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.

Abstract

LBA8 Background: SRC kinases may contribute to androgen independence of mCRPC.Dasatinib (DAS) inhibits tyrosine kinases including SRC kinases with preclinical evidence for antimetastatic activity, inhibition of osteoclast function in tumor microenvironment, and synergistic activity with docetaxel (D). In phase I/II trials of mCRPC patients (pts), DAS in combination with D had an acceptable safety profile with objective response rates (ORR) improved over historical data and decreased levels of bone turnover markers. Methods: READY was a multinational, randomized, double-blinded, placebo-controlled, phase III study. Pts with mCRPC (n = 1,522) were randomized (1:1) to receive either D 75 mg/m2q3wk + prednisone with double-blinded DAS 100 mg qd (DAS/D, n = 762) or placebo (PBO/D, n = 760). Primary endpoint was overall survival (OS). Secondary endpoints were ORR, time to first skeletal-related event (TFSRE), time to prostate-specific antigen progression (TPSAP), urinary N-telopeptide (uNTX) reduction, pain reduction, progression-free survival (PFS), and safety. Results: No OS difference between DAS/D and PBO/D (median, 21.5 vs. 21.2 mos; hazard ratio [HR], 0.99; log-rank P = 0.90) was observed. Results of secondary endpoints for DAS/D vs. PBO/D were: ORR (30.5 vs. 31.9%); TFSRE (median, not reached vs. 31.1 mos; HR, 0.81 [95% CI, 0.64-1.02]); uNTX reduction (66.0 vs. 60.6%); PFS (median, 11.8 vs. 11.1 mos; HR, 0.92); TPSAP (median, 8.0 vs. 7.6 mos; HR, 0.91), and pain reduction (66.6 vs. 71.5%). Twenty-three percent of DAS/D and 14% of PBO/D pts received therapy for <3 mos. Most common AEs in DAS/D arm included diarrhea, fatigue, alopecia, and nausea. Grade 3-4 AEs of interest for DAS/D vs. PBO/D included anemia (8.0 vs.5.9%), neutropenia (6.2 vs. 5.5%), hypocalcemia (3.5 vs.3.1%), GI bleeding (2.6 vs.1.3%), and pleural effusion (1.3 vs. 0.4%). Conclusions: The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS. There was a modest reduction in the risk of TFSRE with DAS/D vs. PBO/D. With a median follow-up of 19 mos of 761 DAS/D-treated pts, no unexpected toxicities for DAS were observed. Clinical trial information: NCT00744497.