Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Addition of Darolutamide to First Line Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): a Randomized Open Label Phase II Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: Darolutamide; Other: Standard of care

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.

• Study Type: Interventional
• Enrollment (Estimated): 162
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Simone Rahel Wyss-Neyer; Phone Number: +41 31 389 91 91; Email: trials@swisscancerinstitute.ch

Study Locations

• Switzerland
  • Aarau, Switzerland, 5000
    • Recruiting
    • Tumorzentrum Aarau TZA
    • Contact: Konstantinos Tyriakidis, MD; Phone Number: +41 62 836 78 30; Email: konstantinos.tyriakidis@tumor-zentrum.ch
    • Principal Investigator: Konstantinos Tyriakidis, MD
  • Baden, Switzerland, 5404
    • Recruiting
    • Kantonsspital Baden
    • Contact: Andreas Erdmann, MD; Phone Number: +41 56 486 27 62; Email: andreas.erdmann@ksb.ch
    • Principal Investigator: Andreas Erdmann, MD
  • Bellinzona, Switzerland, 6500
    • Recruiting
    • Istituto Oncologico Della Svizzera Italiana (IOSI)
    • Contact: Ursula Vogl, MD; Phone Number: +41 91 811 84 63; Email: ursula.vogl@eoc.ch
    • Principal Investigator: Ursula Vogl, MD
  • Bern, Switzerland
    • Recruiting
    • Inselspital
    • Contact: Dilara Akhoundova, MD; Phone Number: +41 31 63 2 03 91; Email: dilara.akhoundovasanoyan@insel.ch
    • Principal Investigator: Dilara Akhoundova Dilara Akhoundova, MD
  • Chur, Switzerland, 7000
    • Recruiting
    • Kantonsspital Graubuenden
    • Contact: Richard Cathomas, MD; Phone Number: 41-81-256-6695; Email: richard.cathomas@ksgr.ch
    • Principal Investigator: Richard Cathomas, MD
  • Geneva, Switzerland, 1211
    • Recruiting
    • Hôpitaux Universitaires Genève HUG
    • Contact: Petros Tsantoulis, MD; Phone Number: +41 79 553 23 53; Email: petros.tsantoulis@hcuge.ch
    • Principal Investigator: Petros Tsantoulis, MD
  • Lausanne, Switzerland, CH-1011
    • Recruiting
    • Centre Hospitalier Universitaire Vaudois CHUV
    • Contact: Dominik Berthold, MD; Phone Number: +41 21 314 80 83; Email: dominik.berthold@chuv.ch
    • Principal Investigator: Dominik Berthold, MD
  • Lucerne, Switzerland, 6004
    • Recruiting
    • Luzerner Kantonsspital
    • Contact: Christian Rothermundt, MD; Phone Number: +41 41 205 58 60; Email: christian.rothermundt@luks.ch
    • Principal Investigator: Christian Rothermundt, MD
  • Sankt Gallen, Switzerland
    • Recruiting
    • Kantonsspital St. Gallen
    • Contact: Stefanie Fischer, MD; Phone Number: +41 71 494 11 11; Email: stefanie.fischer@kssg.ch
    • Principal Investigator: Stefanie Fischer, MD
  • Winterthur, Switzerland, 8401
    • Recruiting
    • Kantonsspital Winterthur
    • Contact: Gina Treichler, MD; Phone Number: +41 52 266 38 53; Email: gina.treichler@ksw.ch
    • Principal Investigator: Gina Treichler, MD
  • Zurich, Switzerland, 8091
    • Recruiting
    • UniversitaetsSpital Zuerich
    • Principal Investigator: Anja Lorch, Prof
    • Contact: Anja Lorch, Prof; Phone Number: +41 44 255 22 14; Email: anja.lorch@usz.ch
  • Zurich, Switzerland, 8063
    • Recruiting
    • Stadtspital Triemli Zürich
    • Contact: Katharina Hoppe, MD; Phone Number: +41 44 416 34 91; Email: katharina.hoppe@stadtspital.ch
    • Principal Investigator: Katharina Hoppe, MD
  • Zurich, Switzerland, 8038
    • Recruiting
    • OnkoZentrum Zürich - Standort Seefeld
    • Contact: Aurelius Omlin, MD; Phone Number: +41 43 344 33 33; Email: aurelius.omlin@ozh.ch
    • Principal Investigator: Aurelius Omlin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Experimental; Standard of Care + Darolutamide 2 x 600 mg BID until radiographic PD	Drug: Darolutamide; Darolutamide will be supplied in bottles as 300 mg film-coated tablets for oral intake; Other Names: Nubeqa®
Other: Arm B: Control; Standard of Care	Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Radiographic progression-free survival (rPFS)	From the date of randomization until the date of radiographic disease progression or death from any cause, assessed up to 2 years after end of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS is defined as the time from randomization until death due to any cause. Patients not experiencing an event (death) will be censored at the last date they were known to be alive.	From the date of randomization until the date of death from any cause, assessed up to 2 years after end of treatment.
Time to symptomatic/clinical progression	Time to symptomatic/clinical progression is defined as the time from randomization to the time point of symptomatic/clinical progression. Patients not experiencing an event will be censored at the date of the last visit before initiation of a new anti-cancer treatment, if any. Symptomatic/clinical progression is defined by one of the following: Occurrence of a SRE due to bone metastases, defined as pathologic fracture, spinal cord compression, palliative radiation to bone, or surgery to bone; Treating physician decides for intervention due to new disease related complications (e.g., urinary obstruction, hydronephrosis)	From date of randomization until the date of symptomatic/clinical progression, assessed up to 2 years after end of treatment
Time to PSA progression	Time to PSA progression is defined as the time from randomization to the time point of PSA progression. Patients not experiencing an event will be censored at the date of the last available PSA assessment before initiation of a new anti-cancer treatment, if any. PSA progression is defined as:	From date of randomization until the date of PSA progression, assessed up to 2 years after end of treatment.
Event-free survival (EFS)	Event-free survival is defined as the time from randomization until the event of interest. Patients not experiencing an event will be censored at the date of the last available assessment before initiation of a new anti-cancer treatment, if any	From date of randomization until the date of the event of interest, assessed up to 2 years after end of treatment.
Objective response rate according to RECIST	Objective response is defined as any complete response (CR) or partial response (PR) according to RECIST 1.1 criteria (Appendix 1) achieved during treatment. Any patient with CR or PR as best observed response during treatment will be considered as a success; otherwise they will be considered as a failure. Patients without any tumor assessment or with non-evaluable response (NE) during treatment will be considered as failures for this endpoint.	From the date of randomization until date of the end of treatment, estimated up to 2 years after registration
PSA response (30%, 50%, 90% and best)		From the date of randomization until the end of treatment, estimated up to 2 years after registration.
Duration of PSA response (50%)	Duration of PSA response is defined as the time from appearance of 50% PSA response during treatment to the time point of PSA progression. Definition of PSA progression is provided above. In case the patient does not experience PSA progression, the patient will be censored at the last PSA assessment before starting a new anti-cancer treatment, if any. This endpoint will be calculated for the subgroup of patients achieving 50% PSA response.	From the date of randomization until the date of PSA progression, assessed up to 2 years after end of treatment.

Collaborators and Investigators

• Sponsor: Swiss Cancer Institute
• Investigators: Study Chair: Richard Cathomas, Prof, Kantonsspital Graubunden; Study Chair: Ursula Vogl, MD, Istituto Oncologico della Svizzera Italiana

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2024
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: May 2, 2024
• First Submitted That Met QC Criteria: May 2, 2024
• First Posted (Actual): May 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: mCRPC; phase II trial; Metastatic Castration-Resistant Prostate Cancer; Darolutamide
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; darolutamide; Standard of Care
• Other Study ID Numbers: SAKK 08/23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No