This is a multi-center, open-label, phase II, single-arm trial evaluating combination of darolutamide and high testosterone doses - extreme bipolar androgen therapy (ExBAT) - in patients with metastatic castration-resistant prostate cancer (mCRPC).

This is a multi-center, open-label, phase II, single-arm trial evaluating combination of darolutamide and high testosterone doses - extreme bipolar androgen therapy (ExBAT) - in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after abiraterone. Extreme androgen therapy will include alternating 56-day cycles of darolutamide 1,200mg/day (two 300 tablets every 12 hours) p.o. for 28 days followed by testosterone cypionate 400 mg i.m. During the treatment period, patients will be followed with chest, abdomen and pelvis CT and bone scan every 8-9 weeks until cycle 4 and every 12 weeks thereafter during the study period. Patients who present with disease progression but are considered to be benefiting from the treatment may continue receiving it, but will be followed by their treating physician according to local guidelines (follow-up period). All patients who stopped treatment will enter follow-up period and survival data will be collected from medical charts. Additionally, QoL questionnaires (BPI-SF, EQ-5D-3L and FACT-P) will be applied every 8-9 weeks until the end of treatment.

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.

2. Male aged 18 years and above.

3. Histologic confirmation of adenocarcinoma of the prostate.

4. Evidence of M1 metastatic disease (as defined by AJCC criteria) on previous bone, CT, and/or MRI scan.

5. Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) analogue or bilateral orchiectomy (ie, surgical or medical castration) confirmed by testosterone level below 50 ng/dL at the screening visit. Castrate levels of testosterone must be maintained by surgical or medical means (luteinizing hormone-releasing hormone [LHRH]/ GnRH analogues) throughout the conduct of the study.

6. Documented prostate cancer progression as per PCWG3 criteria1-3 with at least one of the following:

   • PSA progression: defined by a minimum of 2 rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the screening visit should be ≥ 2 ng/mL.* Participants who received an anti-androgen must have progression after withdrawal (4 weeks since last flutamide, bicalutamide or nilutamide administration)
   • Radiographic disease progression in soft tissue based on RECIST 1.1 criteria. Participants whose disease spread is limited to regional pelvic lymph nodes will be considered eligible.
   • Radiographic disease progression in bone defined as appearance of 2 or more new bone lesions on bone scan.

7. ECOG performance status 0-1.

8. Participants who are chemotherapy-naive for mCRPC who have received prior treatment with abiraterone acetate for advanced prostate cancer (M1 castration-sensitive or M1 castration-resistant settings). Abiraterone should be stopped at least 14 days prior to study treatment initiation.

9. Participants already receiving agents for the management of skeletal-related events (SREs) are allowed to continue with anti-bone resorptive therapy (including, but not limited to bisphosponate or receptor activator of nuclear factor kappa ligand inhibitor) if on stable dose for more than 28 days prior to treatment arm assignment.

10. Prior prostate cancer vaccine therapy, radiation therapy, radium-223, anti-androgens (eg, flutamide), ketoconazole, and diethylstilbestrol (DES) or other estrogens, are allowed up to 28 days prior to study arm assignment.

11. Asymptomatic or minimally symptomatic mCRPC according to Brief Pain Inventory - Short Form (BPI-SF) performed during screening: asymptomatic is defined as BPI-SF item #3 score of 0 to 1; minimally symptomatic is defined as BPI-SF item #3 score of 2 to 4.

12. Patients must agree to refrain from donating sperm during the course of this study and for at least 1 week after completion of study therapy.

13. Sexually active male subjects with female partners of childbearing potential must agree to use an adequate method of contraception as outlined in "Section 5.3.4 Contraception" during the course of the study treatment with Darolutamide and for 1 week after last dose.

14. Sufficient tumor tissue obtained prior to enrollment from a metastatic tumor lesion or from a primary tumor lesion (formalin fixed paraffin-embedded [FFPE] block or unstained tumor tissue sections). Tumor sample may be from core biopsy, punch biopsy, excisional biopsy, or surgical specimen). For patients without an available archival sample prior to study entry, enrolment without tissue provision will be allowed.

Exclusion Criteria:

1. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the breast.

2. Participants with active brain metastases. Participants with brain metastases are eligible to enroll in this study if brain metastases have been treated and there is no magnetic resonance imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration.

3. Participants must have recovered from the effects of major surgery requiring general anesthesia or significant traumatic injury at least 14 days before treatment arm assignment.

4. Prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥ 12 months elapsed from last dose of docetaxel.

5. Prior treatment with enzalutamide, apalutamide, darolutamide or any 2nd generation anti-androgen for prostate cancer.

6. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent or completing quality of life questionnaires.

7. Participants with serious or uncontrolled medical disorders that, in the opinion of the investigator, would impair the ability of the participant to receive protocol therapy or obscure the interpretation of AEs.

8. Patients who are unable to swallow oral medications.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

10. History of acute myocardial infarction (AMI), cerebrovascular accident and/or coronary artery stent or bypass surgery within 6 months of study entry.

11. Gastrointestinal disorders likely to interfere with absorption of the study medication.

12. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.

13. Uncontrolled hypertension despite medical management as indicated by systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at the screening visit. Patients may be re-screened after adjustments of anti- hypertensive medications.

14. Inadequate organ function and laboratory tests as follows:

    • WBC < 2.0 x 109/L; Neutrophils < 1.5 x 109/L; Platelets <100x109/L; Hemoglobin < 9.0 g/dL (no history of red blood cell transfusion within 4 weeks prior to study entry).
    • Serum creatinine > 2x ULN unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockroft-Gault formula).
    • AST or ALT: > 3.0 x ULN; Total bilirubin >1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0x ULN).

15. History of allergy or hypersensitivity to study drug components.

16. Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up.