Dasatinib Plus Docetaxel Does Not Improve Overall Survival in Men With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer
Data suggest that Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis and that the Src kinase inhibitor dasatinib (Sprycel) might exhibit synergy with docetaxel in prostate cancer. In a phase III trial (READY) reported in The Lancet Oncology, John. C. Araujo, MD, of The University of Texas MD Anderson Cancer Center, and colleagues investigated the effects of adding dasatinib to docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer. No improvement in overall survival was observed with the combination.
Study Details
In this double-blind trial, 1,522 chemotherapy-naive patients from 186 centers in 25 countries were randomly assigned to receive intravenous docetaxel at 75 mg/m2 every 3 weeks and oral prednisone at 5 mg twice daily plus either dasatinib at 100 mg orally once daily (n = 762) or placebo (n = 760) until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0–1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide value (< vs ≥ 60 μmol/mol creatinine).
Patients in the dasatinib and placebo groups were well balanced for age (median, 69 and 68 years, 67% and 65% ≥ 65 years), ethnicity (86% and 85% white), ECOG performance status (0 in 48% and 49%, 1 in 46% in both), urinary N-telopeptide level (≥ 60 µmol/mol creatinine in 55% and 53%), previous or current bisphosphonate use (37% and 35%), median prostate-specific antigen (PSA) level (77.0 and 87.0 ng/mL), abnormal lactate dehydrogenase level (39% and 41%), time from diagnosis of metastatic disease (median, 13.1 and 12.1 months), evidence of disease progression (nodal/visceral progression in 37% and 35%, bone scan/image in 62% and 63%), type of metastatic disease (bone only in 40% and 38%, bone and visceral/nodal in 49% and 53%), number of disease sites (1 in 37% and 39%), previous treatment (surgery in 61% and 60%, radiotherapy in 51% and 49%, two or more systemic therapies in metastatic setting in 33% and 34%, two or more systemic therapies in nonmetastatic setting in 20% and 21%), and region (North America for 26% and 25%, Europe for 42% and 41%).
No Overall Survival Benefit
After a median follow-up of 19.0 months, median overall survival was 21.5 months in the dasatinib group and 21.2 months in the placebo group (stratified hazard ratio [HR] = 0.99, P = .90). Subgroup analysis showed no marked differences between the dasatinib and placebo groups apart from a borderline advantage of dasatinib in patients aged < 65 years (HR = 0.79, 95% confidence interval [CI] = 0.62–1.00) and an advantage of placebo in patients with ECOG performance status of 2 (HR = 1.78, 95% CI = 1.09–2.91).
Poststudy treatment was received by 43% of patients in the dasatinib group and 45% of patients in the placebo group, including radiotherapy (24% vs 26%) and systemic therapies (40% vs 43%), with systemic therapy including abiraterone (Zytiga; 16% vs 17%), docetaxel (12% vs 12%), and cabazitaxel (Jevtana; 7% vs 9%).
Secondary Outcomes
For the dasatinib vs placebo groups, median time to first skeletal-related event was not reached vs 31.1 months (P = .08), and median progression-free survival was 11.8 vs 11.1 months (P = .22). Reduction in urinary N-telopeptide occurred in 66.0% vs 60.6% (P = .13) in dasatanib and placebo groups, respectively, median time to PSA progression was 7.2 vs 6.9 months (P = .08), reduction in pain intensity occurred in 66.6% vs 71.5% (P = .11), and objective response rate was 30.5% vs 31.9% (P = .67).
A post hoc analysis to evaluate whether bisphosphonate use and urinary N-telopeptide levels at baseline could predict outcome showed hazard ratios for time to first skeletal-related event of 0.69 (95% CI = 0.46–1.05) in patients with bisphosphonate use and normal N-telopeptide levels, 0.59 (95% CI = 0.24–1.44) in those with bisphosphonate use and abnormal levels, and 0.80 (95% CI = 0.44–1.45) in those with no bisphosphonate use and abnormal levels. The respective hazard ratios for overall survival were 0.91 (95% CI = 0.70–1.18), 1.56 (95% CI = 1.04–2.35), and 1.19 (95% CI = 0.90–1.58). The investigators noted that these findings suggest a potential interaction between bone and bisphosphonate use and Src kinases.
Toxicity
Grade 3 or 4 adverse events occurred in 60% of the dasatinib group and 55% of the placebo group, including diarrhea in 8% vs 4%, fatigue in 8% vs 6%, and asthenia in 5% vs 3%. Grade 3 or 4 peripheral neuropathy occurred in 1% vs 2%. Gastrointestinal bleeding was more common with dasatinib (all grades, 9% vs 5%; grade 3 or 4, 3% vs 1%). Fluid retention occurred in 39% of each group, including any-grade pleural effusion in 16% vs 4% and grade 3 or 4 pleural effusion in 1% vs < 1%. Grade 3 or 4 laboratory abnormalities including neutropenia (7% vs 6%) were similar in the two groups, except for hypophosphatemia (13% vs 6%).
Grade 5 adverse events occurred in 7% vs 5% of patents. Adverse events led to treatment discontinuation in 38% of dasatinib patients and 25% of placebo patients, most frequently due to fatigue (4% vs 3%), diarrhea (3% vs 1%), and pleural effusion (3% vs < 1%).
The investigators concluded, “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.”
The investigators noted that serial serum and plasma samples obtained from a subgroup of patients during the study are currently being analyzed for cytokines and other markers believed to play important roles in the prostate cancer bone microenvironment.
The study was funded by Bristol-Myers Squibb.
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