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Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA (DECREASE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04319783
Recruitment Status : Recruiting
First Posted : March 24, 2020
Last Update Posted : September 1, 2021
Peter MacCallum Cancer Centre, Australia
Information provided by (Responsible Party):
Trans Tasman Radiation Oncology Group

Tracking Information
First Submitted Date  ICMJE March 9, 2020
First Posted Date  ICMJE March 24, 2020
Last Update Posted Date September 1, 2021
Actual Study Start Date  ICMJE June 2, 2021
Estimated Primary Completion Date June 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2020)
Undetectable PSA at 12 months [ Time Frame: 12 months ]
Undetectable PSA at 12 months
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2020)
  • Radiological progression free survival [ Time Frame: 36 months ]
    Radiological progression free survival
  • Distribution of disease on baseline PSMA-PET/CT imaging [ Time Frame: 36 months ]
    Distribution of bone, nodal, visceral and recurrent primary disease on PSMA-PET/CT
  • Biochemical progression free survival [ Time Frame: 36 months ]
    Biochemical progression free survival
  • Treatment related adverse event [ Time Frame: 36 months ]
    Treatment related adverse events (CTCAE v 5.0)
  • Overall survival [ Time Frame: 36 months ]
    Overall survival
  • Patterns of disease on PSMA PET/CT after 12 weeks of commencing Darolutamide, and at time of disease progression [ Time Frame: 3 months ]
    PSMA avid disease at irradiated site / unirradiated site / bone / local / nodal / visceral
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA
Official Title  ICMJE Darolutamide + Consolidation Radiotherapy in Advanced Prostate Cancer Detected by PSMA
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Prostate Carcinoma
  • Cancer of Prostate
  • PSA
  • Castrate Resistant Prostate Cancer
Intervention  ICMJE
  • Drug: Darolutamide
    Darolutamide alone
    Other Name: NUBEQA, Bayer HealthCare Pharmaceuticals Inc.
  • Radiation: Radiotherapy
    Darolutamide + Consolidation Radiotherapy
Study Arms  ICMJE
  • Experimental: Darolutamide
    Darolutimide 600mg BD
    Intervention: Drug: Darolutamide
  • Experimental: Local consolidation Radiotherapy + Darolutamide
    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
    • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 22, 2020)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2026
Estimated Primary Completion Date June 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Castration-resistant prostate cancer
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rebecca Montgomery +61 2 4014 3910
Contact: Rebekah Di Rico +61 2 4014 3915
Listed Location Countries  ICMJE Australia
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04319783
Other Study ID Numbers  ICMJE TROG 19.06
U1111-1242-9233 ( Other Identifier: UTN- World Health Organisation )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Trans Tasman Radiation Oncology Group
Study Sponsor  ICMJE Trans Tasman Radiation Oncology Group
Collaborators  ICMJE
  • Bayer
  • Peter MacCallum Cancer Centre, Australia
Investigators  ICMJE
Study Chair: Shankar Siva Peter MacCallum Cancer Centre, Australia
Study Chair: Arun Azad Peter MacCallum Cancer Centre, Australia
PRS Account Trans Tasman Radiation Oncology Group
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP