Extreme Bipolar Androgen Therapy With Darolutamide and Testosterone Cypionate in Patients With Metastatic Castration-Resistant Prostate Cancer (ExBAT Trial)

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.

What this study is about