Cypides

1. Written informed consent (IC) obtained.

2. Males aged over 18 years.

3. Life expectancy > 3 months.

4. ECOG performance status 0-1.

5. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.

6. Metastatic disease documented either by a positive bone scan, CT, PET/CT or MRI scan.

7. Castration-resistant prostate cancer with serum testosterone < 50 ng/dl (< 1.7 nmol/l).

8. Patients must maintain ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist), or have had bilateral orchiectomy.

9. Treatment with at least 1 line of chemotherapy or ineligibility or refusal to undergo chemotherapy.

10. Treatment of at least 1 line of novel AR targeted hormonal therapy in castration-sensitive prostate cancer (CSPC) or in CRPC at a minimum of 12 weeks (e.g. abiraterone, enzalutamide, darolutamide, apalutamide).

11. For Part 2 only: no prior use of any investigational AR targeted hormonal therapy.

12. Documented disease progression by one or more of the following criteria:

· PSA progression defined by a minimum of 2 elevated PSA levels with an interval of at least 1 week between the measurements. The PSA value at the screening visit should be 2 ng/ml.

· soft tissue disease progression as defined by RECIST 1.1 criteria.

· bone disease progression as defined by PCWG3 criteria.

13. Adequate marrow, liver and kidney function.

· haemoglobin 10 g/dl (in absence of blood transfusion within 7 days of value obtained)

· absolute neutrophil count (ANC) > 1500/µl (1.5 x 109/l)

· platelet count 100 000/µl (100 x 109/l )

· aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (< 5.0 x ULN if liver metastases present)

· total bilirubin 1.5 x ULN (< 3 ULN if Gilbert’s syndrome)

· albumin > 3.0 g/dl

· creatinine < 1.5 ULN or calculated creatinine clearance > 60 ml/min/1.73 m2 for patients with creatinine levels above normal limit

14. Resolution of acute toxic effects of prior therapy or surgical procedures to NCI CTCAE Grade < 1 (except alopecia and grade 2 peripheral neuropathy).

15. Able to swallow study treatment, to follow study instructions and to comply with study requirements.

16. Sexually active patients must agree to use condoms and an additional effective contraception, unless surgically sterile, during the study and for 3 months after the end of ODM-208 treatment. 

1. History of pituitary or adrenal dysfunction.

2. Known brain metastases or active leptomeningeal disease.

3. Other concurrent malignancies, except adequately treated basal cell or squamous cell carcinoma of the skin. Patients who have undergone potentially curative therapy for a prior malignancy are eligible provided there is no evidence of disease for > 5 years and patient is deemed to be at low risk for recurrence.

4. Active or uncontrolled autoimmune disease requiring concurrent corticosteroid therapy.

5. Active infection or other medical condition that would make corticosteroid contraindicated.

6. Use of aldosterone antagonist (e.g. spironolactone, eplerenone) and phenytoin.

7. Patients on an unstable dose of thyroid hormone therapy within 6 months prior to the start of the study treatment.

8. Prior radiotherapy, chemotherapy within the last 4 weeks (2 weeks for oral or weekly chemotherapy; 6 weeks for nitrosoureas and mitomycin C) prior to the start of the study treatment. Concurrent radiotherapy for palliation is allowed.

9. Use of enzalutamide within 4 weeks and abiraterone acetate within 2 weeks prior to the start of study treatment. Use of other anticancer therapy (excluding GnRH) within 4 weeks prior start of the study treatment.

10. Initiation of treatment with bisphosphonate or denosumab within 4 weeks before the start of the study treatment.

11. Known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study treatment.

12. Poorly controlled diabetes.

13. Hypotension: systolic BP < 110 mmHg, or uncontrolled hypertension: systolic BP > 160 mmHg or diastolic BP > 90 mmHg, in 2 out of 3 recordings with optimised antihypertensive therapy.

14. Clinically significant abnormal serum potassium or sodium level.

15. Active or unstable cardio/cerebro-vascular disease, including thromboembolic events. Examples include recent (within 6 months) myocardial infarction, coronary artery bypass graft or symptomatic cerebrovascular accident or congestive heart failure (New York Heart Association class III-IV).

16. History or family history of long QTc syndrome. Repeatable prolongation (2 out of 3 recordings) of QTcF interval > 450 ms or any clinically significant abnormality in the centrally-read ECG.

17. Major surgery within 4 weeks before the start of the study treatment.

18. Severe or uncontrolled concurrent medical condition or psychiatric illness.

19. Serious persistent infection within 2 weeks prior to the start of the study treatment.

20. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

21. Known hypersensitivity to study treatment or any of its ingredients.

22. Participation in another interventional clinical trial or any concurrent treatment with any investigational drug 4 weeks prior to the start of the study treatment. 

Research Nurse: Catherine Walmsley (x8475) Catherine.Walmsley@lthtr.nhs.uk

Administrator: Zainab Chauhan (x8475)