blood products or use of hematopoietic growth factors in the 28 days prior to start of therapy):
  • Absolute neutrophil count \<1,500/mm3 or \<1.5 × 109/L
  • Platelets \<100,000/mm3 or \<100 × 109/L
  • Hemoglobin \<9 g/dL
• Inadequate renal function defined as estimated creatinine clearance (Clcr) ≤60 mL/min using Cockcroft-Gault formula or eGFR ≤60 mL/min/1.73m3 using the CKD-EPI equation
• Inadequate liver function defined as:
  • Total serum bilirubin \>1.5× upper limit of normal (ULN) unless the participant has documented Gilbert syndrome
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of \>2.5× ULN if there is NO liver involvement secondary to tumor OR \>5.0× ULN if there is liver involvement secondary to tumor

Other

• QTcF \>480 msec at baseline based on ECG
• Electrolyte imbalances of clinically significant hypokalemia, hypomagnesemia, and/or hypocalcemia (Part C only)

• Participants must be able to take oral medication without crushing, dissolving, or chewing tablets
• Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate
• Progression on approved systemic therapies for metastatic prostate cancer (at least one must be a second-generation androgen inhibitor, e.g., abiraterone, enzalutamide, darolutamide, apalutamide) (Parts A and B only)
• Progressive mCRPC (Parts A and B only) defined as:
  • Serum testosterone levels \<50 ng/dL (or ≤0.50 ng/mL or 1.73 nmol/L) using testosterone assays with a sensitivity of ≤30 ng/dL, within 28 days before study drug treatment
  • Radiographic evidence of metastatic disease (soft tissue disease per modified RECIST 1.1 criteria or bone disease per PCWG3)
  • Disease progression on or following the most recent systemic therapy
• Ongoing androgen deprivation therapy (ADT) with a gonadotropin releasing hormone analog or inhibitor, or orchiectomy (surgical or medical castration) (Parts A and B only)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Metastatic castration resistant or sensitive prostate cancer with radiographic evidence of metastatic disease (soft tissue disease per modified RECIST 1.1 criteria or bone disease per PCWG3) (Part C)