Randomized Phase II Trial on Short Term Darolutamide Concomitant to Radiation Therapy for Patients With Intermediate Unfavorable Risk Prostate Cancer

Phase 2

Recruiting

• Conditions: Prostate Cancer
• Interventions: Drug: Association of ADT and EBRT; Drug: Association of darolutamide and EBRT

• Registration Number: NCT05346848
• Lead Sponsor: Institut Bergonié

Brief Summary

Randomized non-comparative phase II trial to assess the preliminary signs of antitumor activity of darolutamide plus radiation therapy in patients with unfavorable intermediate risk prostate cancer.

Detailed Description

Multicentric randomized non-comparative, open-label, phase II trial, based on signle-stage design, to assess the preliminary signs of antitumor activity of darolutamide plus radiation therapy in patients with unfavorable intermediate risk prostate cancer.

Patients satisfying eligibility criteria will be randomized according to 2 treatment modalities

* Arm A (experimental arm): combination of external beam radiotherapy (EBRT) and 6 months darolutamide.

* Arm B (standard arm): combination of external beam radiotherapy (EBRT) and 6 months ADT (androgen deprivation therapy)

Two patients randomized in arm A for one patient randomized in arm B.

Study Timeline

• Study First Submitted: 2022-04-21
• Study First Submitted QC: 2022-04-21
• Study First Posted: 2022-04-26
• Study Start: 2023-02-24
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-01
• Last Update Posted: 2023-03-03
• Primary Completion: 2025-08
• Study Completion: 2030-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 62

Inclusion Criteria

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 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:

   • Gleason = 7 (4+3)
   • ≥ 50% of thecore of biopsies need to be positive for adenocarcinoma

   If these criteria are not being identified, two or three of the following criteria are necessary to define unfavorable intermediate risk prostate cancer:

   • PSA value between 10-20 ng/ml
   • Gleason 7 (3+4) or 6
   • T2b (clinical or radiological) Note: patients with iT3a can be included only if gleason score is 6 and PSA less than 20 .

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

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.

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Exclusion Criteria

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,
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 orchiectomy
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 as defined in the Protocol
15. Uncontrolled hypertension
16. Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of study drug,
17. Major surgery within 4 weeks prior enrolment except pelvic lymph-nodes dissection,
18. Known hypersensitivity to any involved study drug or of its formulation components, to natural gonadotrophin releasing hormone 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard Arm B: combination of radiotherapy and androgen deprivation therapy	Association of ADT and EBRT	Patients with unfavorable intermediate risk prostate cancer will be treated with androgen deprivation therapy (ADT) as per market authorization combined with external beam radiotherapy
Experimental Arm A: combination of radiotherapy and darolutamide	Association of darolutamide and EBRT	Patients with unfavorable intermediate risk prostate cancer will be treated with darolutamide for a maximum of 6 months combined with external beam radiotherapy

Primary Outcome Measures

Name	Time	Method
Assessment of efficacy in terms of 6-month biological response	6 months after randomization	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria

Secondary Outcome Measures

Name	Time	Method
Assessment of efficacy in terms of biological response at the end of darolutamide or ADT	An expected average of 6 months	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
2-month biological response	2 months after randomization	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
3-month biological response	3 months after the end of radiotherapy	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
2-year biological response	2 years after randomization	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
5-year biological response	5 years after randomization	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
3-year biochemical progression-free survival (bPFS)	3 years	Biochemical progression-free survival is defined as the delay between the date of randomization and the date of biochemical disease progression or death, whichever comes first.
6-month biological response	6 months after the end of radiotherapy	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
9-month biological response	9 months after the end of radiotherapy	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
3-year biological response	3 years after randomization	Biological response is defined as a PSA concentration \<=0.1ng/mL according to Phoenix's criteria
2-year biochemical progression-free survival (bPFS)	2 years	Biochemical progression-free survival is defined as the delay between the date of randomization and the date of biochemical disease progression or death, whichever comes first.
2-year metastasis free survival (MFS)	2 years	Metastasis free survival is defined as the delay between the date of randomization and the date of metastasis diagnosis (imaging and/or biopsy)
5-year biochemical progression-free survival (bPFS)	5 years	Biochemical progression-free survival is defined as the delay between the date of randomization and the date of biochemical disease progression or death, whichever comes first.
3-year metastasis free survival (MFS)	3 years	Metastasis free survival is defined as the delay between the date of randomization and the date of metastasis diagnosis (imaging and/or biopsy)
5-year metastasis free survival (MFS)	5 years	Metastasis free survival is defined as the delay between the date of randomization and the date of metastasis diagnosis (imaging and/or biopsy)
2-year disease free survival (DFS)	2 years	Disease free survival is defined as the delay between the date of randomization and the first of the following events: biological PSA progression defined as level higher than PSA nadir + 2ng/mL according to Phoenix's criteria ; progression (local, regional, distant) or death (any cause)
3-year disease free survival (DFS)	3 years	Disease free survival is defined as the delay between the date of randomization and the first of the following events: biological PSA progression defined as level higher than PSA nadir + 2ng/mL according to Phoenix's criteria ; progression (local, regional, distant) or death (any cause)
5-year disease free survival (DFS)	5 years	Disease free survival is defined as the delay between the date of randomization and the first of the following events: biological PSA progression defined as level higher than PSA nadir + 2ng/mL according to Phoenix's criteria ; progression (local, regional, distant) or death (any cause)
2-year prostate cancer-specific survival (PCSS)	2 years	Prostate cancer-specific Survival is defined as the delay between the date of randomization and the date of prostate cancer-related death
3-year prostate cancer-specific survival (PCSS)	3 years	Prostate cancer-specific Survival is defined as the delay between the date of randomization and the date of prostate cancer-related death
5-year prostate cancer-specific survival (PCSS)	5 years	Prostate cancer-specific Survival is defined as the delay between the date of randomization and the date of prostate cancer-related death
2-year overall survival (OS)	2 years	Overall survival is defined as the delay between the date of randomization and the date of death (all cause).
3-year overall survival (OS)	3 years	Overall survival is defined as the delay between the date of randomization and the date of death (all cause).
5-year overall survival (OS)	5 years	Overall survival is defined as the delay between the date of randomization and the date of death (all cause).
Time to testosterone recovery	An expected average of 6 months	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.
Acute safety profile independently for each treatment strategy	3 months	Toxicity graded using the Common Terminology Criteria for Adverse Events version 5
Late 2-year safety profile independently for each treatment strategy	2 years	Toxicity graded using the Common Terminology Criteria for Adverse Events version 5
Late 3-year safety profile independently for each treatment strategy	3 years	Toxicity graded using the Common Terminology Criteria for Adverse Events version 5
Assessment of quality of life	Throughout the follow-up period, an expected average of 5 years	Quality of life will be assessed as per the EORTC QLQ-C30 questionnaire and prostate cancer module PR-25
Assessment of symptoms of benign prostatic hyperplasia	Throughout the follow-up period, an expected average of 5 years	Symptoms of benign prostatic hyperplasia will be assessed as per IPSS
Late 5-year safety profile independently for each treatment strategy	5 years	Toxicity graded using the Common Terminology Criteria for Adverse Events version 5
Assessment of erectile dysfunction	Throughout the follow-up period, an expected average of 5 years	Erectile dysfunction will be assessed as per IIEF5

Trial Locations

Locations (10)

Institut Bergonie; 🇫🇷 Bordeaux, France

Sainte Catherine, Institut du Cancer Avignon-Provence; 🇫🇷 Avignon, France

CHRU Brest - Hôpital Morvan; 🇫🇷 Brest, France

Assitance Publique des Hôpitaux de Marseille - CHU La Timone; 🇫🇷 Marseille, France

IUCT Oncopôle; 🇫🇷 Toulouse, France

CHP Saint-Grégoire; 🇫🇷 Saint-Grégoire, France

CHRU Besançon; 🇫🇷 Besançon, France

Institut de Cancérologie de l'Ouest - Site René Gauducheau; 🇫🇷 Saint-Herblain, France

Hôpital de la Pitié Salpétrière; 🇫🇷 Paris, France

Clinique Pasteur; 🇫🇷 Toulouse, France