Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA

Study Overview
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Brief Summary
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Darolutamide is a drug that has a proven survival benefit in non-metastatic (M0) castrate resistant prostate cancer when using conventional imaging. However, it is estimated that >90% of patients have disease apparent when using PSMA PET. This study investigates the use of local consolidation radiotherapy in this cohort of men.

Detailed Description
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This study explores the use of local consolidation therapy in the setting of Darolutamide in the initial diagnosis of metastatic castrate resistant prostate cancer (mCRPC). In the chemotherapy naïve mCRPC setting, the pattern of disease is of limited volume metastases (1-5) in 34%-40% of cases. As progression at known sites of macroscopic disease is the predominant cause of failure on systemic therapies, local consolidation therapy with stereotactic ablative body radiotherapy (SABR) may improve progression free survival (PFS) and overall survival (OS). This approach has been tested in the setting of lung cancer, in which consolidation SABR has resulted in OS benefit (HR of 0.40) in phase II studies. The novel approach of local consolidation therapy has not been tested as yet in mCRPC. The secondary objective of this study proposal is to better understand the pattern of disease distribution at first diagnosis of CRPC. Previous studies have used conventional bone scan and CT imaging, and with these investigations the proportion of patients that are 'M0' is  35%1. However, in the new era of PSMA PET, which is far more sensitive than conventional imaging, there exists a new group of men who are M0 on conventional imaging but are M1 on PSMA PET staging. Thus, in the DECREASE study population, we expect the vast majority of patients with conventionally imaged 'M0 CRPC' will have disease detectable on PSMA PET scanning. In this context, the central hypothesis of this trial is that the addition of consolidation radiotherapy to darolutamide to PSMA detected sites of disease will improve the clinical outcome of patients compared to those patients receiving darolutamide alone.

Official Title
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Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA

Conditions
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PSA, Advanced Prostate Carcinoma, Cancer of Prostate, Castrate Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Darolutamide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged 18 years or older. Has provided written Informed Consent for participation in this trial. Histological or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features. Castration-resistant prostate cancer (CRPC) defined as at least 2 consecutive PSA rises obtained at least 1 week apart in the setting of castrate testosterone levels (see below). If the patient has a history of anti-androgen use and recent withdrawal, the most recent PSA value must be obtained at least 4 weeks after anti-androgen withdrawal. Castrate level of serum testosterone (<1.7 nmol/l [50 ng/dl]) on gonadotrophin - releasing hormone (GnRH) agonist or antagonist therapy or after bilateral orchiectomy. Patients who have not undergone bilateral orchiectomy must continue GnRH therapy during the study. A baseline PSA level of at least 2ng per millilitre and a PSA doubling time of 10 months or less. An ECOG performance status score of 0 or 1. Blood counts at screening: haemoglobin ≥9.0 g/dl, absolute neutrophil count ≥1500/μl (1.5×109/l), platelet count ≥100,000/μl (100×109/l) (patient must not have received any growth factor or blood transfusion within 7 days of the haematology laboratory obtained at screening). Screening values of serum alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN (except patients with a diagnosis of Gilbert's disease), creatinine ≤2.0 x ULN. At least 1 site of PSMA-avid disease on PSMA-PET imaging in any of the following regions: Local recurrence within the prostate gland or prostate bed Regional lymph node disease (below the aortic bifurcation) Extra-pelvic lymph node, bone or soft tissue metastatic disease Exclusion Criteria: Patients with detectable metastases or a history of metastatic disease on conventional imaging (whole body bone scan and computed tomography (CT) of the pelvis, abdomen and chest). NOTE: Presence of pelvic lymph nodes <2 cm in short axis below the aortic bifurcation is allowed. Prior treatment with: (1) second-generation androgen receptor (AR) antagonists such as enzalutamide and apalutamide, or darolutamide or other investigational AR antagonists; (2) CYP17 enzyme inhibitors, such as abiraterone acetate and orteronel; or (3) oral ketoconazole. Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) or anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 28 days before randomisation. Use of systemic corticosteroid with a dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomisation. Radiation therapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) within 12 weeks prior to randomisation. Initiation of treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent skeletal-related events within 12 weeks before randomisation. NOTE: Patients receiving osteoclast-targeted therapy to prevent bone loss at a dose and schedule indicated for osteoporosis may continue treatment at the same dose and schedule, providing it was commenced at least 28 days before randomisation. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV. Uncontrolled hypertension as indicated by a systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg at screening. Prior malignancy. NOTE: Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which the last anti-cancer therapeutic intervention has been completed - 5 years ago and from which the patient has been disease-free. Gastrointestinal disorder or procedure that expects to interfere significantly with the absorption of study treatment. Unable to swallow study medications and comply with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darolutamide<br>Darolutimide 600mg BD | Drug: Darolutamide<br>* Darolutamide alone<br>* Other names: NUBEQA, Bayer HealthCare Pharmaceuticals Inc.;|
| Experimental: Local consolidation Radiotherapy + Darolutamide<br>Darolutimide 600mg BD + local consolidative radiotherapy, with a biological equivalent dose of 30Gy/10fx or greater if delivered with SABR. SABR is the preferred treatment approach, however conventional radiotherapy is acceptable. To up to 5 sites of disease | Drug: Darolutamide<br>* Darolutamide alone<br>* Other names: NUBEQA, Bayer HealthCare Pharmaceuticals Inc.;Radiation: Radiotherapy<br>* Darolutamide + Consolidation Radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Undetectable PSA at 12 months | Undetectable PSA at 12 months | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological progression free survival | Radiological progression free survival | 36 months | 
| Distribution of disease on baseline PSMA-PET/CT imaging | Distribution of bone, nodal, visceral and recurrent primary disease on PSMA-PET/CT | 36 months | 
| Biochemical progression free survival | Biochemical progression free survival | 36 months | 
| Treatment related adverse event | Treatment related adverse events (CTCAE v 5.0) | 36 months | 
| Overall survival | Overall survival | 36 months | 
| Patterns of disease on PSMA PET/CT after 12 weeks of commencing Darolutamide, and at time of disease progression | PSMA avid disease at irradiated site / unirradiated site / bone / local / nodal / visceral | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSA, Darolutamide, Consolidation Radiotherapy, PSMA PET, Prostate Cancer, Advanced Prostate Cancer