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

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

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.

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.

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.

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.