Clinical trial NCT06401980: Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Official title: Addition of Darolutamide to First Line Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): a Randomized Open Label Phase II Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Metastatic Castration-Resistant Prostate Cancer
mCRPC
Darolutamide
phase II trial
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2024-05-07
Enrollment: 162
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: International, randomized, open label, phase II study.
Primary purpose: TREATMENT

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.

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
* 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 2 out of 3):

  * PSA progression≥ 25% and ≥ 2 ng/mL 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)
  * 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.

Primary outcomes:
measure: Radiographic progression-free survival (rPFS)
timeFrame: 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 outcomes:
measure: Overall survival (OS)
timeFrame: From the date of randomization until the date of death from any cause, assessed up to 2 years after end of treatment.
measure: Time to symptomatic/clinical progression
timeFrame: From date of randomization until the date of symptomatic/clinical progression, assessed up to 2 years after end of treatment
measure: Time to PSA progression
timeFrame: From date of randomization until the date of PSA progression, assessed up to 2 years after end of treatment.
measure: Event-free survival (EFS)
timeFrame: From date of randomization until the date of the event of interest, assessed up to 2 years after end of treatment.
measure: Objective response rate according to RECIST
timeFrame: From the date of randomization until date of the end of treatment, estimated up to 2 years after registration
measure: PSA response (30%, 50%, 90% and best)
timeFrame: From the date of randomization until the end of treatment, estimated up to 2 years after registration.
measure: Duration of PSA response (50%)
timeFrame: From the date of randomization until the date of PSA progression, assessed up to 2 years after end of treatment.
Other outcomes:
Locations:
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana (IOSI)
city: Bern
country: Switzerland
facility: Inselspital
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires Genève HUG
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois CHUV
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
city: Zürich
country: Switzerland
facility: OnkoZentrum Zürich - Standort Seefeld
city: Zürich
country: Switzerland
facility: Stadtspital Triemli Zürich
Study officials:
affiliation: Kantonsspital Graubünden
name: Richard Cathomas, Prof
role: STUDY_CHAIR
affiliation: Istituto Oncologico della Svizzera Italiana
name: Ursula Vogl, MD
role: STUDY_CHAIR
References: