Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

NCT ID: NCT06401980

Last Updated: 2025-08-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 162 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-22
• Study Completion Date: 2030-09-30

Brief Summary

Despite improvements in treatment, metastatic prostate cancer remains incurable, especially in the case of pretreated metastatic castration-resistant disease (mCRPC), where treatment options are limited, leading to an unmet need. The paradigm shift in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has affected the treatment landscape for mCRPC patients. Many have already received androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI), making first-line mCRPC treatment challenging.

The Swiss Group for Clinical Cancer Research (SAKK) has shown in previous studies that maintenance treatment with an ARPI, such as darolutamide, can improve radiographic progression-free survival (rPFS) in pretreated mCRPC patients. In the SAKK 08/16 trial, darolutamide maintenance was found to prolong PFS compared to placebo, especially in patients who responded well to prior ARPI treatment.

Based on these findings, the hypothesis is that continued AR-pathway blockade with darolutamide, initiated in patients progressing from mHSPC to mCRPC on ARPI treatment, can improve outcomes when added to standard first-line mCRPC therapy and continued as maintenance. The proposed study aims to evaluate the efficacy of darolutamide, combined with physician-choice standard of care (including taxane chemotherapy, olaparib, radium 223, or LuPSMA), followed by maintenance therapy, on rPFS for patients in the first-line setting of mCRPC.

Detailed Description

Metastatic prostate cancer remains incurable despite several major improvements in the treatment. In the case of pretreated metastatic castration-resistant disease (mCRPC) the options remain scarce and there is still an unmet need in this patient population.

For the majority of patients with metastatic hormone-sensitive prostate cancer (mHSPC) the combination of androgen deprivation (ADT) and ARPI (or even a triplet treatment with ADT, docetaxel and darolutamide or abiraterone) has become standard of care. However, when patients become metastatic castration resistant (mCRPC) over time a change of systemic treatment is necessary and thus this paradigm switch in treatment of mHSPC has had a major impact on treatment of mCRPC patients. Many patients developing metastatic castration-resistant disease these days have not only received ADT but also an ARPI and, in some cases, also docetaxel. Therefore, the treatment options in the first line setting of mCRPC are restricted and the outcome is poorer compared to the past. Improvement of first line mCRPC is an important unmet clinical need.

The SAKK has demonstrated in two earlier studies that maintenance treatment with an ARPI (orteronel in SAKK 08/11 or darolutamide in SAKK 08/16) can improve radiographic progression-free survival in pretreated mCRPC patients after ARPI and/or taxane based. This maintenance concept could be introduced more generally in the first line setting of mCRPC.

In the SAKK 08/16 trial, darolutamide maintenance was shown to prolong progression-free survival (PFS) compared to placebo, in patients with mCRPC who had received prior ARPI, and whose disease did not progress during taxane therapy. This benefit was more pronounced in patients with prior response to ARPI.

Taken together it is hypothesized that the continued AR-pathway blockade with darolutamide in patients progressing from mHSPC to mCRPC on ARPI treatment can improve outcome when it is added to a standard first line mCRPC therapy and then continued as maintenance. SAKK proposes to add the ARPI darolutamide to standard first line mCRPC treatment consisting of either taxane chemotherapy (docetaxel or cabazitaxel), olaparib, radium 223 or LuPSMA. The choice of standard of care treatment is up to the investigator, respecting the country specific approvals. Darolutamide will be given concomitantly with the chosen first line treatment and will be continued as maintenance afterwards until radiographic progression.

Conditions

Metastatic Castration-resistant Prostate Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Experimental

Standard of Care

+ Darolutamide 2 x 600 mg BID until radiographic PD

Group Type: EXPERIMENTAL

Darolutamide

Intervention Type: DRUG

Darolutamide will be supplied in bottles as 300 mg film-coated tablets for oral intake

Arm B: Control

Standard of Care

Group Type: OTHER

Standard of care

Intervention Type: OTHER

• Docetaxel
• Cabazitaxel
• LuPSMA
• Radium 223
• Olaparib, in case of BRCA1 or 2 mutated or HRR deficient tumors

The standard of care is chosen by the local investigator and respecting the country specific approvals.

Interventions

Darolutamide

Darolutamide will be supplied in bottles as 300 mg film-coated tablets for oral intake

Intervention Type: DRUG

Standard of care

• Docetaxel
• Cabazitaxel
• LuPSMA
• Radium 223
• Olaparib, in case of BRCA1 or 2 mutated or HRR deficient tumors

The standard of care is chosen by the local investigator and respecting the country specific approvals.

Intervention Type: OTHER

Other Intervention Names

Nubeqa®

Eligibility Criteria

Inclusion Criteria

• Written informed consent according to Swiss law and ICH GCP E6(R2) regulations before registration and prior to any trial specific procedures
• Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate
• Castration resistance: tumor progression after orchiectomy or during treatment with GnRH analogues (agonists or antagonists).
• Non-surgically castrated patient agrees on ongoing use of GnRH analogues (agonists or 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
• A minimum of 12 months on ADT+ARPI therapy (calculated from ADT initiation) within mHSPC setting, showing an at least 50% PSA response or partial remission according to RECIST v1.1. ARPI change within mHSPC is only allowed for intolerance.
• Progressive disease according to modified PCWG3 before registration is defined as (at least 2 out of 3):

• PSA progression ≥ 25% above nadir (2 consecutive rises at least 3 weeks apart)
• New metastatic lesion on imaging (at least two or more new bone lesions on bone scan or one new non-bone lesion or progression on PSMA-PET/CT according to PROMISE V2 criteria
• Clinical progression
• Patients with a previously treated malignancy are eligible, when the risk of the prior 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, platelet count ≥ 100 x 109/L, hemoglobin ≥ 90 g/L.
• Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), ALT and AST ≤ 2.5 x ULN, or ≤ 5 x ULN under the assumption that abnormal values are a result of cancer
• Adequate renal function: estimated glomerular filtration rate (eGFR) > 30 mL/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 other experimental drug
• Concomitant use of other anti-cancer drugs or radiotherapy except for local pain control and GnRH analogues
• Severe or uncontrolled cardiovascular disease
• Acute exacerbations of chronic illnesses, serious infections, or major surgery within 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 the approved product information
• Known hypersensitivity to darolutamide
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of darolutamide
• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Richard Cathomas, Prof

Role: STUDY_CHAIR

Kantonsspital Graubünden

Ursula Vogl, MD

Role: STUDY_CHAIR

Istituto Oncologico della Svizzera Italiana

Locations

Tumorzentrum Aarau TZA

Aarau, , Switzerland

Site Status: RECRUITING

Kantonsspital Baden

Baden, , Switzerland

Site Status: RECRUITING

Istituto Oncologico della Svizzera Italiana (IOSI)

Bellinzona, , Switzerland

Site Status: RECRUITING

Inselspital

Bern, , Switzerland

Site Status: RECRUITING

Kantonsspital Graubuenden

Chur, , Switzerland

Site Status: RECRUITING

Hôpitaux Universitaires Genève HUG

Geneva, , Switzerland

Site Status: RECRUITING

Centre Hospitalier Universitaire Vaudois CHUV

Lausanne, , Switzerland

Site Status: RECRUITING

Luzerner Kantonsspital

Lucerne, , Switzerland

Site Status: RECRUITING

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

Site Status: RECRUITING

Kantonsspital Winterthur

Winterthur, , Switzerland

Site Status: RECRUITING

OnkoZentrum Zürich - Standort Seefeld

Zurich, , Switzerland

Site Status: RECRUITING

Stadtspital Triemli Zürich

Zurich, , Switzerland

Site Status: RECRUITING

UniversitaetsSpital Zuerich

Zurich, , Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Simone Rahel Wyss-Neyer

Role: CONTACT

trials@swisscancerinstitute.ch

+41 31 389 91 91

Facility Contacts

Konstantinos Tyriakidis, MD

Role: primary

konstantinos.tyriakidis@tumor-zentrum.ch

+41 62 836 78 30

Andreas Erdmann, MD

Role: primary

andreas.erdmann@ksb.ch

+41 56 486 27 62

Ursula Vogl, MD

Role: primary

ursula.vogl@eoc.ch

+41 91 811 84 63

Dilara Akhoundova, MD

Role: primary

dilara.akhoundovasanoyan@insel.ch

+41 31 63 2 03 91

Richard Cathomas, MD

Role: primary

richard.cathomas@ksgr.ch

41-81-256-6695

Petros Tsantoulis, MD

Role: primary

petros.tsantoulis@hcuge.ch

+41 79 553 23 53

Dominik Berthold, MD

Role: primary

dominik.berthold@chuv.ch

+41 21 314 80 83

Christian Rothermundt, MD

Role: primary

christian.rothermundt@luks.ch

+41 41 205 58 60

Stefanie Fischer, MD

Role: primary

stefanie.fischer@kssg.ch

+41 71 494 11 11

Gina Treichler, MD

Role: primary

gina.treichler@ksw.ch

+41 52 266 38 53

Aurelius Omlin, MD

Role: primary

aurelius.omlin@ozh.ch

+41 43 344 33 33

Katharina Hoppe, MD

Role: primary

katharina.hoppe@stadtspital.ch

+41 44 416 34 91

Anja Lorch, Prof

Role: primary

anja.lorch@usz.ch

+41 44 255 22 14

Other Identifiers

SAKK 08/23

Identifier Type: -

Identifier Source: org_study_id