Dasatinib Combination Fails to Improve Outcomes in mCRPC

Author(s):

The addition of dasatinib to standard therapy with docetaxel failed to improve survival and most other clinical endpoints in men with metastatic castration-resistant prostate cancer in the phase III READY trial.

John C. Araujo, MD, PhD

Although preliminary studies provided a rationale for use of dasatinib in mCRPC and early clinical trials suggested that the combination of dasatinib plus docetaxel had acceptable safety and activity, the phase III results suggest that this combination will not be pursued further. READY is one of a string of trials that fail to show an advantage for the addition of newer agents to docetaxel.

“The disappointing part of this trial is that dasatinib did not improve median overall survival versus docetaxel alone,” stated lead author John C. Araujo, MD, PhD, an assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “The survival curves for both arms were virtually identical.”

Dasatinib inhibits multiple tyrosine kinases including SRC kinases, which are believed to promote androgen independence in mCRPC that makes malignant cells unresponsive to therapies.

The multinational, double-blinded, placebo-controlled READY trial randomized 1522 patients with mCRPC 1:1 to receive either docetaxel 75 mg/m²every three weeks plus prednisone with dasatinib 100 mg every day (n = 762) or docetaxel plus placebo (n = 760). The primary endpoint was overall survival (OS).

No survival benefit was observed for the addition of dasatinib to docetaxel versus docetaxel/placebo: median OS was 21.5 months versus 21.2 months, respectively, (hazard ratio [HR] = 0.99; log-rank P = 0.90). Dasatinib did not improve survival in any of the subgroups analyzed.

Further, no meaningful changes were seen between the two arms for secondary endpoints, including objective response rate, reduction in urinary N-telopeptide (a marker of bone turnover), progression-free survival, or pain reduction.

The only positive finding for dasatinib was an increase in median time to first skeletal-related event; it was not yet reached in the dasatinib arm versus 31.1 months in the placebo arm (HR = 0.81; 95% confidence interval [CI], 0.64-1.02].

“Dasatinib targets bone. The modest decrease in time to first skeletal related event will be analyzed further,” Araujo said.

Patients came off the trial for similar reasons in both arms, Araujo commented. However, treatment-related adverse events were more frequent in the dasatinib arm: 18% versus 9% for placebo. Serious adverse events were reported in 30% of patients in both arms of the study. The rate of death occurring within 30 days of the last study drug was 10% in the dasatinib arm versus 6% in the placebo arm.

Exposure to treatment and use of salvage therapy with abiraterone acetate or cabazitaxel were also similar in both arms.

“Dasatinib has a well-known safety profile. We looked at adverse event of interest and found no new safety signals No new safety signals were found when we looked at serious adverse events occurring in more than 20% of patients,” Araujo said.

Araujo concluded that excess toxicity, docetaxel dose intensity, baseline factors, and differences in salvage therapy do not account for the lack of benefit of dasatinib on most of the endpoints in the study. Studies are ongoing to determine whether persistent androgen receptor signaling accounts for the poor performance of dasatinib and other targeted therapies in CRPC.

The GU symposium is co-sponsored by ASCO, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Araujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. J Clin Oncol. 2013;31(suppl 6): abstr LBA8.

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