ORLANDO, FL, USA (UroToday.com) - Metastasis to bone dominates the clinical phenotype of patients with metastatic castration-resistant prostate cancer (mCRPC), and bone is a common site of treatment-refractory progression.
Current treatment options are palliative and provide only incremental survival improvement. Dasatinib (DAS) inhibits tyrosine kinases, including SFKs. The SRC-family kinases (SFKs) mediate signaling pathways involved in tumor growth and osteoclast function. Preclinically, dasatinib has shown antitumor activity in prostate cancer, inhibition of osteoclast function in bone microenvironment, and synergistic activity with docetaxel (D). Therefore, dasatinib/docetaxel (DAS/D) combination may prove beneficial in mCRPC by targeting both prostate cancer cells and osteoclasts in bone microenvironment. The DAS/D combination was well tolerated in a phase I study in 46 patients, and anti-tumor activity was demonstrated by a 57% reduction in PSA.
The Randomized Trial Evaluating the Addition of Dasatinib to Docetaxel Therapy (READY) was a multi-national, randomized, double-blinded, placebo-controlled, phase III study in 1 522 patients with progressive mCRPC. Patients were randomized to receive either D (75 mg/m2 q3wk) plus prednisone (5 mg bid) with DAS (100 mg daily) or D (75 mg/m2 q3wk) plus prednisone (5 mg bid) with placebo (P). Primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), time to first skeletal-related event (TFSRE), time to PSA progression (TPSAP), urinary N-telopeptide (uNTX) reduction, pain reduction, progression-free survival (PFS), and safety.
Baseline data was well balanced between the groups. The DAS/D group did not show any improvement in OS compared to the P/D group (21.2 months vs. 21.5 months). TFSRE was slightly increased for the DAS/D group but no differences were observed between the groups in other secondary endpoints. Median treatment time was 8.1 months in DAS/D group and 8.4 months in P/D group, while 23% of DAS/D vs. 14% of P/D received treatment ≤3 months. Salvage treatment during 3 years in the study was very similar between the two groups, with any cancer therapy used, by 43% in DAS/D vs. 45% in P/D, and abiraterone acetate was used by 16% in DAS/D vs. 17% in P/D.
As far as safety, 60% in DAS/D vs. 55% in P/D experienced any AE (grade 3-4) during the study, 36% in DAS/D vs. 29% in P/D experienced a serious AE, and 22% in DAS/D vs. 14% in P/D discontinued the study due to an AE. Most common AEs of any grade were diarrhea (56% vs. 41%), fatigue (44% for both groups), alopecia (41% vs. 43%), and nausea (38% vs. 30%).
In conclusion, this study did not demonstrate any improvement in OS with the addition of dasatinib to standard chemotherapy in men with mCRPC. There was a modest delay in TFSRE, while the remaining secondary endpoints did not show any differences between the groups. No unexpected safety-related findings were observed for dasatinib. Investigation of the role of persistent androgen receptor signaling is underway as a resistance mechanism that may explain the poor performance of targeted therapies in mCRPC.
Presented by John Araujo,1 Géralyn C. Trudel,2 Fred Saad,3 Andrew Armstrong,4 Evan Y. Yu,5 Joaquim Bellmunt,6 George Wilding,7 John McCaffrey,8 Sergio V. Serrano,9 Vsevolod Matveev,10 Eleni Efstathiou,11 Stephane Oudard,12 Michael J. Morris,13Bruce Sizer,14 Peter J. Goebell,15 Johann S. de Bono,16 Prashni Paliwa,17 Susan Durham,17 Shinta Cheng,18 and Christopher Logothetis1 at the 2013 Genitourinary Cancers Symposium - February 14 - 16, 2013 - Rosen Shingle Creek - Orlando, Florida USA
1MD Anderson Cancer Center, Houston, Texas, USA; 2Bristol-Myers Squibb, Montréal, Quebéc, Canada; 3Centre Hospitalier de l'Universite de Montreal, Montréal, Quebéc, Canada; 4Duke University, Durham, NC, USA; 5University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA; 6University Hospital del Mar-IMIM, Barcelona, Spain; 7University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 8Irish Clinical Oncology Research Group (ICORG), Dublin, Ireland; 9Hospital Do Cancer de Barretos, Sao Paulo, Brazil; 10Russian Cancer Center, N.A. Blokhin, Moscow, Russian Federation; 11University of Athens, Athens, Greece; 12Hospital European Georges Pompidou, Paris, France; 13Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 14Essex County Hospital, Essex, UK; 15Friedrich-Alexander University, AURONTE, Erlangen, Germany; 16Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK; 17Bristol-Myers Squibb, Wallingford, CT, USA; 18Bristol-Myers Squibb, Lawrenceville, NJ, USA
Written by Anna Forsberg, medical reporter for UroToday.com
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