DASL-HiCaP: Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate (ANZUP1801). A randomised phase 3 double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation in very high risk, clinically localised prostate cancer.

The purpose of this study is to determine the effectiveness of darolutamide as part of
adjuvant androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone
analogue (LHRHA) in men having radiation therapy for localised prostate cancer at very high
risk of recurrence.

Inclusion Criteria:

1. Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the
prostate

2. EITHER planned for primary RT and judged to be at very high risk for recurrence based
on any of the following:

- Grade Group 5, OR

- Grade Group 4 AND one or more of the following: clinical T2b-4 OR MRI with
seminal vesicle invasion OR extracapsular extension OR PSA* > 20ng/mL, OR

- Pelvic nodal involvement (involvement of lymph nodes (LNs) at or below the
bifurcation of the aorta into the common iliac arteries) defined radiologically
as greater than 10mm on short axis using standard CT or MRI, or pathologically
confirmed (PSMA PET alone is not considered enough if ≤ 10mm) OR

Post-radical prostatectomy ≤ 365 days prior to randomisation and planned for RT with
PSA* ≥ 0.1 ng/mL that has risen or remained stable (within ≤ 0.05 ng/mL) since a
previous level at least 1 week earlier, judged to be at very high risk for recurrence
based 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 the
aorta into the common iliac arteries) defined radiologically as greater than 10mm
on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET
alone is not considered enough if ≤ 10mm) * This PSA level must be measured
within 60 days prior to randomisation. However, if a participant has already
commenced endocrine therapy (ET) for prostate cancer, this PSA level must be
measured 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 x
ULN, 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 is
unable to complete because of literacy or limited vision

9. Willing and able to comply with all study requirements, including standard of care
treatment 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 spindle
cell or neuroendocrine small cell or squamous cell components or other
non-adenocarcinoma)

12. Involvement of LNs by conventional CT imaging superior to the common iliac artery
bifurcation, and/or outside the pelvis (distant LNs). LN involvement is defined by
histopathological confirmation, or by a short axis measurement > 10mm on standard
imaging (CT or MRI, but not PET).

13. Evidence of metastatic disease. Minimum imaging requirements to exclude metastatic
disease 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 prior
to randomisation.

- If ET has been started, imaging must have been performed no more than 60 days
prior to starting ET and no more than 30 days after starting ET and prior to
randomisation.

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 are
allowed:

- (i) LHRHA and/or (ii) a first-generation nonsteroidal antiandrogen (NSAA) are
allowed if commenced no more than 90 days before randomisation. If an NSAA has
been used, it must be stopped before starting study treatment with
darolutamide/placebo; and

- Prior use of 5-alpha reductase inhibitor is allowed and if used it must be
stopped before starting study treatment with darolutamide/placebo

17. Bilateral orchidectomy

18. Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of
radiotherapy fields that would preclude the required RT

19. History of

- Loss of consciousness or transient ischemic attack or stroke within 6 months
prior to randomisation, or

- Significant cardiovascular disease within 6 months prior to randomisation:
including myocardial infarction, unstable angina, congestive heart failure (NYHA
grade II or greater), ongoing arrhythmias of Grade > 2 (CTCAE v5.0),
thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism), coronary
artery bypass graft. Chronic stable atrial fibrillation on stable anticoagulant
therapy is allowed.

20. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of darolutamide, including difficulty swallowing tablets

21. History of another malignancy within 5 years prior to randomisation except for those
malignancies treated with curative intent with a predicted risk of relapse of less
than 10% including but not limited to non-melanoma carcinoma of the skin; or
adequately 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 the
last 5 years are to be discussed with study team before randomisation. Melanoma
in-situ and other adequately treated in-situ neoplasms are not considered malignancies
for the purposes of eligibility assessment.

22. Concurrent illness, including severe infection that might jeopardise the ability of
the participant to undergo the procedures outlined in this protocol with reasonable
safety (HIV infection is not an exclusion criterion if it is controlled with
anti-retroviral drugs that are unaffected by concomitant darolutamide)

23. Presence of any psychological, familial, sociological or geographical condition
potentially 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 not
willing/able to use medically acceptable and highly effective forms of contraception
during 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 used
consistently and correctly. E.g. combined (oestrogen and progestogen containing)
hormonal contraception associated with inhibition of ovulation (oral,
intravaginal, transdermal), progestogen-only hormonal contraception associated
with 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 is
in line with the preferred and usual lifestyle of the subject. Periodic abstinence
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of
abstinence for the duration of exposure to study treatment, and withdrawal are not
acceptable methods of contraception.

25. Participation in other clinical trials of investigational agents for the treatment of
prostate cancer or other diseases

26. Major surgery within 21 days prior to randomisation

27. Patients with history of hypersensitivity to the study treatment