ARV-110

1. Patients must have signed and dated, and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written ICF in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal patient care.

2. Patients must be able and willing to conform with visit and treatment schedule and laboratory procedures.

3. Patients must be able to take oral medication without crushing, dissolving, or chewing tablets/capsules.

4. Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate.

5. Ongoing treatment with stable doses of abiraterone (on an empty stomach) and a concomitant corticosteroid for castration-resistant prostate cancer (CRPC) or for metastatic CSPC until C1D1. If a patient had treatment interruptions or dose modifications of abiraterone within 2 weeks of C1D1, eligibility must be discussed with the Medical Monitor.

6. Recent PSA values prior to signing consent must demonstrate:

a. PSA progression at least 16 weeks after initiation of abiraterone

b. A sequence of at least 2 rising PSA values measured at a minimum of 1 week apart (if PSA is <2 ng/mL, a sequence of at least 3 rising PSA values measured a minimum of 1 week apart is required)

7. No known radiographic evidence of disease progression while receiving abiraterone at the time of consent. If there is evidence of radiographic disease progression during screening, the patient may be considered eligible after discussion with the Medical Monitor.

8. Ongoing ADT with a gonadotropin-releasing hormone (GnRH) analogue or inhibitor, or orchiectomy (surgical or medical castration).

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

10. The following historical PSA values with dates must be documented in an electronic case

report form (eCRF) for all patients:

• Last PSA prior to initiation of abiraterone

• PSA nadir while on abiraterone

• PSA progression at least 16 weeks after initiation of abiraterone (including confirmatory PSA values at least 1 week apart)

11. Adequate bone marrow function defined as follows (with no transfusion of blood products or use of hematopoietic growth factors in the 28 days prior to enrollment):

• Absolute neutrophil count ≥1,500/mm3 or ≥1.5×109/L

• Platelets ≥100,000/mm3 or ≥100×109/L

• Hemoglobin ≥9 g/dL

12. Adequate renal function defined as serum creatinine ≤1.5× ULN or an estimated creatinine clearance of ≥50 mL/min.

13. Adequate liver function defined as:

• Total serum bilirubin ≤1.5× ULN

• 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

14. Adverse reactions of any prior therapy (including abiraterone) have not resolved to baseline severity or Grade ≤1 by NCI CTCAE except for the following:

• alopecia

• peripheral neuropathy

15. Males ≥18 years of age, inclusive, at the time of signing the ICF.

16. Males who are sexually active must agree to use contraception (unless confirmed prior castration) as detailed in Appendix 6 of this protocol during the treatment period and for at least 35 days after the last dose of study treatment and refrain from donating sperm for 6 months after the last dose of study drug. Investigators shall counsel male patients who are sexually active with women of childbearing potential (WOCBP) on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception (Appendix 6) that have a failure rate of <1% when used consistently and correctly. 

1. Previously treated with enzalutamide, apalutamide, darolutamide or experimental therapies (e.g., protein degraders or inhibitors) directed at the AR.

2. Treatment with any chemotherapy, investigational agents, immunotherapy, or hormonal therapy other than GnRH agonists within 28 days of the start of treatment on protocol.

3. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to >25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.

4. Patients taking agents that are P-gp or BCRP substrates, CYP3A4 substrates, CYP2D6 substrates that have a narrow therapeutic index, strong CYP3A4 inhibitors or inducers, or any other prohibited and/or restricted medications described in Section 8.6.2 unless specifically approved by the Medical Monitor.

5. Major surgery (as judged by the Investigator) within 4 weeks of first dose of study drug.

Medical Conditions

6. Known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable as judged by the Investigator.

7. 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. Other low-grade, localized malignancies that are adequately treated may be considered eligible after

discussion with the Medical Monitor.

8. 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 II, III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease.

9. 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), or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation). Anticoagulation (heparin/lovenox only, no vitamin K antagonists or factor Xa inhibitors) can be allowed if indicated. If a patient has a cardiac rhythm device/pacemaker placed and QTcF >470 msec, the patient can be considered eligible. Patients with cardiac rhythm device/pacemaker must be discussed in detail with the Medical Monitor to judge eligibility.

10. Hypertension that cannot be controlled by medications (>150/90 mmHg despite optimal medical therapy).

11. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus (HIV), or acquired immune deficiency syndrome (AIDS)-related illness. In equivocal cases, patients whose viral load is negative, may be eligible. The HIV-seropositive patients who are healthy and low risk for AIDS-related outcomes could be considered eligible. Eligibility criteria for HIVpositive patients should be evaluated and discussed with the Medical Monitor and will be based on current and past CD4 and T cell counts, history (if any) of AIDS-defining conditions (e.g., opportunistic infections), and status of HIV treatment.

12. Active inflammatory gastrointestinal disease, uncontrolled chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed.

13. Patients with Child Pugh C.

14. Suspected hypersensitivity to ARV-110.

15. History of allergy or reaction to any of the drug components.

16. Other acute or chronic severe medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. 

Research Nurse: Karen Jones (x2031) Karen.Jones4@lthtr.nhs.uk