DARIUS : A randomized non-comparative phase II multicentric trial on short term DARolutamide (ODM-201) concomitant to radiation therapy for patients with Intermediate Unfavorable risk proState cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Feb 2023 → ongoing

Decision date (initial)

2024-08-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509494-23-00

EudraCT number

2022-002431-53

ClinicalTrials.gov

NCT05346848

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Pharmacogenomic, Efficacy, Safety

- To assess the preliminary signs of antitumor activitity of darolutamide when prescribed for 6 months in association with radiotherapy in patients with unfavorable intermediate risk prostate cancer.
- Activity will be measured in terms of biological response defined as PSA ≤0.1ng/ml and measured 6 months after randomization.

Secondary objectives 5

1. To assess the preliminary signs of antitumor activitity of ADT when prescribed for 6 months in association with radiotherapy in patients with unfavorable intermediate risk prostate cancer. Activity will be measured in terms of biological response defined as PSA ≤0.1ng/ml and measured 6 months after randomization.
2. Independently for each treatment strategy: assessment of antitumor activity in terms of additional efficacy entpoints: a) Biological response (PSA ≤0.1ng/ml) measured a. at the end of darolutamide or ADT, b. 2 months following randomization, c. 3, 6 and 9 post-radiotherapy, d. 2, 3 and 5 years following randomization b) Biochemical Progression-free survival (bPFS), c) Metastases-free survival (MFS), d) Disease-free survival (DFS), e) Prostate cancer-specific survival (PCSS), f) Overall-survival, g) Time to testosterone recovery.
3. Independently for each treatment strategy: Assessment of the safety profile of the therapeutic strategy.
4. Independently for each treatment strategy: Assessment of the quality of life before, during and after treatment.
5. Ancillary Studies: h) Radiomics analysis evaluating response predictive factors (PI: Pr Ulrike Schike, Latim, Brest), testosterone level lowering and recovery, bone mineral density and score FRAX evolution at M12 and M24 after treatment initation; follicle stimulating hormone (FSH) and luteinizing hormone (LH) level at at 3, 6, 9 and 15 months post radiotherapy. i) FFPE tumor samples will be collected at baseline to assess prognostic value of DECIPHER test in this setting compared to d’Amico and Zumsteg criteria

Conditions and MedDRA coding

Adult patients with intermediate unfavorable risk prostate cancer as per NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines Prostate Cancer. Version 2.2021)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥ 18,
2. Histological diagnosis of prostate malignancy cancer
3. Cancer without loco-regional or distant metastasis (tumor assessment must comprise at least Pelvic MRI AND thoraco-abdomino-pelvic contrast-enhanced CT-Scan AND Bone Scintigraphy. (Note that 1) a contrast-injected scintigraphy or a PET-CT scan with injection of choline or PSMA product can replace bone scintigraphy and the TAP scan, 2) additional assessment by PET-Scan is allowed as per investigator judgement),
4. Unfavorable intermediate risk prostate cancer diagnosis defined by the NCCN Guidelines. One of the following criteria is sufficient to define an unfavorable intermediate risk prostate cancer: a) Gleason = 7 (4+3) b) ≥ 50% of thecore of biopsies need to be positive for adenocarcinoma. Note that in case of targeted biopsy, this criterion is valide only if randomized biopsies were also performed. If these criteria are not being identified, two or three of the following criteria are necessary to define unfavorable intermediate risk prostate cancer: c) PSA value between 10-20 ng/ml d) Gleason 7 (3+4) or 6 e) T2b (clinical or radiological) Note: patients with iT3a (extraprostatic extension) can be included only if gleason score is 6 and PSA less than 20 [22].
5. Patients newly diagnosed with an unfavorable intermediate risk prostate cancer according to the protocol criteria or previously diagnosed with low risk (Gleason score < 6, clinical stage < T2a, and PSA< 10) prostate cancer progressing to eligible risk disease according to the protocol criteria within 30 days before registration
6. Patients must have a life expectancy of at least 5 years,
7. Performance status ECOG ≤ 2,
8. Patients without contra-indications to EBRT as per physician judgement,
9. Patients with adequate organ function defined by all the following laboratory values (< ULN (Upper Limit of Normal)) : 1. Hemoglobin ≥ 9 g/dL, 2. Neutrophils ≥ 1.5 G/L 3. Platelets ≥ 80 G/L 4. Total bilirubin < 2X ULN 5. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN 6. Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula)
10. Available archived paraffin-embedded tumor sample for research purpose,
11. Patients with a social security in compliance with the french law,
12. Voluntary signed and dated written informed consent prior to any study specific procedure,
13. Men must agree to use an effective method of contraception throughout the treatment period and for one week after discontinuation of treatment. Acceptable methods of contraception are described in protocol section 7.1.4.

Exclusion criteria 25

1. Stage T3b-T4 prostate cancer by clinical examination or radiologic evaluation,
2. Patients with Gleason score ≥8,
3. Patients with PSA >20 ng/ml,
4. Presence of loco-regional or distant metastasis (MRI/CT-Scan and Bone Scintigraphy),
5. Contra-indications to MRI and to contrast-enhanced CT-scan,
6. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone less than 50 ng/dL or below the normal range for the institution.
7. Previous prostate cancer treated by androgen deprivation, chemotherapy, surgery, or radiotherapy,
8. Patients with previous bilateral orchidectomy
9. Patients actively receiving or having received within 6 months prior enrollment any concurrent androgens, anti-androgens, estrogens, or progestational agents,
10. Patients having received ketoconazole, finasteride or dutasteride within 30 days of inclusion,
11. Previous and current malignancies other than prostate cancer within the last 5 years with the exception of adequately treated basal cell or squamous cell carcinoma of the skin, acute lymphoblastic leukemia, non-muscle invasive bladder cancer,
12. Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection),
13. History of cerebrovascular accident (within the last 6 months)
14. Impaired cardiac function including any one of the following: o Clinically documented myocardial infarction (within the last 6 months) o History of severe/unstable angina (within the last 6 months) o History of peripheral artery/coronary bypass surgery (within the last 6 months) o History of or presence of congestive heart failure according to the New York Heart Association (NYHA) class 3 or 4 with LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram or multi-gated acquisition scan performed in the last 6 months o History of or presence of risk factors for QT interval prolongation o History of or presence of clinically significant ventricular or atrial tachy-arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes) o Clinically significant resting bradycardia (< 50 beats per minute) o History of Mobitz II second degree or third degree heart block without use of ventricular-paced pacemaker o History of or presence of clinically significant hypotension (e.g. systolic blood pressure < 86 mmHg on 2 consecutive measurements) o ECG demonstrating equal to or greater than grade III toxicity according the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Note: patients with cardiac disease controlled under treatment are eligible.
15. Uncontrolled hypertension
16. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery),
17. Major surgery within 4 weeks prior enrolment except pelvic lymph-nodes dissection (extended or limited),
18. Known hypersensitivity to any involved study drug or of its formulation components, to natural gonadotrophin releasing hormone (GnRH) or its analogues
19. Galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome
20. Men who are not using an effective method of contraception as previously described
21. Use of herbal or alternative remedies that may affect hormonal status such as Prostasol or PC-SPES,
22. History of non-compliance to medical regimens or inability to grant consent,
23. Patient unable to follow and comply with the study procedures because of any geographical, social or psychpsychological reasons,
24. Individuals under judicial protection or deprived of liberty.
25. Inability to swallow or to give subcutaneous or intramuscular injections.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy will be assessed in terms of biological response defined as a PSA concentration ≤0.1ng/ml at 6 months post-randomization [23-24].

Secondary endpoints 11

1. Biochemical disease progression is defined asa PSA level higher than PSA nadir + 2 ng/mL according to Phoenix’s criteria [27].
2. Biochemical progression-free survival (bPFS) is defined as the delay between the date of randomization and the date of biochemical disease progression or death, whichever comes first. Median bPFS, as well as 2-, 3-, and 5-year bPFS will be reported.
3. Metastasis Free Survival (MFS) is defined as the delay between the date of randomization and the date of metastasis diagnosis (imaging and/or biopsy). Median MFS, as well as 2-, 3- and 5-year MFS will be reported.
4. Disease Free Survival (DFS) is defined as the delay between randomization and the first of the following events:  biological PSA progression defined as level higher than PSA nadir + 2 ng/mL according to Phoenix’s criteria  progression (local, regional, distant)  death (any cause).Median DFS, as well as 2-, 3- and 5-year DFS will be reported.
5. Prostate cancer-specific Survival (PCSS) is defined as the delay between the date of randomization and the date of prostate cancer-related death. Median PCSS, as well as 2-, 3- and 5-year PCSS will be reported.
6. Overall survival is defined as the delay between the date of randomization and the date of death (all cause). Median OS, as well as 2-, 3- and 5-year OS will be reported.
7. Time to testosterone recovery defined as the time from randomization to the time when serum of total testosterone level increases to above the lower limit of the normal range.
8. The safety profile (acute, i.e. < 3 months and late 2-, 3- and 5-year) of each treatment strategy will be graded using NCI CTCAE v5. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
9. Quality of life will be assessed as follows (M0, M3, M6, M12, M24, M60): o As per the EORTC QLQ-C30 questionnaire and prostate cancer module PR-25 o Assessment of erectile dysfunction, as per IIEF5 [41], o Assessement of symptoms of benign prostatic hyperplasia as per IPSS questionnaire [42]
10. ANCILLARY STUDY : MRI Radiomics efficacy predictive factors exploratory analysis; testosterone level lowering and recovery at 3, 6 and 9 months post radiotherapy, bone mineral density and score FRAX evolution at M12 and M24 after treatment initiation, FSH and LHlevel at 3, 6, 9 and 15 months post radiotherapy. MRI radiomics efficacy will be centrally analyzed based on multiparametric MRI performed at baseline and M6 (Pr Ulrike Schike, LATIM, Brest).
11. ANCILLARY STUDY : FFPE tumor samples will be collected at baseline to assess prognostic value of DECIPHER test in this setting compared to d’Amico and Zumsteg criteria.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 15

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Dr Guilhem ROUBAUD

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore Barthod-Malat

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications