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
Swiss Cancer Institute
162 participants
Oct 22, 2024
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria19
- 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 Criteria13
- 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.
Interventions
Darolutamide will be supplied in bottles as 300 mg film-coated tablets for oral intake
* 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.
Locations(13)
View Full Details on ClinicalTrials.gov
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NCT06401980