Docetaxel or Cabazitaxel With or Without Darolutamide in mCRPC

Phase 2RecruitingNCT05762536

Erasmus Medical Center245 enrolled

Overview

Taxane efficacy in metastatic prostate cancer is modest due to resistance development. Several clinical phase III studies in metastatic castration-naïve prostate cancer (mCNPC) patients have shown that adding an androgen receptor signalling inhibitor (ARSi) to patients receiving a taxane and androgen deprivation therapy (ADT) improves survival endpoints. Adding ARSi darolutamide to docetaxel+ADT in mCNPC patients resulted in a robust OS benefit (HR 0.68). Importantly, the combination of a taxane and darolutamide is not prone to a drug-drug interaction, while there is a detrimental CYP3A4 inducing effect in the case of enzalutamide, resulting in a significant and clinically relevant reduction of cabazitaxel plasma concentrations. The investigators have previously reported preclinical data showing that addition of an androgen receptor signaling inhibitor (ARSi) improves cabazitaxel efficacy, even in metastatic castration-resistant prostate cancer (mCRPC). As treatment options for mCRPC) patients are scarce and patients often develop drug resistance relatively early, a new treatment regimen for this population to delay drug resistance is highly desired. The investigators propose a randomized phase II trial to investigate the efficacy of docetaxel or cabazitaxel plus darolutamide compared to docetaxel or cabazitaxel monotherapy in men with metastatic CRPC, who have progressed on an ARSI.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

245

Conditions

Metastatic Castration-resistant Prostate Cancer

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 18 years; 2. A confirmed diagnosis of progressive mCRPC (progression according to Prostate cancer Working Group (PCWG) 3 criteria, castration defined as castrate levels of testosterone of \<0.5 ng/mL) with an indication for docetaxel or cabazitaxel. 3. Patients should have had disease progression previously on at least one ARSi (abiraterone, apalutamide, darolutamide or enzalutamide). ARSi administration is allowed both in the mCNPC and in the mCRPC setting. Previous co-administration of docetaxel in mCNPC (triplet-therapy) is allowed, if patients will receive cabazitaxel in this study. 4. WHO performance ≤ 2 5. Able and willing to sign the Informed Consent Form prior to screening evaluations 6. Adequate haematological, renal and liver function and chemistry. Exclusion Criteria: 1. Impossibility or unwillingness to take oral drugs 2. Hypersensitivity to taxanes 3. Known serious illness or medical unstable conditions that could interfere with this study requiring treatment (e.g. HIV, hepatitis, Varicella zoster or herpes zoster, organ transplants, kidney failure, serious liver disease (e.g. severe cirrhosis), cardiac and respiratory diseases) 4. Symptomatic peripheral neuropathy CTCAE grade ≥2 5. Docetaxel-rechallenge.

Outcomes

Primary Outcomes

Progression free survival

progression free survival, which is defined as time from randomization to radiologic, biochemical or pain progression or death from any cause, whichever occurs first, according to PCWG3

Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first

Secondary Outcomes

Overall survival

Overall survival, defined as time from randomization to death from any cause.

Time frame: From date of randomization until the date of death from any cause

Time to progression

Time to progression, defined as time from randomization to radiologic, biochemical or pain progression, whichever occurs first.

Time frame: From date of randomization until the date of first documented progression

Time to PSA progression

Time to PSA progression, defined as time from randomization to biochemical progression.

Time frame: From date of randomization until the date of first documented PSA progression