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

Prostate Cancer Clinical Trial

— DASL-HiCaP  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04136353
• Other study ID #: ANZUP1801
• Secondary ID: U1111-1239-0771
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 31, 2020
• Est. completion date: July 31, 2028

Study information

• Verified date: July 2023
• Source: University of Sydney
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

This trial aims to demonstrate that the use of darolutamide (in addition to standard of care) will be more effective than current standard of care in enhancing the ability of prostate or prostate bed radiation and 96 weeks of androgen suppression in decreasing the number of patients who develop metastases and subsequently die of prostate cancer. Darolutamide is a novel antagonist of the AR with favourable tolerability due to negligible penetration of the blood-brain barrier. Emergence of metastatic disease is the lethal event after local therapy, either with prostatectomy or definitive radiation. Augmenting adjuvant systemic therapy (either ADT or ADT plus docetaxel) with darolutamide has the potential to eradicate micrometastatic disease after either type of local therapy and decrease the death rate from prostate cancer.

This pragmatic design incorporates current standard of care for all patients and the option for docetaxel to be added to ADT. As such, the data will be applicable for all patients with very high risk prostate cancer treated with local therapy and will be the first study incorporating docetaxel use as one of the standard of care options. Even if docetaxel is definitively proven to improve MFS and OS in the adjuvant setting, not all patients will be fit for docetaxel. This will be the first trial that has the potential to build upon current and future advances that may emerge and be the most effective strategy to decrease death rate from prostate cancer in the near term if it further augments docetaxel efficacy in chemo-fit patients.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1100
• Est. completion date: July 31, 2028
• Est. primary completion date: January 31, 2028
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Darolutamide
2 x 300mg oral tablets twice daily for 96 weeks
• Placebo oral tablet
2 oral tablets twice daily for 96 weeks
• Luteinizing Hormone-Releasing Hormone Analog
All participants are to receive standard background therapy with an LHRHA, as per standard of care. The choice of LHRHA is at the discretion of the treating clinician.

Radiation:
• External Beam Radiotherapy
All participants are to receive standard background therapy with curative-intent RT to the prostate or prostate bed as well as the pelvic lymph nodes using EBRT.

Locations

Country	Name	City	State
Australia	Border Medical Oncology Research Unit	Albury	New South Wales
Australia	Peter MacCallum Cancer Centre - Bendigo Campus	Bendigo	Victoria
Australia	Peter MacCallum Cancer Centre (Moorabbin Campus)	Bentleigh East	Victoria
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	ROPART	Brisbane	Queensland
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Icon Cancer Centre Hobart	Hobart	Tasmania
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Ashford Cancer Centre Research	Kurralta Park	South Australia
Australia	GenesisCare Cabrini (Gandel Wing), Cabrini Hospital Malvern	Malvern	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Newcastle	New South Wales
Australia	GenesisCare Newcastle	Newcastle	New South Wales
Australia	Shoalhaven District Memorial Hospital	Nowra	New South Wales
Australia	Icon Cancer Centre	Southport	Queensland
Australia	Sunshine Hospital	St Albans	Victoria
Australia	Campbelltown hospital	Sydney	New South Wales
Australia	Chris O'Brien Lifehouse	Sydney	New South Wales
Australia	Liverpool Hospital	Sydney	New South Wales
Australia	Northern Cancer Institute	Sydney	New South Wales
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	St George Hospital	Sydney	New South Wales
Australia	St Vincent's Public Hospital	Sydney	New South Wales
Australia	Sydney Adventist Hospital	Sydney	New South Wales
Australia	Townsville Hospital	Townsville	Queensland
Australia	Latrobe Regional Hospital	Traralgon	Victoria
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Canada	Western Manitoba Cancer Centre - Prairie Mountain Health	Brandon	Manitoba
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Centre Integre de Sante et de Services Sociaux de la Monteregie Centre	Greenfield Park	Quebec
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Queen Elizabeth II Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Centre Hospitalier Regional de Trois-Rivieres	Quebec
Canada	Hôtel-Dieu de Québec	Québec	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Regional Health Authority B, Zone 2 Saint John Regional Hospital	Saint John	New Brunswick
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Sault Area Hospital - Algoma District Cancer Program	Sault Ste Marie	Ontario
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec
Canada	Dr. H. Bliss Murphy Cancer Centre, St. John's	St. John's	Newfoundland and Labrador
Canada	BC Cancer Agency (BCCA) Fraser Valley	Surrey	British Columbia
Canada	Odette Cancer Centre - Sunnybrook Hospital	Toronto	Ontario
Canada	Ottawa Hospital Research Institute	Toronto	Ontario
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Ireland	Bon Secours Hospital Cork in association with UPMC Hillman Centre	Cork
Ireland	Cork University Hospital	Cork
Ireland	Beacon Private Hospital Dublin	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	Mater Private Dublin	Dublin
Ireland	St Luke's Radiation Oncology Network at St James's Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Ireland	Galway University Hospital	Galway
Ireland	St. Luke's Hospital	Rathgar	Dublin 6
New Zealand	Auckland City Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Palmerston North Hospital	Palmerston North
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	William Harvey Hospital	Ashford
United Kingdom	Royal United Hospital Bath	Bath
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Kent and Canterbury Hospital	Canterbury
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Guy's and St Thomas Hospital	London
United Kingdom	Royal Marsden Hospital	London
United Kingdom	Nottingham University Hospitals NHS Trust - Nottingham City Hospital	Nottingham
United States	New Mexico Oncology and Hematology Specialists	Albuquerque	New Mexico
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Dana Farber Cancer Institute - St. Elizabeth's	Brighton	Massachusetts
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	New Jersey Urology Saddle Brook	Clifton	New Jersey
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Dayton Physicians Network	Kettering	Ohio
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Dana Farber Cancer Institute - Milford	Milford	Massachusetts
United States	New York University Langone Long Island	Mineola	New York
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	XCancer Omaha/Urology Cancer Center	Omaha	Nebraska
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	New Jersey Urology Voorhees	Voorhees	New Jersey

Sponsors (7)

Lead Sponsor	Collaborator
University of Sydney	Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Bayer, Canadian Cancer Trials Group, Cancer Trials Ireland, Memorial Sloan Kettering Cancer Center, Prostate Cancer Clinical Trials Consortium

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Ireland,  New Zealand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Metastasis-free survival	Evidence of metastases includes findings on WBBS or CT or MRI (as reported by the site investigator) that are either characteristic of metastatic prostate cancer, and/or confirmed by other test results e.g. cytology or histopathology.	Through study completion, an average of 5 years
Secondary	Overall survival	Overall survival is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known follow-up alive.	Through study completion, an average of 5 years
Secondary	Prostate cancer-specific survival	Prostate cancer-specific survival is defined as the interval from the date of randomisation to the date of last known follow-up alive, or the date of death from prostate cancer. Deaths from other causes will be summarised.	Through study completion, an average of 5 years
Secondary	PSA-progression free survival	For participants who receive definitive radiotherapy (i.e. without radical prostatectomy), PSA progression is defined by the Phoenix criteria (requires confirmation by a repeat PSA performed at least 3 weeks later). For participants who have undergone a radical prostatectomy, an increase in PSA of >0.2 ng/mL above the nadir would be considered PSA progression (requires confirmation by a repeat PSA performed at least 3 weeks later).	Through study completion, an average of 5 years
Secondary	Time to subsequent hormonal therapy	Time to subsequent hormone therapy is the interval from randomisation to the first date that endocrine therapy is recommenced or changed for the treatment of recurrent (or progressive) prostate cancer.	Through study completion, an average of 5 years
Secondary	Time to castration-resistance	Defined according to the PCWG3 criteria. If a participant has radiographic progression without serological progression, this will also be deemed castration resistant prostate cancer	Through study completion, an average of 5 years
Secondary	Frequency and severity of adverse events (CTCAE v5.0, RTOG/EORTC acute/late radiation morbidity criteria)	Safety reporting will describe the frequency and severity of AEs. The CTCAE v5.0 will be used to classify and grade the intensity of AEs occurring until 30 days after the last dose of study treatment. The RTOG/EORTC Scoring Criteria will be used to assess morbidities related to radiation therapy (RT) until 6 years after randomisation. Acute AEs are those occurring within 90 days after starting RT, and will be classified and graded according to the RTOG/EORTC Acute Radiation Morbidity Scoring Criteria. Late AEs are those occurring more than 90 days after starting RT, and will be classified and rated according to the RTOG/EORTC Late Radiation Morbidity Scoring Schema.	Approximately 12-weekly for 2 years from randomisation until 30 days after the last dose of study treatment.
Secondary	Health-related quality of life	EORTC Core Quality of Life Questionnaire (QLQC-30). Importance of quality of life issues are assessed using a four-point scale (1 = not at all, 4 = very much); EORTC Quality of Life Questionnaire for Prostate Cancer (PR-25). Importance of quality of life issues are assessed using a four-point scale (1 = not at all, 4 = very much); Euroqol 5 item preference-based measure of health (EQ-5D-5L), comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100.	Through study completion, an average of 5 years
Secondary	Fear of cancer recurrence	Using the Fear of Cancer Recurrence Inventory (FCRI), a 42-item questionnaire with scores of 0 (never/not at all) - 4 (all the time/a great deal) for each.	Through study completion, an average of 5 years