Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Inclusion Criteria:

• Written informed consent according to Swiss law and ICH GCP E6(R2) regulationsbefore registration and prior to any trial specific procedures

• Histologically or cytologically confirmed diagnosis of adenocarcinoma of theprostate

• Castration resistance: tumor progression after orchiectomy or during treatment withGnRH analogues (agonists or antagonists).

• Non-surgically castrated patient agrees on ongoing use of GnRH analogues (agonistsor antagonists) during the trial

• Metastatic disease, documented by imaging according to PCWG3 criteria

• Measurable disease or bone lesions that are evaluable according to PCWG3 criteria

• One line of previous ARPI therapy (abiraterone, enzalutamide, darolutamide,apalutamide) for at least 18 months within mHSPC setting, showing an at least 50%PSA response or partial remission according to RECIST v1.1

• Progressive disease according to PCWG3 before registration is defined as (at least 2out of 3):

• PSA progression≥ 25% and ≥ 2 ng/mL above nadir (2 consecutive rises at least 3weeks apart)

• New metastatic lesion on imaging (at least two or more new bone lesions on bonescan or one new non-bone lesion)

• Clinical progression

• Patients with a previously treated malignancy are eligible, when the risk of theprior malignancy interfering with either safety or efficacy endpoints is very low

• Age ≥ 18 years

• WHO performance status 0-2

• Adequate bone marrow function: absolute neutrophil count ≥ 1.0 x 109/L, plateletcount ≥ 100 x 109/L, hemoglobin ≥ 90 g/L.

• Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients withGilbert's disease ≤ 3.0 x ULN), ALT and AST ≤ 2.5 x ULN, or ≤ 5 x ULN under theassumption that abnormal values are a result of cancer

• Adequate renal function: estimated glomerular filtration rate (eGFR) > 30mL/min/1.73 m2 (according to CKD-EPI formula)

• Men agree not to donate sperm or to father a child during trial treatment and until 3 months after the last dose of trial treatment

• Patients are able and willing to swallow darolutamide as whole tablet.

Exclusion Criteria:

• Presence of a small cell component

• Prior systemic therapy for metastatic castration-resistant disease

• Prior chemotherapy for mHSPC, except docetaxel

• Prior LuPSMA or radium 223 for prostate cancer

• Concomitant or recent (within 28 days of registration) treatment with any otherexperimental drug

• Concomitant use of other anti-cancer drugs or radiotherapy except for local paincontrol and GnRH analogues

• Severe or uncontrolled cardiovascular disease

• Acute exacerbations of chronic illnesses, serious infections, or major surgerywithin 28 days before expected start of treatment

• Clinical or radiological evidence of current spinal cord compression

• Any concomitant drugs contraindicated for use with darolutamide according to theapproved product information

• Known hypersensitivity to darolutamide

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the GIabsorption or tolerance of darolutamide

• Any other serious underlying medical, psychiatric, psychological, familial orgeographical condition, which in the judgment of the investigator may interfere withthe planned staging, treatment and follow-up, affect patient compliance or place thepatient at high risk from treatment-related complications.