Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial

Abstract

Background: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.

Methods: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497.

Findings: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]).

Interpretation: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients.

Funding: Bristol-Myers Squibb.

Figure 1. Trial profile

Immediately after the completion of the primary analysis, patients in the placebo group still on treatment (n=43) at the database lock were taken off the placebo medication. Patients still on treatment (n=39) in the dasatinib group were allowed to remain on dasatinib therapy, provided they signed an updated informed consent form with the knowledge that no survival benefit for docetaxel plus dasatinib had been observed in the trial. uNTx=urinary N-telopeptide. *Two patients declined to participate and one patient no longer met inclusion criteria. †No longer met inclusion criteria.

Figure 2. Kaplan-Meier estimate of overall survival in the intention-to-treat population

Patients who had not died or who were lost to follow-up were censored on the last date on which they were known to have been alive. The circles and triangles along each curve represent censored patients. HR=hazard ratio.

Figure 3. Overall survival in selected subgroups

ECOGPS=Eastern Cooperative Oncology Group performance status. HR=hazard ratio. ITT=intention-to-treat. PSA=prostate-specific antigen. uNTx=urinary N-telopeptide. *Ratio of dasatinib to placebo.

Figure 4. Kaplan-Meier estimate of TFSRE in the intention-to-treat population

Patients who died without a skeletal-related event (SRE) or who had a first SRE while on subsequent cancer therapy were censored on the date of last SRE assessment before the start date of subsequent therapy. Patients who had no SRE assessment were censored on the date of randomisation. The circles and triangles along each curve represent censored patients. SREs consisted of: pathological bone fracture (vertebral or non-vertebral) in the region of cancer involvement that occurred spontaneously or as a result of trivial trauma; radiation therapy to bone, including administration of a radioisotope such as strontium 89; cancer-related surgery to bone; and spinal cord or nerve root compression confirmed by MRI or CT (if MRI was not available). HR=hazard ratio. TFSRE=time to first skeletal-related event.