A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)

Abstract

5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (< 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC. [Table: see text]