Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate

Inclusion Criteria:

1. Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of theprostate
2. EITHER planned for primary RT and judged to be at very high risk for recurrence basedon any of the following:

• Grade Group 5, OR
• Grade Group 4 AND one or more of the following: clinical T2b-4 OR MRI withseminal vesicle invasion OR extracapsular extension OR PSA* > 20ng/mL, OR
• Pelvic nodal involvement (involvement of lymph nodes (LNs) at or below thebifurcation of the aorta into the common iliac arteries) defined radiologicallyas greater than 10mm on short axis using standard CT or MRI, or pathologicallyconfirmed (PSMA PET alone is not considered enough if ≤ 10mm) OR Post-radical prostatectomy ≤ 365 days prior to randomisation and planned for RT withPSA* ≥ 0.1 ng/mL that has risen or remained stable (within ≤ 0.05 ng/mL) since aprevious level at least 1 week earlier, judged to be at very high risk for recurrencebased on any of the following:
• Grade Group 5, OR
• Grade Group 4 AND pT3a or higher, OR
• Pelvic nodal involvement (involvement of LNs at or below the bifurcation of theaorta into the common iliac arteries) defined radiologically as greater than 10mmon short axis using standard CT or MRI, or pathologically confirmed (PSMA PETalone is not considered enough if ≤ 10mm) * This PSA level must be measuredwithin 60 days prior to randomisation. However, if a participant has alreadycommenced endocrine therapy (ET) for prostate cancer, this PSA level must bemeasured within 180 days prior to commencing ET.

3. Adequate bone marrow function: Haemoglobin ≥ 100g/L, white cell count (WCC) ≥ 4.0x109/L, absolute neutrophil count (ANC) ≥ 1.5x109/L and platelets > 100 x 109/L
4. Adequate liver function: alanine aminotransferase (ALT) < 2 x upper limit of normal (ULN) and total bilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 - 2 xULN, they must have a normal conjugated bilirubin)
5. Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
7. Study treatment both planned and able to start within 7 days after randomisation
8. Willing to complete health-related quality of life (HRQL) questionnaires UNLESS isunable to complete because of literacy or limited vision
9. Willing and able to comply with all study requirements, including standard of caretreatment such as EBRT, timing and/or nature of required assessments
10. Signed, written informed consent

Exclusion Criteria: 11. Prostate cancer with predominant non-adenocarcinoma features (sarcomatoid or spindlecell or neuroendocrine small cell or squamous cell components or othernon-adenocarcinoma) 12. Involvement of LNs by conventional CT imaging superior to the common iliac arterybifurcation, and/or outside the pelvis (distant LNs). LN involvement is defined byhistopathological confirmation, or by a short axis measurement > 10mm on standardimaging (CT or MRI, but not PET). 13. Evidence of metastatic disease. Minimum imaging requirements to exclude metastaticdisease are diagnostic quality imaging of both the pelvis and the abdomen (CT or MRI),chest (CXR or CT), and a whole body radioisotope bone scan (WBBS).

• If endocrine therapy (ET) had not started, imaging must be within 60 days priorto randomisation.
• If ET has been started, imaging must have been performed no more than 60 daysprior to starting ET and no more than 30 days after starting ET and prior torandomisation.

14. PSA > 100 ng/mL at any time
15. Any prior use of new generation potent AR inhibition (abiraterone, enzalutamide,apalutamide, darolutamide or similar agents).
16. Prior endocrine therapy for prostate cancer except for the following which areallowed:

• (i) LHRHA and/or (ii) a first-generation nonsteroidal antiandrogen (NSAA) areallowed if commenced no more than 90 days before randomisation. If an NSAA hasbeen used, it must be stopped before starting study treatment withdarolutamide/placebo; and
• Prior use of 5-alpha reductase inhibitor is allowed and if used it must bestopped before starting study treatment with darolutamide/placebo

17. Bilateral orchidectomy
18. Prior pelvic brachytherapy or other radiotherapy that would result in an overlap ofradiotherapy fields that would preclude the required RT
19. History of

• Loss of consciousness or transient ischemic attack or stroke within 6 monthsprior to randomisation, or
• Significant cardiovascular disease within 6 months prior to randomisation:including myocardial infarction, unstable angina, congestive heart failure (NYHAgrade II or greater), ongoing arrhythmias of Grade > 2 (CTCAE v5.0),thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism), coronaryartery bypass graft. Chronic stable atrial fibrillation on stable anticoagulanttherapy is allowed.

20. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oralabsorption or tolerance of darolutamide, including difficulty swallowing tablets
21. History of another malignancy within 5 years prior to randomisation except for thosemalignancies treated with curative intent with a predicted risk of relapse of lessthan 10% including but not limited to non-melanoma carcinoma of the skin; oradequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis,Ta and low grade T1 tumours). All such cases with a history of malignancy within thelast 5 years are to be discussed with study team before randomisation. Melanomain-situ and other adequately treated in-situ neoplasms are not considered malignanciesfor the purposes of eligibility assessment.
22. Concurrent illness, including severe infection that might jeopardise the ability ofthe participant to undergo the procedures outlined in this protocol with reasonablesafety (HIV infection is not an exclusion criterion if it is controlled withanti-retroviral drugs that are unaffected by concomitant darolutamide)
23. Presence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule,including alcohol dependence or drug abuse
24. Patients who are sexually active with women of child-bearing potential and notwilling/able to use medically acceptable and highly effective forms of contraceptionduring study treatment and for at least 4 weeks after completion of study treatment.Contraception must include:

• Condom use (also required if sexual partner is pregnant), and
• Additional birth control with low failure rate (less than 1% per year) when usedconsistently and correctly. E.g. combined (oestrogen and progestogen containing)hormonal contraception associated with inhibition of ovulation (oral,intravaginal, transdermal), progestogen-only hormonal contraception associatedwith inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion,vasectomised partner, true sexual abstinence. True sexual abstinence will only be an acceptable form of contraception when this isin line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration ofabstinence for the duration of exposure to study treatment, and withdrawal are notacceptable methods of contraception.

25. Participation in other clinical trials of investigational agents for the treatment ofprostate cancer or other diseases
26. Major surgery within 21 days prior to randomisation
27. Patients with history of hypersensitivity to the study treatment